Humanized affinity matured antibodies against FcRH5 and methods of use

Abstract

To provide anti-FcRH5 antibodies (e.g. bispecific antibodies, e.g. FcRH5 T cell-dependent bispecific antibodies) for the treatment of cell proliferative disorders (e.g. cancers, e.g. FcRH5-positive cancers, e.g., multiple myeloma), compositions, and methods of using them.SOLUTION: The present invention relates to anti-FcRH5 antibodies, including anti-FcRH5 antibodies (e.g. FcRH5 T cell-dependent bispecific (TDB) antibodies) that comprise an FcRH5 binding domain including a specific amino acid sequence, and a CD3 binding domain including another specific amino acid sequence, and methods of using the same.SELECTED DRAWING: None

Description

[Technical Field]

[0001] Sequence Listing This application contains a Sequence Listing that has been submitted electronically in ASCII format and is incorporated herein by reference in its entirety. The ASCII copy, created on June 14, 2016, is named 50474-134WO2_Sequence_Listing_6_14_16_ST25 and is 133,004 bytes in size.

[0002] The present invention relates to anti-FcRH5 antibodies and methods of using the same. [Background technology]

[0003] Cell proliferative disorders, such as cancer, are characterized by the uncontrolled growth of cell subpopulations. They are the leading cause of death in the developed world and the second leading cause of death in developing countries, with over 14 million new cancer cases diagnosed and over 8 million cancer deaths occurring each year. The National Cancer Institute estimates that over 500,000 Americans will die from cancer in 2016, accounting for nearly one in four deaths in the United States. The growing elderly population is accompanied by a concomitant rise in cancer incidence, as the likelihood of developing cancer more than doubles after age 70. Therefore, cancer care represents a significant and growing societal burden.

[0004] The Fc receptor-like 5 (FcRH5, FcRL5, or IRTA2) gene belongs to a recently identified family of six genes in the immunoglobulin superfamily (IgSF). This gene family is closely related to Fc receptors, sharing conserved genomic structure, extracellular Ig domain composition, and signaling motifs such as immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and immunoreceptor tyrosine-based activation motifs (ITAMs) (Davis et al. Eur. J. Immunol. 35:674-80, 2005). Six members of the FcRH / IRTA receptor family have been described: FcRH1 / IRTA5, FcRH2 / IRTA4, FcRH3 / IRTA3, FcRH4 / IRTA1, FcRH5 / IRTA2, and FcRH6 (Polson et al. Int. Immunol. 18(9):1363-1373, 2006). The FcRH cDNA encodes a type I transmembrane glycoprotein with multiple Ig-like extracellular domains and a cytoplasmic domain containing consensus immunoreceptor tyrosine-based activating and / or inhibitory signaling motifs. FcRH genes are structurally related, and their protein products share 28-60% extracellular identity with each other. They also share 15-31% identity with their closest FcR relatives. A high degree of homology exists between different FcRHs.

[0005] Although the ligand(s) for FcRH5 are unknown, FcRH5 has been linked to enhanced proliferation and downstream isotype expression during antigen-stimulated B cell development (Dement-Brown et al. J. Leukoc. Biol. 91:59-67, 2012). The FcRH5 locus has three major mRNA isoforms (FcRH5a, FcRH5b, and FcRH5c). The major FcRH5 protein isoforms encoded by these transcripts share a common amino acid sequence through residue 560 and feature a common signal peptide and six extracellular Ig-like domains. FcRH5a is a 759-amino acid secreted glycoprotein with eight Ig-like domains followed by 13 unique, primarily polar, amino acids at its C-terminus. FcRH5b diverges from FcRH5a at amino acid residue 560 and extends over a short stretch of 32 additional residues, the hydrophobic nature of which is compatible with docking it to the plasma membrane via a GPI anchor. FcRH5c is the longest isoform, whose sequence diverges from FcRH5a at amino acid 746. FcRH5c encodes a 977-amino acid type I transmembrane glycoprotein with nine extracellular Ig-type domains harboring eight potential N-linked glycosylation sites, a 23-amino acid transmembrane domain, and a 104-amino acid cytoplasmic domain containing three consensus SH2-binding motifs with ITIM consensus.

[0006] The FcRH5 gene is clustered immediately adjacent to the classical FcR genes (FcγRI, FcγRII, FcγRIII, and FcεRI) within the 1q21-23 region of chromosome 1. This region contains one of the most frequent secondary chromosomal abnormalities associated with malignant phenotypes in hematopoietic malignancies, particularly multiple myeloma (Hatzivassiliou et al. Immunity. 14:277-89, 2001). FcRH5 is expressed exclusively in the B cell lineage, beginning as early as pre-B cells but not fully expressed until the mature B cell stage. Unlike most other known B cell-specific surface proteins (e.g., CD20, CD19, and CD22), FcRH5 continues to be expressed on plasma cells, while other B cell-specific markers are downregulated (Polson et al. Int. Immunol. 18:1363-73, 2006). Additionally, FcRH5 mRNA is overexpressed in multiple myeloma cell lines with 1q21 abnormalities as detected by oligonucleotide array (Inoue Am. J. Pathol. 165:71-81, 2004). This expression pattern suggests that FcRH5 may be a target for antibody-based therapy for the treatment of multiple myeloma. Multiple myeloma is a malignant tumor of plasma cells characterized by skeletal lesions, renal failure, anemia, and hypercalcemia, and is essentially incurable with current therapies. Current drug treatments for multiple myeloma include a combination of the proteosome inhibitor bortezomib (VELCADE®), the immunomodulatory agent lenalidomide (REVLIMID®), and the steroid dexamethasone.

[0007] Monoclonal antibody (mAb)-based therapy has become an important treatment modality for cancer. FcRH5c-specific antibody-based therapy and detection methods can be particularly effective because they specifically recognize membrane-associated FcRH5 on target cells, compared to antibodies that recognize both soluble and membrane isoforms of FcRH5. However, only the final Ig-like domain of FcRH5 (Ig-like domain 9) is a unique extracellular region that differs among the three major isoforms of FcRH5 (e.g., FcRH5a, FcRH5b, and FcRH5c), and significant homology exists among the Ig-like domains within FcRH5. Furthermore, the final Ig-like domain is highly conserved among FcRH1, FcRH2, FcRH3, and FcRH5. Any antibody-based therapy specifically targeting FcRH5 should have minimal cross-reactivity with other FcRHs (e.g., FcRH3 is expressed on normal NK cells) to avoid adverse off-target effects.

[0008] In view of the above, there is an unmet need in the art for safe and effective agents for use in treating cell proliferative disorders (eg, cancer, eg, FcRH5-positive cancers, eg, multiple myeloma). Summary of the Invention

[0009] The present invention provides anti-FcRH5 antibodies (e.g., bispecific antibodies, e.g., FcRH5 T-cell-dependent bispecific (TDB) antibodies), compositions, and methods of use thereof for the treatment of cell proliferative disorders (e.g., cancer, e.g., FcRH5-positive cancer, e.g., multiple myeloma).

[0010] In a first aspect, the invention features an anti-Fc receptor-like 5 (FcRH5) antibody comprising a binding domain that includes the following six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0011] In some embodiments, an anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23. In some embodiments, the binding domain comprises (a) a heavy chain variable (VH) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 104, (b) a light chain variable (VL) domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 105, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following heavy chain variable region framework regions (FR): (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 52, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 54, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 46, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 104. In some embodiments, the antibody further comprises the following light chain variable region FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 48, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 57, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 50, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 105. In some embodiments, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 104, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 105.

[0012] In other embodiments, the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 10, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 106, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 107, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 53, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 54, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 46, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 106. In some embodiments, the antibody further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 48, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 57, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 50, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 107. In some embodiments, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 106, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 107.

[0013] In other embodiments, the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 82, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 83, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 52, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 54, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 46, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 82. In some embodiments, the antibody further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 48, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 56, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 50, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 83. In some embodiments, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 82, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 83.

[0014] In other embodiments, the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 84, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 85, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 52, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 54, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 46, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 84. In some embodiments, the antibody further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 48, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 57, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 50, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 85. In some embodiments, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 84, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 85.

[0015] In other embodiments, the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 17, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 86, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 87, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 52, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 54, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 46, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 86. In some embodiments, the antibody further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 48, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 57, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 50, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 87. In some embodiments, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 86, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 87.

[0016] In other embodiments, the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 88, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 89, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 52, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 54, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 46, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 88. In some embodiments, the antibody further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 48, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 57, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 50, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 89. In some embodiments, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 88, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 89.

[0017] In other embodiments, the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 90, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 91, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 52, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 54, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 46, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 90. In some embodiments, the antibody further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 48, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 57, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 50, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 91. In some embodiments, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 90, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 91.

[0018] In other embodiments, the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 18, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 92, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 93, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 52, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 54, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 46, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 92. In some embodiments, the antibody further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 48, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 56, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 50, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 93. In some embodiments, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 92, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 93.

[0019] In other embodiments, the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 19, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 24. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 94, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 95, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 52, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 54, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 46, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 94. In some embodiments, the antibody further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 48, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 57, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 50, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 95. In some embodiments, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 94, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 95.

[0020] In other embodiments, the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 18, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 25. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 96, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 97, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 53, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 54, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 46, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 96. In some embodiments, the antibody further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 48, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 57, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 50, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 97. In some embodiments, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 96, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 97.

[0021] In other embodiments, the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 18, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 25. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 98, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 99, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 52, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 55, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 46, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 98. In some embodiments, the antibody further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 48, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 57, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 50, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 99. In some embodiments, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 98, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 99.

[0022] In other embodiments, the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 18, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 25. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 100, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 101, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 52, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 54, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 46, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 100. In some embodiments, the antibody further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 48, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 57, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 50, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 101. In some embodiments, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 100, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 101.

[0023] In other embodiments, the anti-FcRH5 antibody comprises a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 102, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 103, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 52, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 54, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 46, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 47. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 102. In some embodiments, the antibody further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 48, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 56, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 50, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 51. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 103. In some embodiments, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 102, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 103.

[0024] In another aspect, the invention features an anti-FcRH5 antibody comprising a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 32, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 34, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 35, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 37. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 110, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 111, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 66, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 67, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 68, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 69. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 110. In some embodiments, the antibody further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 70, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 71, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 72, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 73. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 111. In some embodiments, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 110, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 111.

[0025] In another aspect, the invention features an anti-FcRH5 antibody comprising a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 38, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 39, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 40, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 41, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 42, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 43. In other embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 112, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 113, or (c) a VH domain as in (a) and a VL domain as in (b). In another embodiment, the antibody further comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 74, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 75, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 76, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 77. In another embodiment, the VH domain comprises the amino acid sequence of SEQ ID NO: 112. In another embodiment, the antibody further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 78, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 79, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 80, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 81. In another embodiment, the VL domain comprises the amino acid sequence of SEQ ID NO: 113. In another embodiment, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 112, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 113.

[0026] In another aspect, the invention features an anti-FcRH5 antibody comprising a binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 26, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 27, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 28, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 29, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 31. In some embodiments, the binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 108, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 109, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the antibody further comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 58, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 59, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 60, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 61. In some embodiments, the VH domain comprises the amino acid sequence of SEQ ID NO: 108. In some embodiments, the antibody further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 62, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 63, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 64, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 65. In some embodiments, the VL domain comprises the amino acid sequence of SEQ ID NO: 109. In some embodiments, the anti-FcRH5 antibody comprises a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 108, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 109.

[0027] In some embodiments of any one of the foregoing aspects, the anti-FcRH5 antibody binds to an epitope within Ig-like domain 9 of FcRH5. In some embodiments, the epitope comprises a portion of amino acids 743-850 of SEQ ID NO: 114. In some embodiments, the binding domain binds to human FcRH5, cynomolgus monkey (cyno) FcRH5, or both. In some embodiments, the binding domain does not specifically bind to FcRH1, FcRH2, FcRH3, and / or FcRH4. In some embodiments, the anti-FcRH5 antibody has a K D In some embodiments, the anti-FcRH5 antibody binds to human FcRH5 with a K of about 10 pM to about 100 nM. D In some embodiments, the anti-FcRH5 antibody binds to human FcRH5 with a K of about 100 pM to about 100 nM. D In some embodiments, the anti-FcRH5 antibody binds to human FcRH5 with a K of about 1 nM to about 20 nM. D In some embodiments, the anti-FcRH5 antibody binds to human FcRH5 with a K of about 1 nM to about 10 nM. D In some embodiments, the anti-FcRH5 antibody binds to human FcRH5 with a K of about 100 nM or less. D In some embodiments, the anti-FcRH5 antibody binds to cynomolgus monkey FcRH5 with a K of about 10 pM to about 100 nM. D In some embodiments, the anti-FcRH5 antibody binds to cynomolgus monkey FcRH5 with a K of about 100 pM to about 100 nM. D In some embodiments, the anti-FcRH5 antibody binds to cynomolgus monkey FcRH5 with a K of about 1 nM to about 50 nM. D binds to cynomolgus monkey FcRH5.

[0028] In other embodiments, the anti-FcRH5 antibody comprises a non-glycosylation site mutation. In some embodiments, the non-glycosylation site mutation is a substitution mutation. In some embodiments, the non-glycosylation site mutation reduces the effector function of the anti-FcRH5 antibody. In some embodiments, the substitution mutation is at amino acid residues N297, L234, L235, D265, and / or P329 (EU numbering). In some embodiments, the substitution mutation is selected from the group consisting of N297G, N297A, L234A, L235A, D265A, and P329G. In some embodiments, the substitution mutation is an N297G mutation.

[0029] In other embodiments, the anti-FcRH5 antibody is an IgG antibody.

[0030] In some embodiments, the anti-FcRH5 antibody is an antibody fragment that binds to FcRH5. In some embodiments, the antibody fragment is selected from the group consisting of bis-Fab, Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments. In some embodiments, the antibody fragment is a bis-Fab fragment.

[0031] In other embodiments, the anti-FcRH5 antibody is a full-length antibody.

[0032] In some embodiments, the anti-FcRH5 antibody is a monospecific antibody.

[0033] In some embodiments, the anti-FcRH5 antibody is a multispecific antibody. In some embodiments, the multispecific antibody is a bispecific antibody. In some embodiments, the bispecific antibody comprises a second binding domain that binds to cluster of differentiation 3 (CD3). In some embodiments, the second binding domain binds to an epitope of CD3 that includes amino acid residue Glu6 of CD3. In some embodiments, the epitope further comprises one or more additional amino acid residues selected from the group consisting of Gln1, Asp2, and Met7 of CD3. In some embodiments, the epitope includes amino acid residues Gln1, Asp2, and Glu6 of CD3. In some embodiments, the epitope includes amino acid residues Gln1, Asp2, Glu6, and Met7 of CD3. In some embodiments, the epitope does not include amino acid residue Glu5 of CD3. In some embodiments, the epitope does not include amino acid residues Gly3 and Glu5 of CD3. In some embodiments, the epitope consists of amino acid residues Gln1, Asp2, Glu6, and Met7 of CD3. In some embodiments, the second binding domain is capable of binding to a human CD3 polypeptide or a cynomolgus monkey CD3 polypeptide. In some embodiments, the human CD3 polypeptide or the cynomolgus monkey CD3 polypeptide is a human CD3ε polypeptide or a cynomolgus monkey CD3ε polypeptide, respectively. In some embodiments, the human CD3 polypeptide or the cynomolgus monkey CD3 polypeptide is a human CD3γ polypeptide or a cynomolgus monkey CD3γ polypeptide, respectively. In some embodiments, the second binding domain has a K D In some embodiments, the second binding domain binds to a human CD3ε polypeptide with a K of about 10 pM to about 100 nM. D In some embodiments, the second binding domain binds to a human CD3ε polypeptide with a K of about 100 pM to about 50 nM. D In some embodiments, the second binding domain binds to a human CD3ε polypeptide with a K of about 1 nM to about 10 nM. DIt binds to human CD3ε polypeptide at

[0034] In some embodiments, the second binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120. In some embodiments, the second binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 123. In some embodiments, the second binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 133, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 134, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the second binding domain comprises the following heavy chain variable regions FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 125, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 126, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 127, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 128. In some embodiments, the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 133. In some embodiments, the second binding domain further comprises the following light chain variable regions FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 129, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 130, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 131, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 132. In some embodiments, the second binding domain comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 134.In some embodiments, the second binding domain comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 133, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 134.

[0035] In other embodiments, the second binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 124. In some embodiments, the second binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 137, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 138, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the second binding domain comprises the following heavy chain variable region FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 125, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 126, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 127, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 128. In some embodiments, the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 137. In some embodiments, the second binding domain further comprises the following light chain variable region FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 129, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 130, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 131, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 132. In some embodiments, the second binding domain comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 138. In some embodiments, the second binding domain comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 137, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 138.

[0036] In other embodiments, the second binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144. In some embodiments, the second binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 153, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 154, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the second binding domain comprises the following heavy chain variable region FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 145, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 146, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 147, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 148. In some embodiments, the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 153. In some embodiments, the second binding domain further comprises the following light chain variable region FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 149, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 150, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 151, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 152. In some embodiments, the second binding domain comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 154. In some embodiments, the second binding domain comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 153, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 154.

[0037] In other embodiments, the second binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 155, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 156, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 157, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 158, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 159, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 160.

[0038] In some embodiments, the second binding domain comprises the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 155, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 162, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 157, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 158, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 159, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 160. In some embodiments, the second binding domain comprises (a) a VH domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 172, (b) a VL domain comprising an amino acid sequence having at least 95% sequence identity to the amino acid sequence of SEQ ID NO: 173, or (c) a VH domain as in (a) and a VL domain as in (b). In some embodiments, the second binding domain comprises the following heavy chain variable region FR: (a) FR-H1 comprising the amino acid sequence of SEQ ID NO: 164, (b) FR-H2 comprising the amino acid sequence of SEQ ID NO: 165, (c) FR-H3 comprising the amino acid sequence of SEQ ID NO: 166, and (d) FR-H4 comprising the amino acid sequence of SEQ ID NO: 167. In some embodiments, the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 172. In some embodiments, the second binding domain further comprises the following light chain variable region FR: (a) FR-L1 comprising the amino acid sequence of SEQ ID NO: 168, (b) FR-L2 comprising the amino acid sequence of SEQ ID NO: 169, (c) FR-L3 comprising the amino acid sequence of SEQ ID NO: 170, and (d) FR-L4 comprising the amino acid sequence of SEQ ID NO: 171. In some embodiments, the second binding domain comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 173. In some embodiments, the second binding domain comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 172, and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 173.

[0039] In other embodiments, the binding domain that binds to FcRH5 comprises a VH domain (VH1) comprising a charged region (CR1) and a VL domain (VL1) comprising a charged region (CR2), where CR1 in VH1 forms a charge pair with CR2 in VL1. In some embodiments, CR1 comprises a basic amino acid residue and CR2 comprises an acidic amino acid residue. In some embodiments, CR1 comprises a Q39K substitution mutation (EU numbering). In some embodiments, CR1 comprises a Q39K substitution mutation. In some embodiments, CR2 comprises a Q38E substitution mutation (EU numbering). In some embodiments, CR2 comprises a Q38E substitution mutation. In some embodiments, the second binding domain that binds to CD3 comprises a VH domain (VH2) comprising a charged region (CR3) and a VL domain (VL2) comprising a charged region (CR4), where CR4 in VL2 forms a charge pair with CR3 in VH2. In some embodiments, CR4 comprises a basic amino acid residue, and CR3 comprises an acidic amino acid residue. In some embodiments, CR4 comprises a Q38K substitution mutation (EU numbering). In some embodiments, CR4 consists of a Q38K substitution mutation. In some embodiments, CR3 comprises a Q39E substitution mutation (EU numbering). In some embodiments, CR3 consists of a Q39E substitution mutation. In some embodiments, the VL1 domain is linked to a light chain constant (CL) domain (CL1), and the VH1 domain is linked to a first heavy chain constant (CH1) domain (CH11), where CL1 comprises a charged region (CR5), CH11 comprises a charged region (CR6), and CR5 in CL1 forms a charge pair with CR6 in CH11. In some embodiments, CR5 comprises a basic amino acid residue, and CR6 comprises an acidic residue. In some embodiments, CR5 comprises a V133K substitution mutation (EU numbering). In some embodiments, CR5 consists of a V133K substitution mutation. In some embodiments, CR6 comprises a S183E substitution mutation (EU numbering). In some embodiments, CR6 consists of a S183E substitution mutation.

[0040] In other embodiments, the VL2 domain is linked to a CL domain (CL2), and the VH2 domain is linked to a CH1 domain (CH12), wherein CL2 comprises a charged region (CR7), and CH12 comprises a charged region (CR8), and CR8 in CH12 forms a charge pair with CR7 in CL2. In some embodiments, CR8 comprises a basic amino acid residue and CR7 comprises an acidic amino acid residue. In some embodiments, CR8 comprises a S183K substitution mutation (EU numbering). In some embodiments, CR8 consists of a S183K substitution mutation. In some embodiments, CR7 comprises a V133E substitution mutation (EU numbering). In some embodiments, CR7 consists of a V133E substitution mutation.

[0041] In other embodiments, the VL2 domain is linked to a CL domain (CL2), and the VH2 domain is linked to a CH1 domain (CH12), wherein (a) CL2 comprises one or more mutations at amino acid residues F116, L135, S174, S176, and / or T178 (EU numbering), and (b) CH12 comprises one or more mutations at amino acid residues A141, F170, S181, S183, and / or V185 (EU numbering). In some embodiments, CL2 comprises one or more of the following substitution mutations: F116A, L135V, S174A, S176F, and / or T178V. In some embodiments, CL2 comprises the following substitution mutations: F116A, L135V, S174A, S176F, and T178V. In some embodiments, CH12 comprises one or more of the following substitution mutations: A141I, F170S, S181M, S183A, and / or V185A. In some embodiments, CH12 comprises the following substitution mutations: A141I, F170S, S181M, S183A, and V185A.

[0042] In other embodiments, the binding domain that binds to FcRH5 comprises a VH domain (VH1) comprising a charged region (CR1) and a VL domain (VL1) comprising a charged region (CR2), where CR2 in VL1 forms a charge pair with CR1 in VH1. In some embodiments, CR2 comprises a basic amino acid residue and CR1 comprises an acidic amino acid residue. In some embodiments, CR2 comprises a Q38K substitution mutation (EU numbering). In some embodiments, CR2 consists of a Q38K substitution mutation. In some embodiments, CR1 comprises a Q39E substitution mutation (EU numbering). In some embodiments, CR1 consists of a Q39E substitution mutation. In some embodiments, the second binding domain that binds to CD3 comprises a VH domain (VH2) comprising a charged region (CR3) and a VL domain (VL2) comprising a charged region (CR4), where CR3 in VH2 forms a charge pair with CR4 in VL2. In some embodiments, CR3 comprises a basic amino acid residue, and CR4 comprises an acidic amino acid residue. In some embodiments, CR3 comprises a Q39K substitution mutation (EU numbering). In some embodiments, CR3 consists of a Q39K substitution mutation. In some embodiments, CR4 comprises a Q38E substitution mutation (EU numbering). In some embodiments, CR4 consists of a Q38E substitution mutation. In some embodiments, the VL1 domain is linked to a light chain constant (CL) domain (CL1), and the VH1 domain is linked to a first heavy chain constant (CH1) domain (CH11), where CL1 comprises a charged region (CR5), CH11 comprises a charged region (CR6), and CR6 in CH11 forms a charge pair with CR5 in CL1. In some embodiments, CR6 comprises a basic amino acid residue, and CR5 comprises an acidic amino acid residue. In some embodiments, CR6 comprises a S183K substitution mutation (EU numbering). In some embodiments, CR6 consists of a S183K substitution mutation. In some embodiments, CR5 comprises a V133E substitution mutation (EU numbering). In some embodiments, CR5 consists of a V133E substitution mutation.

[0043] In other embodiments, the VL2 domain is linked to a CL domain (CL2), and the VH2 domain is linked to a CH1 domain (CH12), wherein CL2 comprises a charged region (CR7), and CH12 comprises a charged region (CR8), and CR7 in CL2 forms a charge pair with CR8 in CH12. In some embodiments, CR7 comprises a basic amino acid residue and CR8 comprises an acidic residue. In some embodiments, CR7 comprises a V133K substitution mutation (EU numbering). In some embodiments, CR7 consists of a V133K substitution mutation. In some embodiments, CR8 comprises a S183E substitution mutation (EU numbering). In some embodiments, CR8 consists of a S183E substitution mutation.

[0044] In other embodiments, the VL2 domain is linked to a CL domain (CL2), and the VH2 domain is linked to a CH1 domain (CH12), wherein (a) CL2 comprises one or more mutations at amino acid residues F116, L135, S174, S176, and / or T178 (EU numbering), and (b) CH12 comprises one or more mutations at amino acid residues A141, F170, S181, S183, and / or V185 (EU numbering). In some embodiments, CL2 comprises one or more of the following substitution mutations: F116A, L135V, S174A, S176F, and / or T178V. In some embodiments, CL2 comprises the following substitution mutations: F116A, L135V, S174A, S176F, and T178V. In some embodiments, CH12 comprises one or more of the following substitution mutations: A141I, F170S, S181M, S183A, and / or V185A. In some embodiments, CH12 comprises the following substitution mutations: A141I, F170S, S181M, S183A, and V185A. In some embodiments, the anti-FcRH5 antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH2 domain (CH21), a first CH3 domain (CH31), a second CH2 domain (CH22), and a second CH3 domain (CH32). In some embodiments, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some embodiments, CH31 and CH32 each comprise a protuberance (P1) or a cavity (C1), and P1 or C1 in CH31 can be located at C1 or P1 in CH32, respectively. In some embodiments, CH31 and CH32 meet at the interface between P1 and C1. In some embodiments, CH21 and CH22 each comprise a (P2) or a cavity (C2), and P2 or C2 in CH21 can be located at C2 or P2 in CH22, respectively. In some embodiments, CH21 and CH22 meet at the interface between P2 and C2.

[0045] In another aspect, the invention features an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising an anti-FcRH5 arm including a first binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23; and and an anti-CD3 arm comprising a second binding domain comprising (a) HVR-H1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 123, wherein the anti-FcRH5 arm and the anti-CD3 arm each comprise a N297G substitution mutation (EU numbering), the anti-FcRH5 arm comprises a T366W substitution mutation, and the anti-CD3 arm comprises T366S, L368A, and Y407V substitution mutations.

[0046] In another aspect, the invention features an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising an anti-FcRH5 arm that includes a first binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23; and and an anti-CD3 arm comprising a second binding domain comprising: (a) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 123, wherein the anti-FcRH5 arm comprises a light chain comprising Q38E and V133K substitution mutations, and a heavy chain comprising Q39K, S183E, and N297G substitution mutations, and the anti-CD3 arm comprises a light chain comprising Q38K and V133E substitution mutations, and a heavy chain comprising Q39E, S183K, and N297G substitution mutations (EU numbering).

[0047] In another aspect, the invention features an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising: (a) an anti-FcRH5 arm comprising a first binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 104 and a VL domain comprising the amino acid sequence of SEQ ID NO: 105, wherein the anti-FcRH5 arm comprises a light chain comprising Q38E and V133K substitution mutations, and a heavy chain comprising Q39K, S183E, and N297G substitution mutations; and (b) an anti-CD3 arm comprising a second binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 133 and a VL domain comprising the amino acid sequence of SEQ ID NO: 134, wherein the anti-CD3 arm comprises a light chain comprising Q38K and V133E substitution mutations, and a heavy chain comprising Q39E, S183K, and N297G substitution mutations (EU numbering).

[0048] In another aspect, the invention features an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising an anti-FcRH5 arm that includes a first binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23; and and an anti-CD3 arm comprising a second binding domain comprising: (a) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 121; (b) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 123, wherein the anti-FcRH5 arm comprises a light chain comprising Q38K and V133E substitution mutations, and a heavy chain comprising Q39E, S183K, and N297G substitution mutations, and the anti-CD3 arm comprises a light chain comprising Q38E and V133K substitution mutations, and a heavy chain comprising Q39K, S183E, and N297G substitution mutations (EU numbering).

[0049] In another aspect, the invention features an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising: (a) an anti-FcRH5 arm comprising a first binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 104 and a VL domain comprising the amino acid sequence of SEQ ID NO: 105, wherein the anti-FcRH5 arm comprises a light chain comprising Q38K and V133E substitution mutations, and a heavy chain comprising Q39E, S183K, and N297G substitution mutations; and (b) an anti-CD3 arm comprising a second binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 133 and a VL domain comprising the amino acid sequence of SEQ ID NO: 134, wherein the anti-CD3 arm comprises a light chain comprising Q38E and V133K substitution mutations, and a heavy chain comprising Q39K, S183E, and N297G substitution mutations (EU numbering).

[0050] In another aspect, the invention features an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising an anti-FcRH5 arm that includes a first binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23; and and an anti-CD3 arm comprising a second binding domain comprising: (a) an HVR-H5 arm comprising an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 1; (b) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (c) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (d) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 123, wherein the anti-FcRH5 arm comprises a light chain comprising Q38E and V133K substitution mutations, and a heavy chain comprising Q39K, S183E, and N297G substitution mutations, and the anti-CD3 arm comprises a light chain comprising Q38K, F116A, L135V, S174A, S176F, and T178V substitution mutations, and a heavy chain comprising Q39E, A141I, F170S, S181M, S183A, V185A, and N297G substitution mutations (EU numbering).

[0051] In another aspect, the invention features an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising: (a) an anti-FcRH5 arm comprising a first binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 104 and a VL domain comprising the amino acid sequence of SEQ ID NO: 105, the anti-FcRH5 arm comprising a light chain comprising Q38E and V133K substitution mutations, and a heavy chain comprising Q39K, S183E, and N297G substitution mutations; (b) an anti-CD3 arm comprising a second binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 133 and a VL domain comprising the amino acid sequence of SEQ ID NO: 134, wherein the anti-CD3 arm comprises a light chain comprising Q38K, F116A, L135V, S174A, S176F, and T178V substitution mutations, and a heavy chain comprising Q39E, A141I, F170S, S181M, S183A, V185A, and N297G substitution mutations (EU numbering).

[0052] In another aspect, the invention features an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising an anti-FcRH5 arm that includes a first binding domain comprising the following six HVRs: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23; and and an anti-CD3 arm comprising a second binding domain comprising: (a) an HVR-H5 arm comprising an HVR-H3 comprising the amino acid sequence of SEQ ID NO: 1; (b) an HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (c) an HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (d) an HVR-L3 comprising the amino acid sequence of SEQ ID NO: 123, wherein the anti-FcRH5 arm comprises a light chain comprising Q38K and V133E substitution mutations, and a heavy chain comprising Q39E, S183K, and N297G substitution mutations, and the anti-CD3 arm comprises a light chain comprising Q38E, F116A, L135V, S174A, S176F, and T178V substitution mutations, and a heavy chain comprising Q39K, A141I, F170S, S181M, S183A, V185A, and N297G substitution mutations (EU numbering).

[0053] In another aspect, the invention features an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising: (a) an anti-FcRH5 arm comprising a first binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 104 and a VL domain comprising the amino acid sequence of SEQ ID NO: 105, the anti-FcRH5 arm comprising a light chain comprising Q38K and V133E substitution mutations, and a heavy chain comprising Q39E, S183K, and N297G substitution mutations; (b) an anti-CD3 arm comprising a second binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 133 and a VL domain comprising the amino acid sequence of SEQ ID NO: 134, wherein the anti-CD3 arm comprises a light chain comprising Q38E, F116A, L135V, S174A, S176F, and T178V substitution mutations, and a heavy chain comprising Q39K, A141I, F170S, S181M, S183A, V185A, and N297G substitution mutations (EU numbering).

[0054] In some embodiments of any one of the aspects of the invention, the anti-FcRH5 antibody has a clearance after intravenous injection of about 10 ml / kg / day to about 35 ml / kg / day. In some embodiments, the anti-FcRH5 antibody has a clearance after intravenous injection of about 10 ml / kg / day to about 20 ml / kg / day in mice. In some embodiments, the anti-FcRH5 antibody has a clearance after intravenous injection of about 12 ml / kg / day to about 16 ml / kg / day in mice. In some embodiments, the anti-FcRH5 antibody has a clearance after intravenous injection of about 20 ml / kg / day to about 40 ml / kg / day in cynomolgus monkeys. In some embodiments, the anti-FcRH5 antibody has a clearance after intravenous injection of about 25 ml / kg / day to about 35 ml / kg / day in cynomolgus monkeys. In some embodiments, the anti-FcRH5 antibody has a clearance after intravenous injection of about 30 ml / kg / day to about 35 ml / kg / day in cynomolgus monkeys.

[0055] In another aspect, the invention features an isolated nucleic acid encoding an anti-FcRH5 antibody of any one of the preceding aspects, or a portion thereof comprising a binding domain thereof that binds FcRH5.

[0056] In another aspect, the invention features a vector including the isolated nucleic acid of the previous aspect.

[0057] In another aspect, the invention features a host cell including the vector of the previous aspect. In some embodiments, the host cell is a mammalian cell. In some embodiments, the mammalian cell is a Chinese hamster ovary (CHO) cell. In some embodiments, the host cell is a prokaryotic cell. In some embodiments, the prokaryotic cell is an E. coli cell.

[0058] In another aspect, the invention features a method for producing an anti-FcRH5 antibody according to any one of the preceding aspects of the invention, the method comprising culturing a host cell according to the preceding aspect in a culture medium. In some embodiments, the method further comprises recovering the anti-FcRH5 antibody from the host cell or the culture medium. In some embodiments, the method further comprises culturing a second host cell comprising a second nucleic acid encoding an anti-CD3 antibody comprising a binding domain that binds to CD3. In some embodiments, the host cells are co-cultured. In some embodiments, the method further comprises recovering the bispecific anti-FcRH5 antibody from the host cell or the culture medium.

[0059] In another aspect, the method features an immunoconjugate comprising an anti-FcRH5 antibody of any one of the preceding aspects and a cytotoxic agent.

[0060] In another aspect, the invention features a composition comprising an anti-FcRH5 antibody of any one of the aspects of the invention. In some embodiments, the composition further comprises a pharmaceutically acceptable excipient or diluent. In some embodiments, the pharmaceutically acceptable excipient is a buffer, carrier, stabilizer, or preservative. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the composition further comprises a PD-1 axis binding antagonist or an additional therapeutic agent.

[0061] In another aspect, the invention features an anti-FcRH5 antibody according to any one of the preceding aspects of the invention for use as a medicament.

[0062] In another aspect, the invention features an anti-FcRH5 antibody of any one of the preceding aspects of the invention for use in treating or delaying the progression of an FcRH5-positive cancer in a subject in need thereof.

[0063] In another aspect, the invention features an anti-FcRH5 antibody of any one of the preceding aspects of the invention for use in enhancing immune function in a subject with an FcRH5-positive cancer. In some embodiments, the FcRH5-positive cancer is a B-cell cancer. In another aspect, the B-cell cancer is selected from the group consisting of multiple myeloma (MM), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL). In another embodiment, the B-cell cancer is MM.

[0064] In another aspect, the invention features the use of an anti-FcRH5 antibody or composition of any one of the preceding aspects in the manufacture of a medicament for treating or delaying the progression of an FcRH5-positive cancer in a subject. In another aspect, the invention features the use of an anti-FcRH5 antibody or composition of any one of the preceding aspects in the manufacture of a medicament for enhancing immune function in a subject with an FcRH5-positive cancer. In some embodiments, the FcRH5-positive cancer is a B-cell cancer. In some embodiments, the B-cell cancer is selected from the group consisting of MM, CLL, MCL, DLBCL, and FL. In some embodiments, the B-cell cancer is MM.

[0065] In another aspect, the invention features a method for treating or delaying the progression of an FcRH5-positive cancer in a subject in need thereof, the method comprising administering to the subject an anti-FcRH5 antibody described in any one of the preceding aspects of the invention. In another aspect, the invention features a method for enhancing immune function in a subject with an FcRH5-positive cancer, the method comprising administering to the subject an effective amount of an anti-FcRH5 antibody described in any one of the preceding aspects of the invention. In some embodiments, the FcRH5-positive cancer is a B-cell cancer. In some embodiments, the B-cell cancer is selected from the group consisting of MM, CLL, MCL, DLBCL, and FL. In some embodiments, the B-cell cancer is MM. In some embodiments, the anti-FcRH5 antibody binds to (a) an FcRH5 molecule located on target cells and (b) a CD3 molecule located on immune effector cells. In some embodiments, the anti-FcRH5 antibody activates immune effector cells after binding to the FcRH5 molecule and the CD3 molecule. In some embodiments, the activated immune effector cells can exert a cytotoxic and / or apoptotic effect on target cells. In some embodiments, the target cells are plasma cells. In some embodiments, the plasma cells are short-lived plasma cells. In some embodiments, the plasma cells are long-lived plasma cells. In some embodiments, the plasma cells are myeloma cells. In some embodiments, the method comprises administering to the subject an anti-FcRH5 antibody at a dosage of about 0.01 mg / kg / week to about 50 mg / kg / week. In some embodiments, the method comprises administering to the subject an anti-FcRH5 antibody at a dosage of about 0.1 mg / kg / week to about 10 mg / kg / week. In some embodiments, the method comprises administering to the subject an anti-FcRH5 antibody at a dosage of about 1 mg / kg / week.

[0066] In other embodiments, the method further comprises administering a PD-1 axis-binding antagonist and / or an additional therapeutic agent to the subject. In some embodiments, the PD-1 axis-binding antagonist or additional therapeutic agent is administered before or after administration of the anti-FcRH5 antibody. In some embodiments, the PD-1 axis-binding antagonist or additional therapeutic agent is administered simultaneously with the anti-FcRH5 antibody. In some embodiments, the PD-1 axis-binding antagonist is selected from the group consisting of a PD-L1-binding antagonist, a PD-1-binding antagonist, and a PD-L2-binding antagonist. In some embodiments, the PD-1 axis-binding antagonist is a PD-L1-binding antagonist. In some embodiments, the PD-L1-binding antagonist is selected from the group consisting of MPDL3280A (atezolizumab), YW243.55.S70, MDX-1105, MEDI4736 (durvalumab), and MSB0010718C (avelumab). In some embodiments, the PD-L1 binding antagonist is MPDL3280A (atezolizumab). In some embodiments, the PD-1 axis binding antagonist is a PD-1 binding antagonist. In some embodiments, the PD-1 binding antagonist is selected from the group consisting of MDX 1106 (nivolumab), MK-3475 (pembrolizumab), CT-011 (pidilizumab), MEDI-0680 (AMP-514), PDR001, REGN2810, and BGB-108. In some embodiments, the PD-1 axis binding antagonist is a PD-L2 binding antagonist. In some embodiments, the PD-L2 binding antagonist is an antibody or immunoadhesin. In some embodiments, the subject is a steroid, an immunomodulatory drug (IMiD), a proteosome inhibitor (PI), or a combination thereof. In some embodiments, the steroid is a glucocorticoid. In some embodiments, the glucocorticoid is dexamethasone. In some embodiments, the IMiD is lenalidomide. In some embodiments, the PI is bortezomib.

[0067] In other embodiments, the method comprises administering the anti-FcRH5 antibody, PD-1 axis binding antagonist, steroid, IMiD, PI, or a combination thereof described in any one of the preceding aspects intravenously, subcutaneously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intracerebroventricularly, or intranasally. In some embodiments, the method comprises administering the anti-FcRH5 antibody, PD-1 axis binding antagonist, steroid, IMiD, PI, or a combination thereof intravenously. In some embodiments, the method comprises administering the anti-FcRH5 antibody, PD-1 axis binding antagonist, steroid, IMiD, PI, or a combination thereof subcutaneously. In some embodiments of any one of the preceding aspects, the subject is a human.

[0068] In another aspect, the invention features a method for detecting FcRH5 in a biological sample from a subject, the method including: (a) contacting the biological sample with an anti-FcRH5 antibody of any one of the aspects of the invention under conditions that allow binding of the anti-FcRH5 antibody to naturally occurring FcRH5 in the biological sample; and (b) detecting whether a complex between the anti-FcRH5 antibody and naturally occurring FcRH5 is formed in the biological sample. In some embodiments, the biological sample is a blood sample. In some embodiments of this aspect, the subject is a human.

[0069] In another aspect, the invention features a kit including an anti-FcRH5 antibody of any one of the preceding aspects of the invention and a package insert containing instructions for using the anti-FcRH5 antibody to treat or delay the progression of an FcRH5-positive cancer in a subject. In another aspect, the invention features a kit including an anti-FcRH5 antibody of any one of the preceding aspects of the invention and a package insert containing instructions for using the anti-FcRH5 antibody to enhance immune function in a subject with an FcRH5-positive cancer. In some embodiments of these aspects, the subject is a human. [Brief explanation of the drawings]

[0070] [Figure 1A] 1 is a schematic diagram showing an exemplary rationally designed configuration (Configuration 1) of the FcRH5 TDB having VL, VH, CL, and CH1 domains comprising one or more charged regions. In Configuration 1, the VH1, CL1, VL2, and CH12 domains comprise basic charged regions, and the VL1, CH11, VH2, and CL2 domains comprise acidic charged regions. [Figure 1B] 1 is a schematic diagram showing an exemplary rationally designed configuration (Configuration 2) of the FcRH5 TDB having VL, VH, CL, and CH1 domains comprising one or more charged regions. In Configuration 2, the VH1, CL1, VL2, and CH12 domains comprise acidic charged regions, and the VL1, CH11, VH2, and CL2 domains comprise basic charged regions. [Figure 1C] Schematic diagram showing an exemplary Rosetta design configuration (Configuration 1) of the FcRH5 TDB having VL, VH, CL, and CH1 domains containing one or more charged regions. In Configuration 1, the VH1, CL1, and VL2 domains contain basic charged regions, and the VL1, CH11, and VH2 domains contain acidic charged regions. Additionally, the CH12 domain contains a cavity, and the CL2 domain contains a protuberance. The cavity and protuberance are depicted as black boxes at the CH12 / CL2 interface. [Figure 1D] 1 is a schematic diagram showing an exemplary Rosetta design configuration (Configuration 2) of the FcRH5 TDB having VL, VH, CL, and CH1 domains containing one or more charged regions. In Configuration 2, the VH1, CL1, and VL2 domains contain acidic charged regions, and the VL1, CH11, and VH2 domains contain basic charged regions. Additionally, the CH12 domain contains a cavity, and the CL2 domain contains a bulge. The cavity and bulge are depicted as black boxes at the CH12 / CL2 interface. [Figure 1E]1 is a schematic diagram showing an exemplary alternative Rosetta design configuration (Alternative Configuration 1) of the FcRH5 TDB having VL, VH, CL, and CH1 domains comprising one or more charged regions. In Alternative Configuration 1, the VL1, VH2, and CL2 domains comprise acidic charged regions, and the VH1, CH12, and VL2 domains comprise basic charged regions. Additionally, the CH11 domain comprises a cavity, and the CL1 domain comprises a protuberance. The cavity and protuberance are depicted as black boxes at the CH11 / CL1 interface. [Figure 1F] 1 is a schematic diagram showing an exemplary alternative Rosetta design configuration (Alternative Configuration 2) of the FcRH5 TDB having VL, VH, CL, and CH1 domains comprising one or more charged regions. In Alternative Configuration 2, the VL1, VH2, and CL2 domains comprise basic charged regions, and the VH1, CH12, and VL2 domains comprise acidic charged regions. Additionally, the CH11 domain comprises a cavity, and the CL1 domain comprises a protuberance. The cavity and protuberance are depicted as black boxes at the CH11 / CL1 interface. [Figure 2]

[0023] Figure 1 is an alignment of light chain variable (VL) domain sequences of selected anti-FcRH5 antibodies. Changes from 1G7 (see U.S. Publication No. 2015-0098900, incorporated herein by reference in its entirety) are indicated in dark boxes. Hypervariable regions (HVRs) are indicated by lines above and / or below the alignment. These VL domain sequences are also disclosed as SEQ ID NOs: 83, 85, 87, 89, 91, 93, 95, 97, 99, and 101. [Figure 3]

[0023] Figure 1 is an alignment of heavy chain variable (VH) domain sequences of selected anti-FcRH5 antibodies. Changes from clone 1G7 (see U.S. Publication No. 2015-0098900) are indicated in dark boxes. Hypervariable regions (HVRs) are indicated by lines above and / or below the alignment. These VH domain sequences are also disclosed as SEQ ID NOs: 82, 84, 86, 88, 90, 92, 94, 96, 98, and 100. [Figure 4] 1 is a table showing the effect on binding affinity of amino acid substitutions at position 52 of the indicated anti-FcRH5 antibodies. [Figure 5A]

[0023] Figure 1 is an alignment of the heavy chain variable (VH) domain sequences of hu1G7.v85 and hu1G7.v93. Changes from the human germline sequence hIGHV4-59*01 are indicated within the shaded boxes. Hypervariable regions (HVRs) are indicated by labels above the alignment. These VH domain sequences are also disclosed as SEQ ID NOs: 104 (hu1G7.v85) and 106 (hu1G7.v93). [Figure 5B]

[0023] Figure 1 is an alignment of the light chain variable (VL) domain sequences of hu1G7.v85 and hu1G7.v93. Changes from the human germline sequence hIGKV1-16*01 are indicated within the shaded boxes. Hypervariable regions (HVRs) are indicated by labels above the alignment. These VL domain sequences are also disclosed as SEQ ID NOs: 105 (hu1G7.v85) and 107 (hu1G7.v93). [Figure 6A]

[0023] Figure 1 is an alignment of the heavy chain variable (VH) domain sequences of hu1G7.v85.1G7 and consensus H4. Changes from humanized, affinity matured, and polished clone 1G7 (see U.S. Publication No. 2015-0098900, incorporated herein by reference in its entirety) are indicated in dark boxes. Hypervariable regions (HVRs) are indicated by labels above the alignment. The VH domain sequence of hu1G7.v85 is disclosed as SEQ ID NO: 104. [Figure 6B]

[0023] Figure 1 is an alignment of the light chain variable (VL) domain sequences of hu1G7.v85, 1G7, and consensus KI. Changes from humanized, affinity matured, and refined clone 1G7 are shown in the shaded box. The VL domain sequence of hu1G7.v85 is disclosed as SEQ ID NO: 105. [Figure 7A] 1 shows the heavy chain variable (VH) domain sequence of anti-FcRH5 antibody hu1G7.v93 (SEQ ID NO: 106). [Figure 7B] 1 shows the light chain variable (VL) domain sequence of anti-FcRH5 antibody hu1G7.v93 (SEQ ID NO: 107). [Figure 8]1 is a graph showing antibody titers of 1G7.v85 antibody and 1G7.v87 antibody. [Figure 9A] 1 is a histogram overlay comparing the binding of FcRH5 / 38E4.v1 TDBs with different anti-FcRH5 arms (i.e., m1G7 ("1G7 TDB"), 1G7.v85 ("1G7.v85 TDB"), and 1G7.v1.4 ("1G7.v1.4 TDB")) to FcRH3-overexpressing cells. [Figure 9B] 1 is a graph showing that 1G7.v85 TDB does not deplete natural killer (NK) cells at concentrations of ≦20 μg / mL, and that 1G7.v85 TDB has a median EC50 of 25 ng / mL against plasma cells (PC). [Figure 10A] 1 is a series of graphs comparing the ability of FcRH5 TDB, 1G7.v1.4 / 38E4.v1 ("1G7.v1.4 TDB"), to bind FcRH3, human FcRH5, and cynomolgus monkey FcRH5. [Figure 10B] 1 is a series of graphs comparing the ability of 1G7.v85 TDB to bind FcRH3, human FcRH5, and cynomolgus monkey FcRH5. [Figure 10C] 1 is a series of graphs comparing the ability of FcRH5 TDB, 1G7 / 38E4.v1 ("1G7 TDB"), to bind FcRH3, human FcRH5, and cynomolgus monkey FcRH5. [Figure 10D] 1 is a series of graphs comparing the ability of control antibodies to bind to FcRH3, human FcRH5, and cynomolgus monkey FcRH5. [Figure 11A]

[0023] Figure 1 shows the sequence of the heavy chain variable (VH) domain sequence of humanized rabbit-derived anti-FcRH5 antibody hu7D8.L1H2. The VH domain sequence of hu7D8.L1H2 is disclosed as SEQ ID NO: 108. [Figure 11B]

[0023] Figure 1 shows the sequence of the light chain variable (VL) domain sequence of humanized rabbit-derived anti-FcRH5 antibody hu7D8.L1H2. The VL domain sequence of hu7D8.L1H2 is disclosed as SEQ ID NO: 109. [Figure 12A]1 shows the sequence of the heavy chain variable (VH) domain sequence of murine-derived anti-FcRH5 antibody 17B1. The VH domain sequence of 17B1 is disclosed as SEQ ID NO: 110. [Figure 12B] 1 shows the sequence of the light chain variable (VL) domain sequence of murine-derived anti-FcRH5 antibody 17B1. The VL domain sequence of 17B1 is disclosed as SEQ ID NO: 111. [Figure 13A] 1 shows the sequence of the heavy chain variable (VH) domain sequence of the murine-derived anti-FcRH5 antibody 15G8. The VH domain sequence of 15G8 is disclosed as SEQ ID NO: 112. [Figure 13B] 1 shows the sequence of the light chain variable (VL) domain sequence of the murine-derived anti-FcRH5 antibody 15G8. The VL domain sequence of 15G8 is disclosed as SEQ ID NO: 113. [Figure 14] 1 is a series of graphs showing the binding affinity of humanized variants of rabbit-derived anti-FcRH5 antibodies 7D8.Rb and h7D8.L1H2 to human FcRH5 and cynomolgus monkey FcRH5. [Figure 15] 1 is a series of graphs showing that FcRH5 TDBs 1G7.v85 TDB and hu1G7.v93 / 38E4.v1 ("1G7.v93 TDB") bind to both human and cynomolgus monkey FcRH5 with comparable affinity. [Figure 16A] Graph showing kinetic analysis of 1G7.v85 TDB, which binds to human FcRH5 and cynomolgus monkey FcRH5 with dissociation constants (KD) of 2.35 nM and 6.76 nM, respectively, as measured by BIACORE® in an hIgG capture format using a 1:1 binding model of monovalent affinity. [Figure 16B] Graph showing kinetic analysis of 1G7.v85 TDB, which binds to human FcRH5 and cynomolgus monkey FcRH5 with dissociation constants (KD) of 2.35 nM and 6.76 nM, respectively, as measured by BIACORE® in an hIgG capture format using a 1:1 binding model of monovalent affinity. [Figure 17A]Figures 17A and 17B are graphs showing increased FcRH5-induced cytotoxicity of MOLP-2 cells (i.e., human multiple myeloma cells that endogenously express FcRH5) using a humanized and affinity matured variant of 1G7 formatted into a T cell-dependent bispecific (TDB) antibody with the CD3-binding arm of 38E4.v1 (see PCT Publication No. WO 2015-095392 A1, which is incorporated by reference in its entirety). In Figure 17A, 1G7 TDB, hu1G7.v1.1 / 38E4.v1 ("1G7.v1.1 TDB"), hu1G7.v1.2 / 38E4.v1 ("1G7.v1.2 TDB"), hu1G7.v1.3 / 38E4.v1 ("1G7.v1.3 TDB"), and 1G7.v1.4 TDB were evaluated. In Figure 17B, 1G7.v1.4 TDB, hu1G7.v1.5 / 38E4.v1 ("1G7.v1.5" TDB), hu1G7.v1.13 / 38E4.v1 ("1G7.v1.13 TDB"), hu1G7.v1.7 / 38E4.v1 ("1G7.v1.7 TDB"), and hu1G7.v1.13.1 / 38E4.v1 ("1G7.v1.13.1") were evaluated. 1G7.v1.4 TDB demonstrated 5- to 13-fold improved target cell killing (EC50) compared to murine 1G7 TDB (n=10). [Figure 17B]Figures 17A and 17B are graphs showing increased FcRH5-induced cytotoxicity of MOLP-2 cells (i.e., human multiple myeloma cells that endogenously express FcRH5) using a humanized and affinity matured variant of 1G7 formatted into a T cell-dependent bispecific (TDB) antibody with the CD3-binding arm of 38E4.v1 (see PCT Publication No. WO 2015-095392 A1, which is incorporated by reference in its entirety). In Figure 17A, 1G7 TDB, hu1G7.v1.1 / 38E4.v1 ("1G7.v1.1 TDB"), hu1G7.v1.2 / 38E4.v1 ("1G7.v1.2 TDB"), hu1G7.v1.3 / 38E4.v1 ("1G7.v1.3 TDB"), and 1G7.v1.4 TDB were evaluated. In Figure 17B, 1G7.v1.4 TDB, hu1G7.v1.5 / 38E4.v1 ("1G7.v1.5" TDB), hu1G7.v1.13 / 38E4.v1 ("1G7.v1.13 TDB"), hu1G7.v1.7 / 38E4.v1 ("1G7.v1.7 TDB"), and hu1G7.v1.13.1 / 38E4.v1 ("1G7.v1.13.1") were evaluated. 1G7.v1.4 TDB demonstrated 5- to 13-fold improved target cell killing (EC50) compared to murine 1G7 TDB (n=10). [Figure 18A] Figures 18A-18D are graphs comparing the ability of 1G7.v1.4 TDB and 1G7.v85 TDB to activate T cells (Figure 18A), kill target MOLP-2 cells (Figure 18B), kill target cynomolgus monkey plasma cells (Figure 18C), and kill target cynomolgus monkey B cells (Figure 18D). [Figure 18B] Figures 18A-18D are graphs comparing the ability of 1G7.v1.4 TDB and 1G7.v85 TDB to activate T cells (Figure 18A), kill target MOLP-2 cells (Figure 18B), kill target cynomolgus monkey plasma cells (Figure 18C), and kill target cynomolgus monkey B cells (Figure 18D). [Figure 18C]Figures 18A-18D are graphs comparing the ability of 1G7.v1.4 TDB and 1G7.v85 TDB to activate T cells (Figure 18A), kill target MOLP-2 cells (Figure 18B), kill target cynomolgus monkey plasma cells (Figure 18C), and kill target cynomolgus monkey B cells (Figure 18D). [Figure 18D] Figures 18A-18D are graphs comparing the ability of 1G7.v1.4 TDB and 1G7.v85 TDB to activate T cells (Figure 18A), kill target MOLP-2 cells (Figure 18B), kill target cynomolgus monkey plasma cells (Figure 18C), and kill target cynomolgus monkey B cells (Figure 18D). [Figure 19A] 1 is a series of histograms comparing the ability of 1G7.v85 TDB and hu1G7.v87 / 38E4.v1 TDB (“1G7.v87 TDB”) to bind and cross-react with mouse SVT2 cells expressing human FcRH5 (panel 1), cynomolgus monkey FcRH5 (panel 2), and human FcRH3 (panel 3). [Figure 19B] Figures 19B-19D are graphs comparing the ability of 1G7.v85 TDB and 1G7.v87 TDB to kill target MOLP-2 cells (Figure 19B), human B cells (Figure 19C), and cynomolgus monkey B cells (Figure 19D). [Figure 19C] Figures 19B-19D are graphs comparing the ability of 1G7.v85 TDB and 1G7.v87 TDB to kill target MOLP-2 cells (Figure 19B), human B cells (Figure 19C), and cynomolgus monkey B cells (Figure 19D). [Figure 19D] Figures 19B-19D are graphs comparing the ability of 1G7.v85 TDB and 1G7.v87 TDB to kill target MOLP-2 cells (Figure 19B), human B cells (Figure 19C), and cynomolgus monkey B cells (Figure 19D). [Figure 20A]Figures 20A-20D are graphs showing the reduced ability of 1G7.v85 TDB to bind to FcRH5 after undergoing either a 2,2'-azobis(2-amidopropane) dihydrochloride (AAPH) stress test (Figure 20B) or a light stress test (Figure 20D) compared to the respective unstressed controls (Figures 20A and 20C). [Figure 20B] Figures 20A-20D are graphs showing the reduced ability of 1G7.v85 TDB to bind to FcRH5 after undergoing either a 2,2'-azobis(2-amidopropane) dihydrochloride (AAPH) stress test (Figure 20B) or a light stress test (Figure 20D) compared to the respective unstressed controls (Figures 20A and 20C). [Figure 20C] Figures 20A-20D are graphs showing the reduced ability of 1G7.v85 TDB to bind to FcRH5 after undergoing either a 2,2'-azobis(2-amidopropane) dihydrochloride (AAPH) stress test (Figure 20B) or a light stress test (Figure 20D) compared to the respective unstressed controls (Figures 20A and 20C). [Figure 20D] Figures 20A-20D are graphs showing the reduced ability of 1G7.v85 TDB to bind to FcRH5 after undergoing either a 2,2'-azobis(2-amidopropane) dihydrochloride (AAPH) stress test (Figure 20B) or a light stress test (Figure 20D) compared to the respective unstressed controls (Figures 20A and 20C). [Figure 21A] 1 is a graph showing the size distribution analysis of 1G7.v85 TDB, which lost 0.1% of the monomer peak after two weeks of stress in pH 5.5 his-acetate solution. [Figure 21B] 1 is a graph showing charge heterogeneity of 1G7.v85 TDB, which lost 7.7% of its monomer peak after two weeks of stress in pH 5.5 his-acetate solution. [Figure 22A]1 is a graph showing that 1G7.v85 TDB has no observable change in the reduced mass profile of light chain mass after two weeks of stress in pH 5.5 his-acetate solution. [Figure 22B] 1 is a graph showing that 1G7.v85 TDB has no observable change in the reduced mass profile of heavy chain mass after two weeks of stress in pH 5.5 his-acetate solution. [Figure 23A] Phospho-SLP76 Western blot of peripheral CD8 cells from a healthy donor stimulated with 1 μg / ml of 1G7 / UCHT1.v9 TDB, 10A8 / UCHT1.v9 TDB ("10A8 TDB"), and anti-gD / UCHT1.v9 TDB ("anti-gD TDB"), and cells expressing human FcRH5 with an N-terminal gD expression tag. Blotting for total SLP76, indicative of TCR signaling, was used to confirm equal sample loading. [Figure 23B] 1 is a graph showing FcRH5 target cell killing by either 1G7 / UCHT1.v9 TDB or anti-gD TDB and CD8+ T cells. [Figure 23C] FIG. 1 is a schematic diagram of a truncated FcRH5 construct in which the gD epitope is now membrane-proximal. [Figure 23D]

[0023] Figure 1 shows a graph showing target cell killing using truncated FcRH5 constructs containing 1G7 TDB or anti-gD TDB. Removal of interference caused by the ECD increased the activity of the proximal 1G7 / UCHT1.v9 TDB by 25-fold (EC50 = 20 pM), while the anti-gD TDB was able to effectively mediate cell killing (EC50 = 0.19 nM). The truncated constructs were expressed in 293 cells. [Figure 23E] 1 is a graph showing that target cell killing (dashed lines) of five alternative FcRH5 TDBs that recognize membrane-proximal epitopes is comparable to killing mediated by 1G7 / UCHT1.v9 TDB and significantly better than 10A8 TDB. [Figure 24A] Histogram overlay of flow cytometry analysis of SVT2-parental, gD-FcRH5 full-length, and gD-FcRH5-domain 9 cells. [Figure 24B] 1 is a graph showing the percent target cell killing by 1G7 / UCHT1.v9 TDB, 2H7 / UCHT1.v9 TDB ("2H7 TDB"), 3G7 / UCHT1.v9 TDB ("3G7 TDB"), 10A8 TDB, and anti-gD TDB. [Figure 25A] Figure 2 shows an overlay histogram of six cell lines (SVT2-vector, SVT2-FcRH1, SVT2-FCRH2, SVT2-FcRH3, SVT2-FcRH4, and SVT2-FcRH5) showing that 1G7.v85 TDB binds to FcRH5 but not other family members. [Figure 25B] Histogram overlay of three cell lines (293 parental, 293-FcRH5 full-length, and 293-FcRH5-D9-deleted) showing that 1G7.v85 TDB binds to the membrane proximal domain of FcRH5. [Figure 25C] 1 is an overlay histogram of three cell lines (SVT2-vector, SVT2-huFcRH5, and SVT2-cynomolgus FcRH5) showing that 1G7.v85 TDB binds to cynomolgus FcRH5 and human FcRH5. [Figure 26A] Figures 26A-26D are overlay histograms of three cell lines (SVT2-vector, SVT2-huFcRH5, and SVT2-cynomolgus FcRH5) showing the binding of 1G7 / 38E4.v1 TDB ("1G7 TDB") to multiple myeloma (MM) cell lines and primary cells. Overlay histograms are shown for isotype-PE and 1G7 TDB to MOLP-2 cells (Figure 26A), human CD20+ B cells (Figure 26B), human CD38+CD138+ plasma cells (Figure 26C), and CD38+CD138+ MM tumor cells from MM bone marrow aspirate (Figure 26D). [Figure 26B]Figures 26A-26D are overlay histograms of three cell lines (SVT2-vector, SVT2-huFcRH5, and SVT2-cynomolgus FcRH5) showing the binding of 1G7 / 38E4.v1 TDB ("1G7 TDB") to multiple myeloma (MM) cell lines and primary cells. Overlay histograms are shown for isotype-PE and 1G7 TDB to MOLP-2 cells (Figure 26A), human CD20+ B cells (Figure 26B), human CD38+CD138+ plasma cells (Figure 26C), and CD38+CD138+ MM tumor cells from MM bone marrow aspirate (Figure 26D). [Figure 26C] Figures 26A-26D are overlay histograms of three cell lines (SVT2-vector, SVT2-huFcRH5, and SVT2-cynomolgus FcRH5) showing the binding of 1G7 / 38E4.v1 TDB ("1G7 TDB") to multiple myeloma (MM) cell lines and primary cells. Overlay histograms are shown for isotype-PE and 1G7 TDB to MOLP-2 cells (Figure 26A), human CD20+ B cells (Figure 26B), human CD38+CD138+ plasma cells (Figure 26C), and CD38+CD138+ MM tumor cells from MM bone marrow aspirate (Figure 26D). [Figure 26D] Figures 26A-26D are overlay histograms of three cell lines (SVT2-vector, SVT2-huFcRH5, and SVT2-cynomolgus FcRH5) showing the binding of 1G7 / 38E4.v1 TDB ("1G7 TDB") to multiple myeloma (MM) cell lines and primary cells. Overlay histograms are shown for isotype-PE and 1G7 TDB to MOLP-2 cells (Figure 26A), human CD20+ B cells (Figure 26B), human CD38+CD138+ plasma cells (Figure 26C), and CD38+CD138+ MM tumor cells from MM bone marrow aspirate (Figure 26D). [Figure 27A] 1 is a graph showing dose-dependent activation of CD8+ cells upon stimulation with target cells (MOLP-2) and 1G7 TDB, as detected by flow cytometry analysis. [Figure 27B](Figure 1) is a graph showing target cell-dependent killing by 1G7 TDB. The inset shows a flow cytometry overlay of the parental Fox-NY cell line and clones transfected to express low or high levels of human FcRH5. Error bars represent standard deviations of triplicates. [Figure 27C] Figures 27C-27E are graphs showing that 1G7 TDB induced CD8 proliferation responses (5 days) as detected by measuring CSFE fluorescence intensity dilution by flow cytometry in CFSE-labeled human CD8+ cells alone (Figure 27C), in coculture with MOLP-2 (Figure 27D), or in coculture with MOLP-2 and 1000 ng / ml 1G7.v85 TDB (Figure 27E). [Figure 27D] Figures 27C-27E are graphs showing that 1G7 TDB induced CD8 proliferation responses (5 days) as detected by measuring CSFE fluorescence intensity dilution by flow cytometry in CFSE-labeled human CD8+ cells alone (Figure 27C), in coculture with MOLP-2 (Figure 27D), or in coculture with MOLP-2 and 1000 ng / ml 1G7.v85 TDB (Figure 27E). [Figure 27E] Figures 27C-27E are graphs showing that 1G7 TDB induced CD8 proliferation responses (5 days) as detected by measuring CSFE fluorescence intensity dilution by flow cytometry in CFSE-labeled human CD8+ cells alone (Figure 27C), in coculture with MOLP-2 (Figure 27D), or in coculture with MOLP-2 and 1000 ng / ml 1G7.v85 TDB (Figure 27E). [Figure 27F]1 is a graph showing target-dependent cell killing by FcRH5 TDBs containing different anti-CD3 arms (e.g., UCHT1.v9, 38E4.v1, and 40G5c) (see PCT Publication No. WO 2015 / 095392 A1, which is incorporated herein by reference in its entirety). The anti-CD3 arms 38E4.v1 (monovalent KD 0.5 nM, BIACORE®), UCHT1.v9 (monovalent KD = 2.5 nM, BIACORE® and Scatchard), and 40G5c (monovalent KD = 51 nM, BIACORE®) were each paired with the anti-FcRH5 arm of m1G7 (KD = 11 nM, BIACORE®) and tested for binding to purified human CD8+ cells. [Figure 27G] 1 is a graph showing target-dependent cell killing by 1G7 TDB and 1G7 / 38E4.v1 bis-Fab (“1G7 bis-Fab”). [Figure 28A]

[0023] Figure 1 shows graphs depicting FcRH5 expression in primary multiple myeloma tumor cells, peripheral B cells from healthy donors, and bone marrow plasma cells. FcRH5 expression was analyzed by flow cytometry and normalized to expression in the MOLP-2 internal control and assay control. Relative levels of FcRH5 were calculated as follows: (geometric mean of FcRH5 in "X" / geometric mean of isotype control in "X") / (geometric mean of FcRH5 in MOLP-2 / geometric mean of isotype control in MOLP-2). [Figure 28B] Figure 1 shows the cytotoxic activity of 1G7.v85 TDB against human plasma cells. Human bone marrow mononuclear cells (BMMCs) were cultured with 1G7.v85 TDB, and the number of viable CD38+CD138+ cells was analyzed by flow cytometry. [Figure 28C] Figure 1 shows the cytotoxic activity of 1G7.v85 TDB against primary myeloma cells from different patients. Human myeloma BMMCs were co-cultured with CD8+ T cells isolated from healthy donors and 1G7.v85 TBD. [Figure 28D]1 is a graph showing that extremely low FcRH5 expression in target cells is sufficient for potent killing activity. The number of FcRH5 copies per cell was determined by Scatchard assay. [Figure 28E] (Top) Graph showing qRT-PCR analysis of FcRH5 mRNA levels in bone marrow biopsies from high-risk myeloma patients with 1q21 gain. mRNA expression levels were calculated by the delta Ct (dCt) method. Statistical analysis was performed using the Mann-Whitney U test. (Bottom) Images of FISH analysis of primary multiple myeloma biopsies showing normal diploidy at 1q21 (left) and a mixture of approximately three to six copies of 1q21 (right). Tumor samples were identified as having 1q21 gain when >20% of scored tumor cells had three or more copies of the 1q21.3 locus. [Figure 29A] 1 is a histogram overlay of isotype-PE and anti-FcRH5 clone 1G7-PE illustrating the expression of FcRH5 on cynomolgus monkey CD20+ B cells. [Figure 29B] 1 is a histogram overlay of isotype-PE and anti-FcRH5 clone 1G7-PE illustrating the expression of FcRH5 on cynomolgus monkey CD45-CD20-CD38+PC+ plasma cells. [Figure 29C] Figures 29C and 29D are graphs showing comparable dose-dependent cytotoxic activity between cynomolgus monkey CD8+ T cells and human CD8+ T cells in an in vitro killing assay using SVT2-cynomolgus monkey FcRH5 (Figure 29C) and MOLP-2 (Figure 29D) together with human CD8+ T cells or cynomolgus monkey CD8+ T cells. [Figure 29D] Figures 29C and 29D are graphs showing comparable dose-dependent cytotoxic activity between cynomolgus monkey CD8+ T cells and human CD8+ T cells in an in vitro killing assay using SVT2-cynomolgus monkey FcRH5 (Figure 29C) and MOLP-2 (Figure 29D) together with human CD8+ T cells or cynomolgus monkey CD8+ T cells. [Figure 29E]1 is a graph showing the in vitro killing activity of 1G7.v85 TDB against cynomolgus monkey CD20+ B cells (n=14). [Figure 29F] 1 is a graph showing the in vitro killing activity of 1G7.v85 TDB against CD45-CD20-CD38+PC+ plasma cells derived from cynomolgus monkey bone marrow from eight different donors (n=8). [Figure 30A] 1 is a graph showing that splenic human T cells isolated from the spleens of humanized NOD / SCID gamma mice (NSG) have activity comparable to peripheral human T cells from healthy donors. [Figure 30B]

[0023] Figure 1 shows that 1G7 TDB treatment induces regression of subcutaneous MOLP-2 xenograft tumors in humanized NSG mice. Mice were treated with a single intravenous dose of vehicle or 0.5 mg / kg of 1G7.v85 TDB. The mean tumor volume (thick black line), individual tumor volumes (thin lines), and the control group mean (dashed line) are shown. [Figure 31A] 1 is a graph showing serum concentrations of FcRH5 TDB plotted over the study period following administration of a single dose of 1 mg / kg, 2 mg / kg, or 4 mg / kg of 1G7.v85 TDB to 3 animals / group. A table showing pharmacodynamic parameters is shown below. [Figure 31B] 1 is a graph showing serum concentrations of FcRH5 TDB (1G7.v85 TDB and 1G7.v87 / 38E4.v1 TDB ("1G7.v87 TDB")) plotted over the study period following administration of a single dose of 3 mg / kg anti-gD TDB or 0.3 mg / kg or 3 mg / kg FcRH5 TDB to 3 animals / group. A table showing pharmacodynamic parameters is shown below. [Figure 31C] Figures 31C and 31D are graphs showing 1G7.v85 TDB-induced transient T cell activation in the peripheral blood of cynomolgus monkeys after a single intravenous dose of vehicle or 1G7.v85 TDB (1 mg / kg, 2 mg / kg, or 4 mg / kg) to three animals per group. [Figure 31D]Figures 31C and 31D are graphs showing 1G7.v85 TDB-induced transient T cell activation in the peripheral blood of cynomolgus monkeys after a single intravenous dose of vehicle or 1G7.v85 TDB (1 mg / kg, 2 mg / kg, or 4 mg / kg) to three animals per group. [Figure 31E] Figures 31E-31H are graphs showing absolute CD20+ B cell counts in peripheral blood (Figure 31E), spleen (Figure 31F), mandibular lymph node (Figure 31G), and bone marrow (Figure 31H) in cynomolgus monkeys after a single intravenous dose of vehicle or 1G7.v85 TDB (1 mg / kg, 2 mg / kg, or 4 mg / kg) to three animals / group. Figures 31F-31H are plotted along with the group mean and standard error of the mean (SEM). [Figure 31F] Figures 31E-31H are graphs showing absolute CD20+ B cell counts in peripheral blood (Figure 31E), spleen (Figure 31F), mandibular lymph node (Figure 31G), and bone marrow (Figure 31H) in cynomolgus monkeys after a single intravenous dose of vehicle or 1G7.v85 TDB (1 mg / kg, 2 mg / kg, or 4 mg / kg) to three animals / group. Figures 31F-31H are plotted along with the group mean and standard error of the mean (SEM). [Figure 31G] Figures 31E-31H are graphs showing absolute CD20+ B cell counts in peripheral blood (Figure 31E), spleen (Figure 31F), mandibular lymph node (Figure 31G), and bone marrow (Figure 31H) in cynomolgus monkeys after a single intravenous dose of vehicle or 1G7.v85 TDB (1 mg / kg, 2 mg / kg, or 4 mg / kg) to three animals / group. Figures 31F-31H are plotted along with the group mean and standard error of the mean (SEM). [Figure 31H]Figures 31E-31H are graphs showing absolute CD20+ B cell counts in peripheral blood (Figure 31E), spleen (Figure 31F), mandibular lymph node (Figure 31G), and bone marrow (Figure 31H) in cynomolgus monkeys after a single intravenous dose of vehicle or 1G7.v85 TDB (1 mg / kg, 2 mg / kg, or 4 mg / kg) to three animals / group. Figures 31F-31H are plotted along with the group mean and standard error of the mean (SEM). [Figure 31I] 1 is a graph showing that 1G7.v85 TDB depletes bone marrow plasma cells in cynomolgus monkeys, where SEM measurements for the groups are plotted. [Figure 31J] Graph showing change in cynomolgus monkey IgG level response to treatment, calculated using the formula {(pre-dose IgG level)-(end-of-study IgG level)} / (pre-dose IgG) x 100. Differences between pre-dose and post-treatment are analyzed by unpaired t-test. The data are plotted along with group means and standard errors of the means (SEM). [Figure 32A] Figures 32A and 32B are graphs showing absolute CD4+ T cell counts in peripheral blood (Figure 32A) and CD8+ T cells (Figure 32B) in four animal groups after a single intravenous dose of vehicle, 1 mg / kg 1G7.v85 TDB, 2 mg / kg 1G7.v85 TDB, or 4 mg / kg 1G7.v85 TDB. [Figure 32B] Figures 32A and 32B are graphs showing absolute CD4+ T cell counts in peripheral blood (Figure 32A) and CD8+ T cells (Figure 32B) in four animal groups after a single intravenous dose of vehicle, 1 mg / kg 1G7.v85 TDB, 2 mg / kg 1G7.v85 TDB, or 4 mg / kg 1G7.v85 TDB. [Figure 32C] 1 is a graph showing the reduction in absolute numbers of CD20+ B cells in mesenteric lymph nodes following 1G7.v85 TDB treatment. The plot is graphed as individual animals and group means with SEM. [Figure 32D]1 is a graph showing FcRH5 occupancy following a single dose intravenous administration of 1G7.v85 TDB at 1 mg / kg, 2 mg / kg, or 4 mg / kg. [Figure 33A] Figures 33A-33F are graphs showing the changes in concentrations of cytokines IL-6 (Figure 33A), IL-2 (Figure 33B), IFN-γ (Figure 33C), IL-1Rα (Figure 33D), IL-5 (Figure 33E), and MCP-1 (Figure 33F) in four animal groups after single intravenous dose administration of vehicle, 1 mg / kg 1G7.v85 TDB, 2 mg / kg 1G7.v85 TDB, and 4 mg / kg 1G7.v85 TDB. [Figure 33B] Figures 33A-33F are graphs showing the changes in concentrations of cytokines IL-6 (Figure 33A), IL-2 (Figure 33B), IFN-γ (Figure 33C), IL-1Rα (Figure 33D), IL-5 (Figure 33E), and MCP-1 (Figure 33F) in four animal groups after single intravenous dose administration of vehicle, 1 mg / kg 1G7.v85 TDB, 2 mg / kg 1G7.v85 TDB, and 4 mg / kg 1G7.v85 TDB. [Figure 33C] Figures 33A-33F are graphs showing the changes in concentrations of cytokines IL-6 (Figure 33A), IL-2 (Figure 33B), IFN-γ (Figure 33C), IL-1Rα (Figure 33D), IL-5 (Figure 33E), and MCP-1 (Figure 33F) in four animal groups after single intravenous dose administration of vehicle, 1 mg / kg 1G7.v85 TDB, 2 mg / kg 1G7.v85 TDB, and 4 mg / kg 1G7.v85 TDB. [Figure 33D] Figures 33A-33F are graphs showing the changes in concentrations of cytokines IL-6 (Figure 33A), IL-2 (Figure 33B), IFN-γ (Figure 33C), IL-1Rα (Figure 33D), IL-5 (Figure 33E), and MCP-1 (Figure 33F) in four animal groups after single intravenous dose administration of vehicle, 1 mg / kg 1G7.v85 TDB, 2 mg / kg 1G7.v85 TDB, and 4 mg / kg 1G7.v85 TDB. [Figure 33E]Figures 33A-33F are graphs showing the changes in concentrations of cytokines IL-6 (Figure 33A), IL-2 (Figure 33B), IFN-γ (Figure 33C), IL-1Rα (Figure 33D), IL-5 (Figure 33E), and MCP-1 (Figure 33F) in four animal groups after single intravenous dose administration of vehicle, 1 mg / kg 1G7.v85 TDB, 2 mg / kg 1G7.v85 TDB, and 4 mg / kg 1G7.v85 TDB. [Figure 33F] Figures 33A-33F are graphs showing the changes in concentrations of cytokines IL-6 (Figure 33A), IL-2 (Figure 33B), IFN-γ (Figure 33C), IL-1Rα (Figure 33D), IL-5 (Figure 33E), and MCP-1 (Figure 33F) in four animal groups after single intravenous dose administration of vehicle, 1 mg / kg 1G7.v85 TDB, 2 mg / kg 1G7.v85 TDB, and 4 mg / kg 1G7.v85 TDB. [Figure 34]

[0023] Figure 1 is a series of plots showing that 1G7.v85 TDB treatment induces PD1 expression in human T cells. CD8+ T cells were stimulated with 1G7.v85 TDB and MOLP-2 target cells for 48 hours and analyzed by flow cytometry. [Figure 35A] 1 is a graph showing the percentage of PD1+ among CD8+ T cells in cynomolgus monkeys after single intravenous dose administration of vehicle, 1 mg / kg, 2 mg / kg, and 4 mg / kg of 1G7.v85 TDB. 1G7.v85 TDB treatment results in the induction of PD1 in cynomolgus monkey T cells in vivo. [Figure 35B] 1 is a graph showing the percentage of PD1+ among CD4+ T cells in cynomolgus monkeys after a single intravenous dose of vehicle, 1 mg / kg, 2 mg / kg, and 4 mg / kg of 1G7.v85 TDB. [Figure 36A] Figures 36A-36D are plots showing PD-1 expression on CD4+ T cells from blood (Figure 36A), CD8+ T cells from spleen (Figure 36B), CD8+ T cells from lymph nodes (Figure 36C), and CD8+ T cells from bone marrow (Figure 36D) as analyzed by FACS 7 days after dosing with 1G7.v85 TDB or vehicle. [Figure 36B] Figures 36A-36D are plots showing PD-1 expression on CD4+ T cells from blood (Figure 36A), CD8+ T cells from spleen (Figure 36B), CD8+ T cells from lymph nodes (Figure 36C), and CD8+ T cells from bone marrow (Figure 36D) as analyzed by FACS 7 days after dosing with 1G7.v85 TDB or vehicle. [Figure 36C] Figures 36A-36D are plots showing PD-1 expression on CD4+ T cells from blood (Figure 36A), CD8+ T cells from spleen (Figure 36B), CD8+ T cells from lymph nodes (Figure 36C), and CD8+ T cells from bone marrow (Figure 36D) as analyzed by FACS 7 days after dosing with 1G7.v85 TDB or vehicle. [Figure 36D] Figures 36A-36D are plots showing PD-1 expression on CD4+ T cells from blood (Figure 36A), CD8+ T cells from spleen (Figure 36B), CD8+ T cells from lymph nodes (Figure 36C), and CD8+ T cells from bone marrow (Figure 36D) as analyzed by FACS 7 days after dosing with 1G7.v85 TDB or vehicle. [Figure 37A] Figures 37A and 37B are graphs showing the ability of 1G7.v85 TDB to redirect the activity of pre-stimulated CD8+ T cells to kill HEK-293T cells expressing FcRH5 and PD-1 ("293-FcRH5-PD-L1 cells") in the presence or absence of anti-PD-L1 or anti-PD-1 antibodies. The curves in Figure 37A are graphed with the mean and standard error (SD) of triplicates. [Figure 37B] Figures 37A and 37B are graphs showing the ability of 1G7.v85 TDB to redirect the activity of pre-stimulated CD8+ T cells to kill HEK-293T cells expressing FcRH5 and PD-1 ("293-FcRH5-PD-L1 cells") in the presence or absence of anti-PD-L1 or anti-PD-1 antibodies. The curves in Figure 37A are graphed with the mean and standard error (SD) of triplicates. [Figure 38A]1 is a graph showing target cell killing of SVT2-FcRH5 by 1G7.v85 TDB in the presence or absence of dexamethasone (Dex). [Figure 38B] 1 is a series of graphs showing cytokine (i.e., IL-2, IL-6, TNF-α, and IFN-γ) release following treatment with 1G7.v85 TDB in the presence and absence of 1 μM Dex. [Figure 39] FIG. 1 is a schematic diagram showing the production of bis-Fab from human IgG1. [Figure 40A] 1 is a graph showing the binding of bis-Fab AD and F(ab')2 A to FcRH5 as determined by ELISA assay. [Figure 40B] 1 is a graph showing CD3 binding by bis-Fab AD and F(ab')2 A as determined by ELISA assay. [Figure 41] 1 is a graph showing the amount of target-mediated T cell activation by bis-Fab AD and F(ab')2A. DETAILED DESCRIPTION OF THE INVENTION

[0071] I. Definition The term "about" as used herein refers to a normal error range for the respective value, which is readily apparent to one of ordinary skill in the art. Reference herein to "about" a value or parameter includes (and describes) embodiments that are directed to the value or parameter itself.

[0072] For purposes herein, an "acceptor human framework" is a framework that comprises the amino acid sequence of a light chain variable domain (VL) framework or a heavy chain variable domain (VH) framework derived from a human immunoglobulin framework or a human consensus framework, as defined below. An acceptor human framework "derived from" a human immunoglobulin framework or a human consensus framework may comprise the same amino acid sequence thereto, or may contain amino acid sequence changes. In some embodiments, the number of amino acid changes is 10 or less, 9 or less, 8 or less, 7 or less, 6 or less, 5 or less, 4 or less, 3 or less, or 2 or less. In some embodiments, the VL acceptor human framework is identical in sequence to the VL human immunoglobulin framework sequence or the human consensus framework sequence.

[0073] "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, "binding affinity," as used herein, refers to the intrinsic binding affinity, which reflects a 1:1 interaction between members of a binding pair (e.g., an antibody and an antigen). The affinity of a molecule X for its partner Y is generally determined by the dissociation constant (K D ) Affinity can be measured by common methods known in the art, including those described herein. Specific illustrative and exemplary embodiments for measuring binding affinity are described below.

[0074] An "affinity matured" antibody refers to an antibody that has one or more alterations in one or more hypervariable regions (HVRs), compared to a parent antibody that does not possess those alterations, which alterations improve the affinity of the antibody for antigen.

[0075] The terms "anti-FcRH5 antibody" or "antibody that binds to FcRH5" refer to an antibody that can bind to FcRH5 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting FcRH5. In one embodiment, the extent to which an anti-FcRH5 antibody binds to an unrelated, non-FcRH5 protein is less than about 10% of the antibody's binding to FcRH5, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to FcRH5 has an affinity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g. 10 -8 M~10 -13 M, e.g. 10 -9 M~10 -13 Dissociation constant (K D In certain embodiments, the anti-FcRH5 antibody binds to an epitope of FcRH5 that is conserved among FcRH5 from different species.

[0076] The terms "anti-CD3 antibody" and "antibody that binds to CD3" refer to an antibody that can bind to CD3 with sufficient affinity such that the antibody is useful as a diagnostic and / or therapeutic agent in targeting CD3. In one embodiment, the extent to which an anti-CD3 antibody binds to an unrelated, non-CD3 protein is less than about 10% of the binding of the antibody to CD3, as measured, for example, by radioimmunoassay (RIA). In certain embodiments, an antibody that binds to CD3 has an affinity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g. 10 -8 M~10 -13 M, e.g. 10 -9 M~10 -13 Dissociation constant (K D In certain embodiments, the anti-CD3 antibody binds to an epitope of CD3 that is conserved among CD3 from different species.

[0077] The term "antibody" as used herein is used in the broadest sense and encompasses a variety of antibody structures, including, but not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), and antibody fragments (e.g., bis-Fab), so long as they exhibit the desired antigen-binding activity.

[0078] "Antibody fragment" refers to a molecule other than an intact antibody that contains a portion of an intact antibody that binds to the antigen to which the intact antibody binds. Examples of antibody fragments include, but are not limited to, bis-Fab, Fv, Fab, Fab, Fab'-SH, F(ab')2, diabodies, linear antibodies, single-chain antibody molecules (e.g., scFv), and multispecific antibodies formed from antibody fragments.

[0079] "Binding domain" refers to a portion of a compound or molecule that specifically binds to a target epitope, antigen, ligand, or receptor. Binding domains include, but are not limited to, antibodies (e.g., monoclonal, polyclonal, recombinant, humanized, and chimeric antibodies), antibody fragments or portions thereof (e.g., bis-Fab fragments, Fab fragments, F(ab')2, scFv antibodies, SMIPs, domain antibodies, diabodies, minibodies, scFv-Fc, affibodies, nanobodies, and antibody VH and / or VL domains), receptors, ligands, aptamers, and other molecules with identified binding partners.

[0080] As used herein, the term "charged region" refers to a position in a polypeptide (e.g., an antibody) that contains one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) basic or acidic amino acids and that can form a charge pair with a cognate charged region that also has one or more (e.g., 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10) basic or acidic amino acids, when the charged region and its cognate charged region have opposite overall relative charges.

[0081] As used herein, the term "charge pair" refers to a bond formed between two charged regions that have opposite overall charges.

[0082] A "chemotherapeutic agent" is a chemical compound useful in the treatment of cancer. Examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide (CYTOXAN®); alkyl sulfonates such as busulfan, improsulfan, and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethyleneimines including altretamine, triethylenemelamine, triethylenephosphoramide, triethylenethiophosphoramide, and trimethylmelamine; acetogenins (especially bullatacin and bullatacinone); delta-9-tetrahydrocannabinol (dronabinol, MARINOL®); beta-lapachone; lapachol; colchicine; betulinic acid; camptothecins (including synthetic analogs topotecan (HYCAMTIN®), CPT-11 (irinotecan, CAMPTOSAR®), acetylcamptothecin, scopolectin, and 9-aminocamptothecin); bryophyte Statins; callystatin; CC-1065 (including its synthetic analogs adozelesin, calzelesin, and bizelesin); podophyllotoxin; podophyllic acid; teniposide; cryptophycins (especially cryptophycin 1 and cryptophycin 8); dolastatins; duocarmycins (including synthetic analogs KW-2189 and CB1-TM1); eluterobin; pancratistatin; sarcodictyin; spongista nitrogen mustards, such as chlorambucil, chlornaphazine, chlorophosphamide, estramustine, ifosfamide, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, trofosfamide, uracil mustard; nitrosoureas, such as carmustine, chlorozotocin, fotemustine, lomustine, nimustine, and ranimnustine;Antibiotics, such as enediyne antibiotics (e.g., calicheamicin, particularly calicheamicin gamma 1I and calicheamicin omega II (see, e.g., Nicolaou et al. Angew. Chem Intl. Ed. Engl. 33:183-186, 1994); CDP323, an oral alpha 4 integrin inhibitor; dynemicins, including dynemicin A; esperamicin; and neocarzinostatin chromophores and related chromoprotein enediyne antibiotic chromophores), aclacinomycin, actinomycin, authramycin, azaserine, bleomycin, cactinomycin, carabimycin bicin), caminomycin, carzinophilin, chromomycin, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (ADRIAMYCIN®), morpholino-doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrolino-doxorubicin, doxorubicin HCl liposome injection (DOXIL®), liposomal doxorubicin TLC D-99 (MYOCET®), pegylated liposomal doxorubicin (including CAELYX® and deoxydoxorubicin), mitomycins such as epirubicin, esorubicin, idarubicin, marcelomycin, mitomycin C, mycophenolic acid, nogalamycin, olivomycin, peplomycin, porfiromycin, puromycin, quelamycin, rodorubicin, streptonigrin, streptozocin , tubercidin, ubenimex, zinostatin, zorubicin; antimetabolites such as methotrexate, gemcitabine (GEMZAR®), tegafur (UFTORAL®), capecitabine (XELODA®), epothilones, and 5-fluorouracil (5-FU); combretastatins; folic acid analogs such as denopterin, methotrexate, pteropterin, trimetrexate; purine analogs such as fludarabine, 6-mercaptopurine, thiamiprine, thioguanine;Pyrimidine analogues such as ancitabine, azacitidine, 6-azauridine, carmofur, cytarabine, dideoxyuridine, doxifluridine, enocitabine, and floxuridine; androgens such as calsterone, dromostanolone propionate, epithiostanol, mepitiostane, and testolactone; anti-adrenals such as aminoglutethimide, mitotane, and trilostane; florinic acid Folic acid supplements such as aceglatone; aldophosphamide glycosides; aminolevulinic acid; eniluracil; amsacrine; bestravcil; bisantrene; edatraxate; defofamine; demecolcine; diaziconazole; elformithine; elliptinium acetate; epothilone; etoglucide; gallium nitrate; hydroxyurea; lentinan; lonidainine; maytansinoids such as maytansine and ansamitocin; mitoguazone; mitoxantrone; mopidanmol; nitraerine; pentostatin; fenamet; pirarubicin; losoxantrone; 2-ethylhydrazide; procarbazine; PSK® polysaccharide complex (JHS Natural Products, Eugene, Oreg.); razoxane; rhizoxin; sizofuran; spirogermanium; tenuazonic acid; triazicon; 2,2',2'-trichlorotriethylamine; trichothecines (especially T-2 toxin, verracurin A, roridin A, and anguidine); urethane; vindesine (ELDISINE®, FILDESIN®); dacarbazine; mannomustine; mitobronitol; mitolactol; pipobroman; gacytosine; arabinoside ("Ara-C"); thiotepa;Taxoids, such as paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, NJ), albumin-engineered nanoparticle formulations of paclitaxel (ABRAXANE™), and docetaxel (TAXOTERE®, Rhome-Poulene) Rorer, Antony, France; chloranbucil; 6-thioguanine; mercaptopurine; methotrexate; platinum drugs such as cisplatin, oxaliplatin (e.g., ELOXATIN®), and carboplatin; vincas, including vinblastine (VELBAN®), vincristine (ONCOVIN®), vindesine (ELDISINE®, FILDESIN®), and vinorelbine (NAVELBINE®), which prevent tubulin polymerization from forming microtubules; etoposide (VP-16); ifosfamide; mitoxantrone; leucovorin; novantrone; edatrexate; daunomycin; aminopterin; ibandronate; the topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoids such as retinoic acid, including bexarotene (TARGRETIN®); clodronate (e.g., BONEFOS® or OSTAC®), etidronate (DIDROCAL®), NE-58095, zoledronic acid / zoledronate (ZOMETA®), alendronate (FOSAMAX®), pamidronate (AREDIA®), tiludronate (SKEL bisphosphonates such as bromocyclodopahexyl benzoate (BDC), bromocyclodopahexyl benzoate (BDC), or risedronate (ACTONEL®); troxacitabine (a 1,3-dioxolane nucleoside cytosine analog); antisense oligonucleotides, particularly those that inhibit the expression of genes in signaling pathways linked to abnormal cell proliferation, such as PKC alpha, Raf, H-Ras, and epidermal growth factor receptor (EGF-R) (e.g., erlotinib (Tarceva™)); and VEGF-A, which reduces cell proliferation;vaccines, such as THERATOPE® vaccines and gene therapy vaccines, e.g., ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; topoisomerase 1 inhibitors (e.g., LURTOTECAN®); rmRH (e.g., ABARELIX®); BAY439006 (sorafenib; Bayer); SU-11248 (sunitinib, SUTENT®, Pfizer); perifosine, COX-2 inhibitors (e.g., celecoxib or etoricoxib), proteosome inhibitors (e.g., PS341); bortezomib (VELCADE®); CCI-779; tipifarnib (R11577); orafenib, ABT510; Bcl-2 inhibitors such as oblimersen sodium (GENASENSE®); pixantrone; EGFR inhibitors; tyrosine kinase inhibitors; serine-threonine kinase inhibitors such as rapamycin (sirolimus, RAPAMUNE®); lonafarnib (SCH 6636, SARASAR™); and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of the above, such as CHOP (an abbreviation for the combination therapy of cyclophosphamide, doxorubicin, vincristine, and prednisolone); and FOLFOX (an abbreviation for the treatment regimen of oxaliplatin (ELOXATIN™) in combination with 5-FU and leucovorin), and pharmaceutically acceptable salts, acids, or derivatives of any of the above; and combinations of two or more of the above;

[0083] Chemotherapeutic agents, as defined herein, include "antihormonal agents" or "endocrine therapeutic agents" that act to regulate, reduce, block, or inhibit the action of hormones that can promote cancer growth. As such, they include antiestrogens and selective estrogen receptor modulators (SERMs), including, for example, tamoxifen (including NOLVADEX® tamoxifen), raloxifene, droloxifene, 4-hydroxytamoxifen, trioxifene, ketoxifene, LY117018, onapristone, and FARESTON.cndot. toremifene; aromatase inhibitors, which inhibit aromatase, an enzyme that controls estrogen production in the adrenal glands, such as 4-hydroxy-2-methyl-2-propanol; (5)-imidazoles, aminoglutethimide, MEGASE® megestrol acetate, AROMASIN® exemestane, formestanie, fadrozole, RIVISOR® vorozole, FEMARA® letrozole, and ARIMIDEX® anastrozole; and antiandrogens, such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and troxacitabi antisense oligonucleotides, particularly those that inhibit the expression of genes in signal transduction pathways linked to aberrant cell proliferation, such as PKC alpha, Raf, and H-Ras; ribozymes such as VEGF expression inhibitors (e.g., ANGIOZYME® ribozyme) and HER2 expression inhibitors; vaccines, such as gene therapy vaccines, for example, ALLOVECTIN® vaccine, LEUVECTIN® vaccine, and VAXID® vaccine; PROLEUKIN® rIL-2; LURTOTECAN® topoisomerase 1 inhibitors; ABARELIX® rmRH; vinorelbine and esperamicin (see U.S. Pat. No. 4,675,187), as well as pharmaceutically acceptable salts, acids, or derivatives of any of the foregoing; and hormones, including, but not limited to, combinations of two or more of the foregoing.

[0084] The term "immunomodulatory agent" or "IMiD" refers to a class of drugs that modify immune system responses or immune system function, such as by stimulating antibody formation and / or inhibiting peripheral blood cell activity, and includes, but is not limited to, thalidomide (α-N-phthalimido-glutarimide) and its analogs, REVLIMID® (lenalidomide), ACTI-MID™ (pomalidomide), OTEZLA® (apremilast), and pharmaceutically acceptable salts or acids thereof.

[0085] The term "chimeric" antibody refers to an antibody in which a portion of the heavy and / or light chain is derived from a particular source or species, and the remainder of the heavy and / or light chain is derived from a different source or species.

[0086] The term "FcRH5" as used herein refers to any native FcRH5 resulting from the production of FcRH5 protein in a cell. The term includes FcRH5 from any vertebrate source, including mammals such as primates (e.g., humans and cynomolgus monkeys) and rodents (e.g., mice and rats), unless otherwise indicated. The term also includes naturally occurring variants of FcRH5, such as splice variants or allelic variants. The amino acid sequence of an exemplary human FcRH5 protein sequence is set forth in SEQ ID NO: 114. The amino acid sequence of an exemplary cynomolgus monkey FcRH5 protein is set forth in SEQ ID NO: 215.

[0087] As used herein, the term "cluster of differentiation 3" or "CD3," unless otherwise indicated, refers to any native CD3 from any vertebrate source, including mammals such as primates (e.g., humans) and rodents (e.g., mice and rats), including, for example, the CD3ε, CD3γ, CD3α, and CD3β chains. The term encompasses "full-length" unprocessed CD3 (e.g., unprocessed or unmodified CD3ε or CD3γ) as well as any form of CD3 resulting from processing in cells. The term also encompasses naturally occurring variants of CD3, including, for example, splice variants or allelic variants. CD3 includes, for example, the 207-amino acid long human CD3ε protein (NCBI Reference SEQ ID NO: NP_000724) and the 182-amino acid long human CD3γ protein (NCBI Reference SEQ ID NO: NP_000064).

[0088] The "class" of an antibody refers to the type of constant domain or constant region possessed by its heavy chain. There are five major classes of antibodies: IgA, IgD, IgE, IgG, and IgM, and some of these can be further divided into subclasses (isotypes), e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2. The heavy-chain constant domains corresponding to the different classes of immunoglobulins are called α, δ, ε, γ, and μ, respectively.

[0089] It is understood that aspects and embodiments of the invention described herein include "comprising," "consisting of," and "consisting essentially of" aspects and embodiments.

[0090] The term "cytotoxic agent," as used herein, refers to a substance that inhibits or prevents the function of cells and / or causes the death or destruction of cells. Cytotoxic agents include radioisotopes (e.g., At 211 , I 131 , I 125 , Y 90 ,Re 186 ,Re188 , Sm 153 , Bi 212 , P 32 , Pb 212 , and radioactive isotopes of Lu); chemotherapeutic agents or drugs (e.g., methotrexate, adriamycin, vinca alkaloids (vincristine, vinblastine, etoposide), doxorubicin, melphalan, mitomycin C, chlorambucil, daunorubicin, or other intercalating agents); growth inhibitory agents; enzymes and fragments thereof, such as nucleases; antibiotics; toxins, such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant, or animal origin, including fragments and / or variants thereof; and various anti-tumor or anti-cancer agents disclosed below.

[0091] A "disorder" is any condition that would benefit from treatment, including, but not limited to, chronic and acute disorders or diseases, including pathological conditions that predispose a mammal to the disorder in question.

[0092] The terms "cell proliferative disorder" and "proliferative disorder" refer to disorders associated with some degree of abnormal cell proliferation. In one embodiment, the cell proliferative disorder is cancer. In one embodiment, the cell proliferative disorder is a tumor.

[0093] The terms "cancer" and "cancerous" refer to or describe the physiological condition in mammals that is typically characterized by unregulated cell growth / proliferation. Examples of cancer include, but are not limited to, myeloma, carcinoma, lymphoma (e.g., Hodgkin's and non-Hodgkin's lymphoma), blastoma, sarcoma, and leukemia. In some embodiments, the cancer is an FcRH5-positive cancer. More specific examples of such cancers include multiple myeloma (MM), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), chronic myelogenous leukemia (CML), chronic myelomonocytic leukemia, acute promyelocytic leukemia (APL), chronic myeloproliferative disorders, thrombocytosis, precursor B-cell acute lymphoblastic leukemia (pre-B-ALL), precursor T-cell acute lymphoblastic leukemia (pre-T-ALL), mastocytosis, mast cell leukemia, mast cell sarcoma, myeloid sarcoma, lymphocytic leukemia, and undifferentiated leukemia. In some embodiments, the cancer is a B-cell cancer. In particular, cancer can include conditions involving excess antibody production, such as monoclonal gammopathy, light chain amyloidosis, monoclonal gammopathy of undetermined significance, and solitary plasmacytoma, solitary plasmacytoma, and extramedullary plasmacytoma.

[0094] As used herein, "tumor" refers to all neoplastic cell growth and proliferation, whether malignant or benign, and all pre-cancerous and cancerous cells and tissues. The terms "cancer," "cancerous," "cell proliferative disorder," "proliferative disorder," and "tumor" are not mutually exclusive when referred to herein.

[0095] "Effector function" refers to a biological activity attributable to the Fc region of an antibody, which varies depending on the antibody isotype. Examples of antibody effector functions include C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding; antibody-dependent cell-mediated cytotoxicity (ADCC); phagocytosis; down-regulation of cell surface receptors (e.g., B cell receptors); and B cell activation.

[0096] An "effective amount" of a compound, e.g., an anti-FcRH5 antibody of the present invention, or a composition thereof (e.g., a pharmaceutical composition) is at least the minimum amount required to achieve a desired therapeutic or prophylactic result, such as a measurable improvement or prevention of a particular disorder (e.g., a cell proliferative disorder, e.g., cancer). The effective amount herein may vary depending on factors such as the patient's condition, age, sex, and weight, and the ability of the antibody to elicit a desired response in the individual. An effective amount is also one in which any toxic or adverse effects of the treatment are outweighed by the therapeutically beneficial effects. In the case of prophylactic use, beneficial or desired results include results such as eliminating or reducing the risk of disease, reducing the severity of disease, or delaying the onset of disease, including biochemical, histological, and / or behavioral symptoms of disease, its complications, and intermediate pathological phenotypes manifest during disease development. For therapeutic use, beneficial or desired results include clinical results such as a reduction in one or more symptoms resulting from the disease, an improvement in the quality of life of the person suffering from the disease, a reduction in the dose of other drugs required to treat the disease, an enhancement of the effect of another drug by targeting or the like, a delay in disease progression, and / or an increase in survival time. In the case of cancer or tumors, an effective amount of a drug may be effective in reducing the number of cancer cells; reducing tumor size; inhibiting (i.e., slowing to some extent, and preferably stopping) the infiltration of cancer cells into peripheral organs; inhibiting (i.e., slowing to some extent, and preferably stopping) tumor metastasis; inhibiting to some extent tumor growth; and / or alleviating to some extent one of the abnormal symptoms associated with the disorder. An effective amount may be administered in one or more administrations. For purposes of this invention, an effective amount of a drug, compound, or pharmaceutical composition is an amount sufficient to directly or indirectly achieve prophylactic or therapeutic treatment. As understood in the clinical field, an effective amount of a drug, compound, or pharmaceutical composition may or may not be achieved in conjunction with another drug, compound, or pharmaceutical composition. Thus, an "effective amount" can be considered in relation to administering one or more therapeutic agents, and a single agent can be considered to be given in an effective amount if, in conjunction with one or more other agents, a desired result can be or is achieved.

[0097] The term "Fc region" as used herein defines the C-terminal region of an immunoglobulin heavy chain comprising at least a portion of the constant region. This term includes native-sequence Fc regions and variant Fc regions. In one embodiment, a human IgG heavy chain Fc region extends from Cys226, or from Pro230, to the carboxyl terminus of the heavy chain. However, the C-terminal lysine (Lys447) of the Fc region may or may not be present. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region or constant region is according to the EU numbering system, also known as the EU index, as described in Kabat et al., "Sequences of Proteins of Immunological Interest," 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0098] "Framework" or "FR" refers to variable domain residues other than hypervariable region (HVR) residues. The FR of a variable domain generally consists of four FR domains, FR1, FR2, FR3, and FR4. Thus, the HVR and FR sequences generally appear in VH (or VL) in the following order: FR1-H1(L1)-FR2-H2(L2)-FR3-H3(L3)-FR4.

[0099] The term "FcRH5-positive cell" refers to a cell that expresses FcRH5 on its surface. In some embodiments, the FcRH5 is one or more of FcRH5a, FcRH5b, FcRH5c, UniProt identifier Q96RD9-2, and / or FcRH5d. In some embodiments, the FcRH5 is FcRH5c.

[0100] The term "FcRH5-positive cancer" refers to a cancer comprising cells that express FcRH5 on their surface. To determine whether a cell expresses FcRH5 on its surface, FcRH5 mRNA expression is considered to correlate with FcRH5 expression on the cell surface. In some embodiments, FcRH5 mRNA expression is quantified by a method selected from in situ hybridization and RT-PCR (including quantitative RT-PCR). Alternatively, FcRH5 expression on the cell surface may be quantified using an antibody against FcRH5 in methods such as immunohistochemistry, FACS, etc. In some embodiments, FcRH5 is one or more of FcRH5a, FcRH5b, FcRH5c, UniProt identifier Q96RD9-2, and / or FcRH5d. In some embodiments, FcRH5 is FcRH5c.

[0101] 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 native antibody or an antibody having a heavy chain that includes an Fc region as defined herein.

[0102] The term "glycosylated form of FcRH5" refers to a naturally occurring form of FcRH5 that has been post-translationally modified by the addition of carbohydrate residues.

[0103] As used herein, a "growth inhibitory agent" refers to a compound or composition that inhibits cell growth either in vitro or in vivo. In one embodiment, the growth inhibitory agent is a growth inhibitory antibody that prevents or reduces proliferation of cells expressing the antigen to which the antibody binds. In another embodiment, the growth inhibitory agent can significantly reduce the proportion of cells in S phase. Examples of growth inhibitory agents include agents that block cell cycle progression (outside of S phase), such as agents that induce G1 arrest and M-phase arrest. Classical M-phase blockers include vincas (vincristine and vinblastine), taxanes, and topoisomerase II inhibitors such as doxorubicin, epirubicin, daunorubicin, etoposide, and bleomycin. Agents that arrest G1, such as DNA alkylating agents such as tamoxifen, prednisone, dacarbazine, mechlorethamine, cisplatin, methotrexate, 5-fluorouracil, and ara-C, also induce S-phase arrest. Further information can be found in Murakami et al., Mendelsohn and Israel, eds., The Molecular Basis of Cancer, Chapter 1, entitled "Cell cycle regulation, oncogenes, and antitineoplastic drugs" (WB Saunders, Philadelphia, 1995), e.g., p. 13. Taxanes (paclitaxel and docetaxel) are anticancer drugs, both derived from the yew tree. Docetaxel (TAXOTERE®, Rhone-Poulenc Rorer), derived from the European yew, is a semisynthetic analog of paclitaxel (TAXOL®, Bristol-Myers Squibb). Paclitaxel and docetaxel promote the assembly of microtubules from tubulin dimers, stabilize microtubules by preventing depolymerization, and inhibit cell mitosis.

[0104] The terms "host cell," "host cell line," and "host cell culture" are used interchangeably and refer to cells into which exogenous nucleic acid has been introduced, including the progeny of such cells. Host cells include "transformants" and "transformed cells," which include the primary transformed cell and its progeny regardless of the number of passages. The progeny may not be completely identical in nucleic acid content to the parent cell and may contain mutations. Mutant progeny that have the same function or biological activity as screened or selected for in the originally transformed cell are included herein.

[0105] A "human antibody" is one having an amino acid sequence corresponding to that of an antibody produced by a human or human cell, or an antibody derived from a non-human source using a human antibody repertoire, or other human antibody coding sequence. This definition of a human antibody specifically excludes humanized antibodies, which contain non-human antigen-binding residues. Human antibodies can be produced using a variety of 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 described in Cole et al., Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, p. 77 (1985); Boerner et al., J. Immunol., 147(1):86-95, 1991, can also be used to prepare human monoclonal antibodies. See also van Dijk and van de Winkel. Curr. Opin. Pharmacol. 5:368-74, 2001. Human antibodies can be prepared by administering antigen to transgenic animals, e.g., immunized xenomice, that have been engineered to produce such antibodies in response to antigen challenge but have their endogenous gene loci disabled (see, e.g., U.S. Pat. Nos. 6,075,181 and 6,150,584 for XENOMOUSE™ technology). See also, e.g., Li et al. Proc. Natl. Acad. Sci. USA. 103:3557-3562, 2006 for human antibodies generated by human B cell hybridoma technology.

[0106] A "human consensus framework" is a framework that represents the most commonly occurring amino acid residues in the selection of human immunoglobulin VL or VH framework sequences. Generally, the selection of human immunoglobulin VL or VH sequences is made from a subgroup of variable domain sequences. Generally, the subgroup of sequences is a subgroup as in Kabat et al., Sequences of Proteins of Immunological Interest, Fifth Edition, NIH Publication 91-3242, Bethesda, MD (1991), vols. 1-3. In one embodiment, for VL, the subgroup is subgroup kappa I as in Kabat et al., supra. In one embodiment, for VH, the subgroup is subgroup III as in Kabat et al., supra.

[0107] A "humanized" antibody refers to a chimeric antibody comprising amino acid residues from non-human HVRs and amino acid residues from human FRs. In certain embodiments, a humanized antibody comprises substantially all of at least one, and typically two, variable domains, in which all or substantially all of its HVRs (e.g., CDRs) correspond to those of a non-human antibody and all or substantially all of its FRs correspond to those of a human antibody. A humanized antibody may optionally comprise at least a portion of an antibody constant region derived from a human antibody. A "humanized form" of an antibody, e.g., a non-human antibody, refers to an antibody that has undergone humanization.

[0108] The term "hypervariable region" or "HVR" as used herein refers to each of the regions of an antibody variable domain where the sequence is hypervariable ("complementarity determining regions" or "CDRs") and / or which form structurally defined loops ("hypervariable loops") and / or which contain antigen-bearing residues ("antigen contacts"). Antibodies generally contain six HVRs: three in the VH (H1, H2, H3) and three in the VL (L1, L2, L3). Exemplary HVRs herein include the following: (a) hypervariable loops occurring at amino acid residues 26-32 (L1), 50-52 (L2), 91-96 (L3), 26-32 (H1), 53-55 (H2), and 96-101 (H3) (Chothia and Lesk, J. Mol. Biol. 196:901-917, 1987); (b) CDRs occurring at amino acid residues 24-34 (L1), 50-56 (L2), 89-97 (L3), 31-35b (H1), 50-65 (H2), and 95-102 (H3) (Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed., Public Health Service, National Institutes of Health, Bethesda, MD (1991)); (c) antigenic contacts occurring at amino acid residues 27c-36 (L1), 46-55 (L2), 89-96 (L3), 30-35b (H1), 47-58 (H2), and 93-101 (H3) (MacCallum et al. J. Mol. Biol. 262:732-745, 1996), and (d) A combination of (a), (b), and / or (c) comprising HVR amino acid residues 46-56 (L2), 47-56 (L2), 48-56 (L2), 49-56 (L2), 26-35 (H1), 26-35b (H1), 49-65 (H2), 93-102 (H3), and 94-102 (H3).

[0109] Unless otherwise indicated, HVR residues and other residues in the variable domain (e.g., FR residues) are numbered herein according to Kabat et al. (supra).

[0110] An "immunoconjugate" is an antibody conjugated to one or more heterologous molecule(s), including, but not limited to, a cytotoxic agent.

[0111] A "subject" or "individual" is a mammal. Mammals include, but are not limited to, domestic animals (e.g., cows, sheep, cats, dogs, and horses), primates (e.g., humans and non-human primates such as monkeys), rabbits, and rodents (e.g., mice and rats). In certain embodiments, the subject or individual is a human.

[0112] An "isolated" antibody is one that is separated from components of its natural environment. In some embodiments, the antibody is purified to greater than 95% or 99% purity, for example, as determined by electrophoresis (e.g., SDS-PAGE, isoelectric focusing (IEF), capillary electrophoresis) or chromatography (e.g., ion exchange or reverse-phase HPLC). For a review of methods for assessing antibody purity, see, e.g., Flatman et al. J. Chromatogr. B 848:79-87, 2007.

[0113] An "isolated" nucleic acid refers to a nucleic acid molecule that has been separated from a component of its natural environment. Isolated nucleic acid includes a nucleic acid molecule contained in cells that normally contain the nucleic acid molecule, but where the nucleic acid molecule is present extrachromosomally or in a chromosomal location that is different from its natural chromosomal location.

[0114] An "isolated nucleic acid encoding an anti-FcRH5 antibody" refers to one or more nucleic acid molecules encoding the antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and including such nucleic acid molecule(s) present in one or more locations within a host cell.

[0115] An "isolated nucleic acid encoding an anti-CD3 antibody" refers to one or more nucleic acid molecules encoding the antibody heavy and light chains (or fragments thereof), including such nucleic acid molecule(s) in a single vector or separate vectors, and including such nucleic acid molecule(s) present in one or more locations within a host cell.

[0116] As used herein, the term "monoclonal antibody" refers to an antibody obtained from a population of substantially homogeneous antibodies. That is, except for possible variant antibodies, including, for example, naturally occurring mutations or arising during the generation of a monoclonal antibody preparation (such variants are generally present in minor amounts), each individual antibody within the population is identical and / or binds to the same epitope. In contrast to polyclonal antibody preparations, which typically contain different antibodies directed against different determinants (epitopes), each monoclonal antibody of a monoclonal antibody preparation is directed against a single determinant on an antigen. Thus, the modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous antibody population and is not to be construed as requiring production of the antibody by any particular method. For example, monoclonal antibodies used in accordance with the present invention can be produced by a variety of techniques, including, but not limited to, hybridoma methods, recombinant DNA methods, phage display methods, and methods using transgenic animals containing all or part of the human immunoglobulin loci; such methods and other exemplary methods for producing monoclonal antibodies are described herein.

[0117] A "naked antibody" refers to an antibody that is not conjugated to a heterologous moiety (e.g., a cytotoxic moiety) or a radiolabel. The naked antibody may be present in a pharmaceutical formulation.

[0118] "Native antibodies" refer to naturally occurring immunoglobulin molecules with various structures. For example, native IgG antibodies are heterotetrameric glycoproteins of approximately 150,000 daltons composed of two identical light chains and two identical heavy chains that are disulfide-bonded. From the N-terminus to the C-terminus, each heavy chain has a variable region (VH), also called a variable heavy domain or a heavy chain variable domain, followed by three constant domains (CH1, CH2, and CH3). Similarly, from the N-terminus to the C-terminus, each light chain has a variable region (VL), also called a variable light domain or a light chain variable domain, followed by a constant light (CL) domain. The light chain of an antibody can be assigned to one of two types, called kappa (κ) or lambda (λ), based on the amino acid sequence of its constant domain.

[0119] The term "package insert" is used to refer to instructions customarily included in commercial packaging of a therapeutic product that contain information regarding the indications, uses, dosages, administration, concomitant therapy, contraindications, and / or warnings regarding its use.

[0120] The term "PD-1 axis-binding antagonist" refers to a molecule that inhibits the interaction of a PD-1 axis binding partner with one or more of its binding partners to eliminate T cell dysfunction resulting from signaling in the PD-1 signaling axis, thereby restoring or enhancing T cell function (e.g., proliferation, cytokine production, target cell killing). As used herein, PD-1 axis-binding antagonists include PD-1 binding antagonists, PD-L1 binding antagonists, and PD-L2 binding antagonists.

[0121] The term "PD-1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-1 with one or more of its binding partners, e.g., PD-L1, PD-L2. In some embodiments, a PD-1 binding antagonist is a molecule that inhibits the binding of PD-1 to one or more of its binding partners. In specific embodiments, a PD-1 binding antagonist inhibits the binding of PD-1 to PD-L1 and / or PD-L2. For example, PD-1 binding antagonists include anti-PD-1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or prevent signaling resulting from the interaction of PD-1 with PD-L1 and / or PD-L2. In one embodiment, the PD-1 binding antagonist mediates signaling through PD-1 to reduce negative costimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes, so as to render dysfunctional T cells less dysfunctional (e.g., enhance effector responses to antigen recognition). In some embodiments, the PD-1 binding antagonist is an anti-PD-1 antibody. In a specific embodiment, the PD-1 binding antagonist is MDX-1106 (nivolumab). In another specific embodiment, the PD-1 binding antagonist is MK-3475 (pembrolizumab). In another specific embodiment, the PD-1 binding antagonist is CT-011 (pidilizumab). In another specific embodiment, the PD-1 binding antagonist is AMP-224. In another specific embodiment, the PD-1 binding antagonist is MED1-0680. In another specific embodiment, the PD-1 binding antagonist is PDR001. In another specific embodiment, the PD-1 binding antagonist is REGN2810. In another specific embodiment, the PD-1 binding antagonist is BGB-108.

[0122] The term "PD-L1 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-L1 with one or more of its binding partners, e.g., PD-1 and B7-1. In some embodiments, a PD-L1 binding antagonist is a molecule that inhibits the binding of PD-L1 to its binding partners. In a specific embodiment, a PD-L1 binding antagonist inhibits the binding of PD-L1 to PD-1 and / or B7-1. In some embodiments, PD-L1 binding antagonists include anti-PD-L1 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or prevent signaling resulting from the interaction of PD-L1 with one or more of its binding partners, e.g., PD-1 and B7-1. In one embodiment, the PD-L1 binding antagonist mediates signaling through PD-L1 to reduce negative costimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes, so as to render dysfunctional T cells less dysfunctional (e.g., enhance the effector response to antigen recognition). In some embodiments, the PD-L1 binding antagonist is an anti-PD-L1 antibody. In yet another specific embodiment, the anti-PD-L1 antibody is MPDL3280A (atezolizumab, marketed as TECENTRIQ™ in WHO Drug Information (International Nonproprietary Names for Pharmaceutical Substances), Recommended INN:List 74, Vol. 29, No. 3, 2015 (see page 387)). In a specific embodiment, the anti-PD-L1 antibody is YW243.55.S70. In another specific embodiment, the anti-PD-L1 antibody is MDX-1105. In another specific embodiment, the anti-PD-L1 antibody is MSB0015718C. In yet another specific embodiment, the anti-PD-L1 antibody is MEDI4736.

[0123] The term "PD-L2 binding antagonist" refers to a molecule that reduces, blocks, inhibits, abrogates, or prevents signaling resulting from the interaction of PD-L2 with one or more of its binding partners, e.g., PD-2. In some embodiments, a PD-L2 binding antagonist is a molecule that inhibits the binding of PD-L2 to one or more of its binding partners. In a specific embodiment, a PD-L2 binding antagonist inhibits the binding of PD-L2 to PD-1. In some embodiments, PD-L2 antagonists include anti-PD-L2 antibodies, antigen-binding fragments thereof, immunoadhesins, fusion proteins, oligopeptides, and other molecules that reduce, block, inhibit, abrogate, or prevent signaling resulting from the interaction of PD-L2 with one or more of its binding partners, e.g., PD-1. In one embodiment, the PD-L2 binding antagonist mediates signaling through PD-L2 to reduce negative costimulatory signals mediated by or through cell surface proteins expressed on T lymphocytes, so as to render dysfunctional T cells less dysfunctional (e.g., enhance the effector response to antigen recognition). In some embodiments, the PD-L2 binding antagonist is an immunoadhesin.

[0124] The term "protein," as used herein, unless otherwise indicated, refers to 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 encompasses "full-length," unprocessed proteins, as well as any form of protein that results from processing in a cell. The term also encompasses naturally occurring variants of the protein, such as splice variants or allelic variants.

[0125] "Percent (%) amino acid sequence identity" to a reference polypeptide sequence is defined as the percentage of amino acid residues in a candidate sequence that are identical to those in the reference polypeptide sequence, after aligning the sequences and introducing gaps as necessary to achieve the maximum percent sequence identity, not counting any conservative substitutions as part of the sequence identity. Alignment for purposes of determining percent amino acid sequence identity can be achieved in a variety of ways within the skill of the art, 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 algorithms necessary to achieve maximum alignment across the entire length of the sequences being compared. However, for purposes herein, percent amino acid sequence identity values ​​are generated using the sequence comparison computer program ALIGN-2. The ALIGN-2 sequence comparison computer program was created by Genentech, Inc., and the source code, together with user documentation, has been submitted to the U.S. Copyright Office (Washington, DC, 20559) and is registered under U.S. Copyright Registration No. TXU510087. The ALIGN-2 program is publicly available through Genentech, Inc., South San Francisco, California, or can be compiled from the source code. The ALIGN-2 program must 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 do not vary.

[0126] In situations where ALIGN-2 is used for amino acid sequence comparison, the % amino acid sequence identity of a given amino acid sequence A to, with, or against a given amino acid sequence B (which can alternatively be expressed as a given amino acid sequence A having or comprising a certain % amino acid sequence identity to, with, or against a given amino acid sequence B) is calculated as follows: 100 x fraction X / Y (where X is the number of amino acid residues in an alignment of A and B by the sequence alignment program ALIGN-2 that are scored as perfect matches by the program, and Y is the total number of amino acid residues in B.) It will be understood that if the length of amino acid sequence A is not equal to the length of amino acid sequence B, then the % amino acid sequence identity of A to B will not be equal to the % amino acid sequence identity of B to A. Unless expressly stated otherwise, all % amino acid sequence identity values ​​used herein were obtained using the ALIGN-2 computer program as described in the immediately preceding paragraph.

[0127] The term "pharmaceutical formulation" refers to a preparation that is in a form such that the biological activity of the active ingredient contained therein is effective and that does not contain additional ingredients that are unacceptably toxic to the subject to which the formulation is administered.

[0128] A "pharmaceutically acceptable carrier" refers to an ingredient, other than an active ingredient, in a pharmaceutical formulation that is non-toxic to a subject. Pharmaceutically acceptable carriers include, but are not limited to, buffers, excipients, stabilizers, or preservatives.

[0129] 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 performed prophylactically or during the clinical pathological course. Desirable effects of treatment include, but are not limited to, prevention of disease onset or recurrence, alleviation of symptoms, reduction of any direct or indirect pathological consequence of the disease, prevention of metastasis, reduction in the rate of disease progression, remission or reduction of the disease state, and remission or improved prognosis. In some embodiments, the antibodies of the invention are used to delay the onset of disease or slow the progression of disease.

[0130] As used herein, "delaying the progression" of a disorder or disease means postponing, preventing, slowing, retarding, stabilizing, and / or postponing the onset of the disease or disorder (e.g., a cell proliferative disorder, e.g., cancer). The delay can be of varying duration depending on the history of the disease and / or the individual being treated. As will be apparent to one of skill in the art, a sufficient or significant delay can, in effect, encompass prevention, in that the individual does not develop the disease. For example, late-stage cancer, such as the onset of metastases, can be delayed.

[0131] The term "epitope" refers to a specific site on an antigen molecule to which an antibody binds. In some embodiments, the specific site on an antigen molecule to which an antibody binds is determined by hydroxyl radical footprinting (e.g., the FcRH5 binding domain). In some embodiments, the specific site on an antigen molecule to which an antibody binds is determined by crystallography.

[0132] "Reducing" or "inhibiting" refers to the ability to cause an overall decrease, for example, of 20% or more, 50% or more, or 75%, 85%, 90%, 95% or more. In certain embodiments, reducing or inhibiting may refer to antibody effector functions mediated by the Fc region of the antibody, including complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), and antibody-dependent cellular phagocytosis (ADCP).

[0133] The term "variable region" or "variable domain" refers to the domain of an antibody heavy or light chain that is involved in binding the antibody to an antigen. The variable domains of the heavy and light chains (VH and VL, respectively) of a natural antibody generally have a similar structure, with each domain containing four conserved framework regions (FR) and three hypervariable regions (HVR). (See, e.g., Kindt et al., Kuby Immunology, 6 th (See, e.g., W.H. Freeman and Co., page 91 (2007).) A single VH or VL domain may be sufficient to confer antigen-binding specificity. Furthermore, antibodies that bind to a specific antigen may be isolated using the VH or VL domain of an antibody that binds to that antigen to screen a library of complementary VL or VH domains, respectively. See, e.g., Portolano et al. J. Immunol. 150:880-887, 1993; Clarkson et al. Nature 352:624-628, 1991.

[0134] A "variant Fc region" comprises an amino acid sequence that differs from that of a native-sequence Fc region by at least one amino acid modification, preferably one or more amino acid substitution(s). Preferably, the variant Fc region comprises at least one amino acid substitution, e.g., about one to about ten amino acid substitutions, preferably about one to about five amino acid substitutions, in the native-sequence Fc region or the Fc region of the parent polypeptide compared to the native-sequence Fc region or the Fc region of the parent polypeptide. A variant Fc region herein preferably has at least about 80% homology with the native-sequence Fc region and / or the Fc region of the parent polypeptide, most preferably at least about 90% homology thereto, and more preferably at least about 95% homology thereto.

[0135] As used herein, the term "vector" refers to a nucleic acid molecule capable of propagating another nucleic acid to which it is linked. The term includes vectors as self-replicating nucleic acid structures as well as vectors that integrate into the genome of a host cell into which they are introduced. Certain vectors are capable of directing the expression of nucleic acids to which they are operatively linked. Such vectors are referred to herein as "expression vectors."

[0136] As used herein, "administering" refers to a method of providing a subject with a dosage of a compound (e.g., an anti-FcRH5 antibody of the present invention, or a nucleic acid encoding an anti-FcRH5 antibody of the present invention) or composition (e.g., a pharmaceutical composition, e.g., a pharmaceutical composition comprising an anti-FcRH5 antibody of the present invention). The compositions used in the methods described herein can be administered, for example, intramuscularly, intravenously, intradermally, transdermally, intra-arterially, intraperitoneally, intralesionally, intracranially, intra-articularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intratumorally, subcutaneously, subconjunctivally, intravesicularly, mucosally, intrapericardially, intraumbilically, intraocularly, orally, topically, locally, by inhalation, by injection, by infusion, by continuous infusion, by local perfusion directly bathing target cells, by catheter, by lavage, in a lipid composition. The method of administration can vary depending on various factors, such as the compound or composition being administered and the severity of the condition, disease, or disorder being treated.

[0137] II. Compositions and Methods In one aspect, the present invention is based, in part, on an anti-FcRH5 antibody. In certain embodiments, the anti-FcRH5 antibody is multispecific (e.g., bispecific) and binds to FcRH5 or a fragment thereof, as well as a second biomolecule (e.g., a cell surface antigen, e.g., a T cell marker, e.g., CD3 (e.g., CD3ε and / or CD3γ)). The antibodies of the present invention are useful, for example, for diagnosing and / or treating or delaying the progression of a cell proliferative disorder (e.g., cancer, e.g., an FcRH5-positive cancer, e.g., multiple myeloma) in a subject.

[0138] A. Exemplary Anti-FcRH5 Antibodies In one aspect, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 2; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 3; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 4; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 5; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 6.

[0139] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23. In some cases, the anti-FcRH5 antibody comprises a heavy chain variable (VH) amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 104, or the sequence of SEQ ID NO: 104. The anti-FcRH5 antibody may have a light chain variable (VL) domain and / or an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or comprising the sequence of, SEQ ID NO: 105. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 54, 46, and 47, respectively. In some cases, the anti-FcRH5 antibody may have a heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 104. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 57, 50, and 51, respectively. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 105. In particular cases, the anti-FcRH5 antibody may be a relative of 1G7.v85, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 104; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 105.

[0140] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 10; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23. In some cases, an anti-FcRH5 antibody may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 106, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 107. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 53, 54, 46, and 47, respectively. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 106. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 57, 50, and 51, respectively. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 107. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v93, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 106; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 107.

[0141] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 82, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 83. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 82. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 83. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 82; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 83.

[0142] In some cases, the anti-FcRH5 antibody comprises a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21. In some cases, the anti-FcRH5 antibody comprises a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 84, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 85. In some cases, the anti-FcRH5 antibody further comprises heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 of SEQ ID NOs: 52, 54, 46, and 47, respectively. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 84. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 57, 50, and 51, respectively. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 85. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1.1, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 84 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 85.

[0143] In some instances, the anti-FcRH5 antibody has a binding domain comprising six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 17; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22. In some cases, the anti-FcRH5 antibody comprises a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 86, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 87. In some cases, the anti-FcRH5 antibody further comprises heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the amino acid sequences of SEQ ID NOs: 52, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 86. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 57, 50, and 51, respectively. In some cases, the claimed anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 87. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1.2, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 86; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 87.

[0144] In some cases, an anti-FcRH5 antibody having a binding domain comprising six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 13; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 21. In some cases, the anti-FcRH5 antibody comprises a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 88, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 89. In some cases, the anti-FcRH5 antibody further comprises heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the amino acid sequences of SEQ ID NOs: 52, 54, 46, and 47, respectively. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 88. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 57, 50, and 51, respectively. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 89. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1.3, or a derivative or clone thereof. In some instances, for example, the invention provides an anti-FcRH5 antibody comprising a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 88 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 89.

[0145] In some cases, the anti-FcRH5 antibody comprises a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23. In some cases, an anti-FcRH5 antibody may have a binding domain comprising a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 90, or the sequence of SEQ ID NO: 90, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 91, or the sequence of SEQ ID NO: 91. In some cases, the anti-FcRH5 antibody further comprises heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 SEQ ID NOs: 52, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 90. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 57, 50, and 51, respectively. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 91. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1.4, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 90; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 91.

[0146] In some cases, the anti-FcRH5 antibody comprises a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 18; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 22. In some cases, the anti-FcRH5 antibody comprises a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 92, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 93. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 54, 46, and 47, respectively. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 92. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51, respectively. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 93. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1.5, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 92; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 93.

[0147] In some cases, the anti-FcRH5 antibody comprises a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 19; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 24. In some cases, the anti-FcRH5 antibody comprises a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 94, or the sequence of SEQ ID NO: 94, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 95, or the sequence of SEQ ID NO: 95. In some cases, the anti-FcRH5 antibody comprises heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the amino acid sequences of SEQ ID NOs: 52, 54, 46, and 47, respectively. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 94. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 57, 50, and 51, respectively. In some cases, the anti-FcRH5 antibody comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 95. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1.6, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 94; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 95.

[0148] In some cases, the anti-FcRH5 antibody comprises a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 18; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 25. In some cases, the anti-FcRH5 antibody comprises a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 96, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 97. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 53, 54, 46, and 47. In some cases, the anti-FcRH5 antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 96. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 57, 50, and 51. In some cases, the anti-FcRH5 antibody comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 97. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1.7, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 96 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 97.

[0149] In some cases, the anti-FcRH5 antibody comprises a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 18; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 25. In some cases, the anti-FcRH5 antibody comprises a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 98, or the sequence of SEQ ID NO: 98, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 99, or the sequence of SEQ ID NO: 99. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 55, 46, and 47, respectively. In some cases, the anti-FcRH5 antibody comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 98. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 57, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 99. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1.13, or a derivative or clone thereof.In some cases, for example, an anti-FcRH5 antibody may comprise (a) a VH domain comprising the amino acid sequence of SEQ ID NO:98 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:99.

[0150] In some cases, the anti-FcRH5 antibody comprises a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 18; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 25. In some cases, the anti-FcRH5 antibody comprises (a) a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of, SEQ ID NO: 100, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 101. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 100. In some cases, the anti-FcRH5 antibody of any one of claims 79 to 82, further comprising at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 57, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 101. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1.13.1, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 100 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 101.

[0151] In some cases, the anti-FcRH5 antibody comprises a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some cases, the anti-FcRH5 antibody comprises (a) an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 102, or a V and / or (b) a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 103, or the sequence of SEQ ID NO: 103. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 54, 46, and 47, respectively. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 102. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 103. In particular cases, the anti-FcRH5 antibody may be a relative of 1G7.v87, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 102 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 103.

[0152] In some cases, an anti-FcRH5 antibody may have a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 32, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 33, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 34, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 35, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 36, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 37. In some cases, the anti-FcRH5 comprises a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 110, or the sequence of SEQ ID NO: 110, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 111, or the sequence of SEQ ID NO: 111. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 66, 67, 68, and 69, respectively. In some cases, the anti-FcRH5 antibody of claim 95, wherein the VH domain comprises the amino acid sequence of SEQ ID NO: 110. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 70, 71, 72, and 73. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 111. In certain cases, the anti-FcRH5 antibody may be a relative of 17B1, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:110 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:111.

[0153] In some cases, an anti-FcRH5 antibody has a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from: (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 38; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 39; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 40; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 41; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 42; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 43. In some cases, the anti-FcRH5 antibody comprises a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of, SEQ ID NO: 112, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 113. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 74, 75, 76, and 77, respectively. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 112. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 78, 79, 80, and 81. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 113. In certain cases, the anti-FcRH5 antibody may be a relative of 15G8, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO:112 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO:113.

[0154] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 26, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 27, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 28, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 29, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 30, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 31. In some cases, the anti-FcRH5 antibody comprises a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of, SEQ ID NO: 108, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 109. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 58, 59, 60, and 61, respectively. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 108. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 62, 63, 64, and 65. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 109. In certain cases, the anti-FcRH5 antibody may be a relative of 7D8, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 108 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 109.

[0155] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of, SEQ ID NO: 185, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 186. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 179, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 185. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 186. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1A, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 185; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 186.

[0156] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 187, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 188. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 180, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 187. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 188. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1B, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 187; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 188.

[0157] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 189, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 190. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 181, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 189. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 190. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1C, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 189; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 190.

[0158] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of, SEQ ID NO: 191, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 192. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 23, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 191. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 192. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1D, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 191; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 192.

[0159] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 193, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 194. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 182, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 193. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 194. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1E, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 193; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 194.

[0160] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 175; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of, SEQ ID NO: 195, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 196. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 195. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 196. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1F, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 195; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 196.

[0161] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 176; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 197, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 198. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 197. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 198. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1G, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 197; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 198.

[0162] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 177; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 199, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 200. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 199. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 200. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1H, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 199; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 200.

[0163] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 178; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of, SEQ ID NO: 201, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 202. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 201. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 202. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1I, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 201 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 202.

[0164] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 203, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 204. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 54, 183, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 203. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 204. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1J, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 203; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 204.

[0165] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of, SEQ ID NO: 205, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 206. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 54, 184, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 205. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 206. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1K, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 205; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 206.

[0166] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 7; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 10; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 11; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 15; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 20. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 207, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 208. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 207. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 208. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v1L, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 207; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 208.

[0167] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 209, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 210. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 209. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 210. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v86, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 209; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 210.

[0168] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of, SEQ ID NO: 211, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 212. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 53, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 211. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 212. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v191, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 211 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 212.

[0169] In some instances, the present invention provides an anti-FcRH5 antibody having a binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1; (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8; (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 10; (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 14; (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16; and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23. In some cases, the claimed anti-FcRH5 antibodies may have a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of, SEQ ID NO: 213, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 214. In some cases, the anti-FcRH5 antibody comprises at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 52, 54, 46, and 47. In some cases, the anti-FcRH5 antibody may have a VH domain comprising the amino acid sequence of SEQ ID NO: 213. In some cases, the anti-FcRH5 antibody further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 48, 56, 50, and 51. In some cases, the anti-FcRH5 antibody may have a VL domain comprising the amino acid sequence of SEQ ID NO: 214. In certain cases, the anti-FcRH5 antibody may be a relative of 1G7.v92, or a derivative or clone thereof.In some instances, for example, the invention provides an anti-FcRH5 antibody having a binding domain comprising: (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 213; and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 214.

[0170] In certain embodiments, the antibodies provided herein are monoclonal, human, humanized, or chimeric antibodies. In some cases, the anti-FcRH5 antibody is an IgG antibody. The anti-FcRH5 antibody can be a full-length antibody and / or a monospecific antibody. In certain embodiments, the anti-FcRH5 antibody can bind to an epitope within Ig-like domain 9 of FcRH5. For example, the epitope can include a portion of amino acids 743-850 of SEQ ID NO: 114. In some cases, the anti-FcRH5 antibody binds to human FcRH5 or cynomolgus monkey (cyno) FcRH5, or both. In other cases, the binding domain does not specifically bind to FcRH1, FcRH2, FcRH3, and / or FcRH4.

[0171] In some cases, the anti-FcRH5 antibody is administered at a dose of about 10 ml / kg / day to about 45 ml / kg / day (e.g., about 1 ml / kg / day, 5 ml / kg / day, 10 ml / kg / day, 11 ml / kg / day, 12 ml / kg / day, 13 ml / kg / day, 14 ml / kg / day, 15 ml / kg / day, 16 ml / kg / day, 17 ml / kg / day, 18 ml / kg / day, 19 ml / kg / day, 20 ml / kg / day, 21 ml / kg / day, 22 ml / kg / day, 23 ml / kg / day, 24 ml / kg / day, 25 ml / kg / day, 26 ml / kg / day, 27 ml / kg / day, 28 ml / kg / day, 29 ml / kg / day, 30 ml / kg / day, 31 ml / kg / day, 32 ml / kg / day, 33 ml / kg / day, 34 ml / kg / day, 35 ml / kg / day, 36 ml / kg / day, 37 ml / kg / day, 38 ml / kg / day, 39 ml / kg / day, 40 ml / kg / day, 41 ml / kg / day, 42 ml / kg / day, 43 ml / kg / day, 44 ml / kg / day, 45 ml / kg / day, 46 ml / kg / day, 47 ml / kg / day, 48 ml / kg / day, 49 ml / kg / day, 50 ml / kg / day, 51 ml / kg / day, 52 ml / kg / day, 53 ml / kg / day, 54 ml / kg / day, 55 ml / kg / day, 56 ml / kg / day, 57 ml / kg / day, 58 ml / kg / day, 59 ml / kg / day, l / kg / day, 26 ml / kg / day, 27 ml / kg / day, 28 ml / kg / day, 29 ml / kg / day, 30 ml / kg / day, 31 ml / kg / day, 32 ml / kg / day, 33 ml / kg / day, 34 ml / kg / day, 35 ml / kg / day, 36 ml / kg / day, 37 ml / kg / day, 38 ml / kg / day, 39 ml / kg / day, 40 ml / kg / day, 41 ml / kg / day, 42 ml / kg / day, 43 ml / kg / day, or 44 ml / kg / day) after intravenous administration.

[0172] In some instances, the anti-FcRH5 antibody has a clearance following intravenous injection in mice of about 1 ml / kg / day to about 5 ml / kg / day, about 6 ml / kg / day to about 10 ml / kg / day, about 11 ml / kg / day to about 15 ml / kg / day, about 16 ml / kg / day to about 20 ml / kg / day, about 21 ml / kg / day to about 25 ml / kg / day, about 26 ml / kg / day to about 30 ml / kg / day, about 31 ml / kg / day to about 35 ml / kg / day, about 36 ml / kg / day to about 40 ml / kg / day, or about 41 ml / kg / day to about 45 ml / kg / day. In some instances, the anti-FcRH5 antibody has a clearance following intravenous injection in mice of about 10 ml / kg / day to about 35 ml / kg / day. In some cases, the anti-FcRH5 antibody has a clearance after intravenous injection in mice of about 10 ml / kg / day to about 20 ml / kg / day, hi some cases, the anti-FcRH5 antibody has a clearance after intravenous injection in mice of about 12 ml / kg / day to about 16 ml / kg / day.

[0173] In some instances, the anti-FcRH5 antibody has a clearance following intravenous injection in cynomolgus monkeys of about 1 ml / kg / day to about 5 ml / kg / day, about 6 ml / kg / day to about 10 ml / kg / day, about 11 ml / kg / day to about 15 ml / kg / day, about 16 ml / kg / day to about 20 ml / kg / day, about 21 ml / kg / day to about 25 ml / kg / day, about 26 ml / kg / day to about 30 ml / kg / day, about 31 ml / kg / day to about 35 ml / kg / day, about 36 ml / kg / day to about 40 ml / kg / day, or about 41 ml / kg / day to about 45 ml / kg / day. In some instances, the anti-FcRH5 antibody has a clearance following intravenous injection in cynomolgus monkeys of about 20 ml / kg / day to about 40 ml / kg / day. In some instances, the anti-FcRH5 antibody has a clearance after intravenous injection of about 25 ml / kg / day to about 35 ml / kg / day in cynomolgus monkeys, hi some instances, the anti-FcRH5 antibody has a clearance after intravenous injection of about 30 ml / kg / day to about 35 ml / kg / day in cynomolgus monkeys.

[0174] In further aspects, anti-FcRH5 antibodies according to any of the above embodiments may incorporate any of the features described in sections 1-7 below, either alone or in combination.

[0175] 1. Antibody affinity In certain cases, the anti-FcRH5 antibody has a cytotoxicity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g. 10 -8 M~10 -13 M, e.g. 10 -9 M~10 -13 M, e.g. 10 -10 ~10 -13 M, e.g. 10 -11 ~10 -13 M, e.g. 10 -12 ~10 -13 Dissociation constant (K D For example, in some cases, the anti-FcRH5 antibody binds to human and / or cynomolgus monkey FcRH5 with a K of ≦100 nM (e.g., ≦90 nM, ≦80 nM, ≦70 nM, ≦60 nM, ≦50 nM, ≦40 nM, ≦30 nM, ≦20 nM, ≦10 nM, ≦5 nM, ≦1 nM, ≦750 pM, ≦500 pM, ≦250 pM, ≦100 pM, ≦50 pM, ≦25 pM, ≦10 pM, ≦5 pM, or ≦1 pM) or less. D It binds to human FcRH5 at

[0176] In some cases, the anti-FcRH5 antibody has a K of about 1 pM to about 500 nM (e.g., about 1 pM to 200 pM, 100 pM to 300 pM, 200 pM to 400 pM, 300 pM to 500 pM, 400 pM to 600 pM, 500 pM to 700 pM, 600 pM to 800 pM, 700 pM to 900 pM, 800 pM to 1 nM, 900 pM to 100 nM, 1 nM to 200 nM, 100 nM to 300 nM, 200 nM to 400 nM, or 300 nM to 500 nM). DIn some cases, the anti-FcRH5 antibody binds to human FcRH5 at a concentration of about 1 pM to about 1 nM (e.g., about 1 pM to 100 pM, 50 pM to 150 pM, 100 pM to 200 pM, 150 pM to 250 pM, 200 pM to 300 pM, 250 pM to 350 pM, 300 pM to 400 pM, 350 pM to 450 pM, 400 pM to 500 pM, 500 pM to 600 pM, 600 pM to 700 pM, 700 pM to 800 pM, 800 pM to 900 pM, 900 pM to 1000 pM, 1000 pM to 1200 pM, 1200 pM to 1400 pM, 1400 pM to 1600 pM, 1600 pM to 1800 pM, 1800 pM to 2000 pM, 1800 pM to 2200 pM, 1800 pM to 2400 pM, 1800 pM to 2600 pM, 1800 pM to 2800 pM, 1800 pM to 2900 pM, 1900 pM to 2900 pM, 2900 pM to 3000 pM, 2900 pM to 350 pM, 300 pM to 400 pM, 350 pM to 450 pM, 400 pM to 500 pM, 500 pM to 6000 pM, 500 pM to 600 pM to 500pM, 450pM to 550pM, 500pM to 600pM, 550pM to 650pM, 600pM to 700pM, 650pM to 750pM, 700pM to 800pM, 750pM to 850pM, 800pM to 900pM, 850pM to 950pM, or 900pM to 1nM) D In some cases, the anti-FcRH5 antibody binds to human FcRH5 with a K of about 100 pM to about 500 pM (e.g., about 100 pM, 125 pM, 150 pM, 175 pM, 200 pM, 225 pM, 250 pM, 275 pM, 300 pM, 325 pM, 350 pM, 375 pM, 400 pM, 425 pM, 450 pM, 475 pM, or 500 pM). D In some instances, the anti-FcRH5 antibody binds to human FcRH5 with a K of about 100 pM to about 160 pM (e.g., about 100 pM, 105 pM, 110 pM, 115 pM, 120 pM, 125 pM, 130 pM, 135 pM, 140 pM, 145 pM, 150 pM, 155 pM, or 160 pM). DIn some cases, the anti-FcRH5 antibody binds to human FcRH5 at a binding affinity of about 1 nM to about 150 nM (e.g., about 1 nM, 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 11 nM, 12 nM, 13 nM, 14 nM, 15 nM, 16 nM, 17 nM, 18 nM, 19 nM, 20 nM, 21 nM, 22 nM, 23 nM, 24 nM, 25 nM, 26 nM, 27 nM, 28 nM, 29 nM, 30 nM, 31 nM, 32 nM, 33 nM, 34 nM, 35 nM, 36 nM, 37 nM, 38 nM, 39 nM, 40 nM, 41 nM, 42 nM, 43 nM, 44 nM, 45 nM, 46 nM, 47 nM, 48 nM, 49 nM, 50 nM, 51 nM, 52 nM, 53 nM, 54 nM, 55 nM, 56 nM, 57 nM, 58 nM, 59 nM, 60 nM, 61 nM, 62 nM, 63 nM, 64 nM, 65 nM, 66 nM, 67 nM, 68 nM, 69 nM, 70 nM, 71 nM, 72 nM, 73 nM, 74 nM, 75 nM, 76 nM, 77 nM, 78 nM, 79 nM, K of 100nM, 35nM, 36nM, 37nM, 38nM, 39nM, 40nM, 41nM, 42nM, 43nM, 44nM, 45nM, 46nM, 47nM, 48nM, 49nM, 50nM, 55nM, 60nM, 65nM, 70nM, 75nM, 80nM, 85nM, 90nM, 95nM, 100nM, 105nM, 110nM, 115nM, 120nM, 125nM, 130nM, 135nM, 140nM, 145nM, or 150nM D It binds to human FcRH5 at

[0177] In some cases, the anti-FcRH5 antibody has a cytotoxicity of ≦100 nM (e.g., ≦90 nM, ≦80 nM, ≦70 nM, ≦60 nM, ≦50 nM, ≦40 nM, ≦30 nM, ≦20 nM, ≦10 nM, ≦5 nM, ≦1 nM, ≦750 pM, ≦500 pM, ≦250 pM, ≦100 pM, ≦50 pM, ≦25 pM, ≦10 pM, ≦5 pM, or ≦1 pM, e.g., 10 -8 M~10 -13 M, e.g. 10 -9 M~10 -13 M, e.g. 10 -10 ~10 -13 M, e.g. 10 -11 ~10 -13 M, e.g. 10 -12 ~10 -13 M) or lower DIn some cases, the anti-FcRH5 antibody binds to cynomolgus monkey FcRH5 with a K of about 1 pM to about 500 nM (e.g., about 1 pM to 200 pM, 100 pM to 300 pM, 200 pM to 400 pM, 300 pM to 500 pM, 400 pM to 600 pM, 500 pM to 700 pM, 600 pM to 800 pM, 700 pM to 900 pM, 800 pM to 1 nM, 900 pM to 100 nM, 1 nM to 200 nM, 100 nM to 300 nM, 200 nM to 400 nM, or 300 nM to 500 nM). D In some cases, the anti-FcRH5 antibody binds to cynomolgus monkey FcRH5 at a concentration of about 1 pM to about 1 nM (e.g., about 1 pM to 100 pM, 50 pM to 150 pM, 100 pM to 200 pM, 150 pM to 250 pM, 200 pM to 300 pM, 250 pM to 350 pM, 300 pM to 400 pM, 350 pM to 450 pM, 400 pM to 500 pM, 500 pM to 600 pM, 600 pM to 700 pM, 700 pM to 800 pM, 800 pM to 900 pM, 900 pM to 1000 pM, 1000 pM to 1200 pM, 1200 pM to 1400 pM, 1400 pM to 1600 pM, 1600 pM to 1800 pM, 1800 pM to 2000 pM, 1800 pM to 2200 pM, 1800 pM to 2400 pM, 1800 pM to 2600 pM, 1800 pM to 2800 pM, 1800 pM to 2900 pM, 1900 pM to 2900 pM, 2900 pM to 3000 pM, 2900 pM to 350 pM, 300 pM to 400 pM, 350 pM to 450 pM, 400 pM to 500 pM, 500 pM to 6000 pM, 500 p pM to 500pM, 450pM to 550pM, 500pM to 600pM, 550pM to 650pM, 600pM to 700pM, 650pM to 750pM, 700pM to 800pM, 750pM to 850pM, 800pM to 900pM, 850pM to 950pM, or 900pM to 1nM) D In some instances, the anti-FcRH5 antibody binds to cynomolgus monkey FcRH5 with a K of about 100 pM to about 500 pM (e.g., about 100 pM, 125 pM, 150 pM, 175 pM, 200 pM, 225 pM, 250 pM, 275 pM, 300 pM, 325 pM, 350 pM, 375 pM, 400 pM, 425 pM, 450 pM, 475 pM, or 500 pM). D In some instances, the anti-FcRH5 antibody binds to cynomolgus monkey FcRH5 with a K of about 100 pM to about 160 pM (e.g., about 100 pM, 105 pM, 110 pM, 115 pM, 120 pM, 125 pM, 130 pM, 135 pM, 140 pM, 145 pM, 150 pM, 155 pM, or 160 pM). DIn some cases, the anti-FcRH5 antibody binds to cynomolgus monkey FcRH5 at a binding affinity of about 1 nM to about 150 nM (e.g., about 1 nM, 2 nM, 3 nM, 4 nM, 5 nM, 6 nM, 7 nM, 8 nM, 9 nM, 10 nM, 11 nM, 12 nM, 13 nM, 14 nM, 15 nM, 16 nM, 17 nM, 18 nM, 19 nM, 20 nM, 21 nM, 22 nM, 23 nM, 24 nM, 25 nM, 26 nM, 27 nM, 28 nM, 29 nM, 30 nM, 31 nM, 32 nM, 33 nM, 34 nM, 35 nM, 36 nM, 37 nM, 38 nM, 39 nM, 40 nM, 41 nM, 42 nM, 43 nM, 44 nM, 45 nM, 46 nM, 47 nM, 48 nM, 49 nM, 50 nM, 51 nM, 52 nM, 53 nM, 54 nM, 55 nM, 56 nM, 57 nM, 58 nM, 59 nM, 60 nM, 61 nM, 62 nM, 63 nM, 64 nM, 65 nM, 66 nM, 67 nM, 68 nM, 69 nM, 70 nM, 71 nM, 72 nM, 73 nM, 74 nM, 75 nM, 76 nM, 77 nM, 78 nM, K of 100nM, 35nM, 36nM, 37nM, 38nM, 39nM, 40nM, 41nM, 42nM, 43nM, 44nM, 45nM, 46nM, 47nM, 48nM, 49nM, 50nM, 55nM, 60nM, 65nM, 70nM, 75nM, 80nM, 85nM, 90nM, 95nM, 100nM, 105nM, 110nM, 115nM, 120nM, 125nM, 130nM, 135nM, 140nM, 145nM, or 150nM D binds to cynomolgus monkey FcRH5.

[0178] In one embodiment, K D is measured by a radiolabeled antigen binding assay (RIA). In one embodiment, an RIA is performed using a Fab version of the antibody of interest and its antigen. For example, the solution binding affinity of the Fab for the antigen is determined by measuring the binding affinity of the Fab to the antigen at the lowest concentration ( 125 I) The antibody titer is measured by equilibrating the labeled antigen with Fab and then capturing the bound antigen on a plate coated with an anti-Fab antibody (see, e.g., Chen et al. J. Mol. Biol. 293:865-881, 1999). To establish assay conditions, MICROTITER® multiwell plates (Thermo Scientific) are coated overnight with 5 μg / ml of capture anti-Fab antibody (Cappel Labs) in 50 mM sodium carbonate (pH 9.6), followed by blocking with 2% (w / v) bovine serum albumin in PBS for 2-5 hours at room temperature (approximately 23°C). In non-adsorbent plates (Nunc #269620), 100 pM or 26 pM [ 125[I] The antigen is mixed with serial dilutions of the Fab of interest (e.g., consistent with the evaluation of the anti-VEGF antibody, Fab-12, in Presta et al. Cancer Res. 57:4593-4599, 1997). The Fab of interest is then incubated overnight; however, incubation may be continued for a longer period (e.g., approximately 65 hours) to ensure equilibrium is reached. The mixture is then transferred to a capture plate for incubation at room temperature (e.g., for 1 hour). The solution is then removed, and the plate is washed eight times with PBS containing 0.1% polysorbate 20 (TWEEN-20®). After the plate has dried, 150 μl / well of scintillant (MICROSCINT-20™, Packard) is added, and the plate is counted for 10 minutes in a TOPCOUNT™ gamma counter (Packard). The concentration of each Fab that results in 20% or less of maximum binding is selected for use in the competitive binding assay.

[0179] According to another embodiment, K Dis measured using a BIACORE® surface plasmon resonance assay. For example, assays using a BIACORE® 2000 or BIACORE® 3000 (BIAcore, Inc., Piscataway, NJ) are performed at 25°C using an immobilized antigen CM5 chip with approximately 10 response units (RU). In one embodiment, a carboxymethylated dextran biosensor chip (CM5, BIACORE, Inc.) is activated with N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) and N-hydroxysuccinimide (NHS) according to the supplier's instructions. The antigen is diluted to 5 μg / ml (approximately 0.2 μM) with 10 mM sodium acetate (pH 4.8) and then injected at a flow rate of 5 μl / min, yielding approximately 10 response units (RU) of coupled protein. After antigen injection, 1 M ethanolamine is injected to block unreacted groups. For kinetic measurements, two-fold serial dilutions of Fab (0.78 nM to 500 nM) are injected at a flow rate of approximately 25 μl / min in PBS containing 0.05% polysorbate 20 (TWEEN-20™) surfactant (PBST) at 25°C. The association rate (k on ) and dissociation rate (k off The equilibrium dissociation constant (K) is calculated by simultaneously fitting the association and dissociation sensorgrams using a simple one-to-one Langmuir binding model (BIACORE® Evaluation Software version 3.2). D ) is k off / k on See, for example, Chen et al. J. Mol. Biol. 293:865-881, 1999. When the on-rate by the surface plasmon resonance assay described above is 10 6 M -1 s -1If greater than , this on-rate can be determined by using a fluorescence quenching technique to measure the increase or decrease in fluorescence emission intensity (excitation = 295 nm, emission = 340 nm, 16 nm bandpass) of 20 nM anti-antigen antibody (Fab form) in PBS (pH 7.2) at 25°C in the presence of increasing concentrations of antigen, as measured in a spectrometer such as a spectrophotometer equipped with stopped flow (Aviv Instruments) or an 8000 Series SLM-AMINCO™ spectrophotometer (ThermoSpectronic) equipped with a stirred cuvette.

[0180] 2. Antibody fragment In certain embodiments, the antibodies provided herein are antibody fragments. Antibody fragments include, but are not limited to, bis-Fab, Fab, Fab', Fab'-SH, F(ab')2, Fv, and scFv fragments, as well as other fragments described below. For a review of certain antibody fragments, see Hudson et al. Nat. Med. 9:129-134, 2003. For a review of scFv fragments, see, e.g., Pluckthun, in The Pharmacology of Monoclonal Antibodies, vol. 113, Rosenburg and Moore eds., (Springer-Verlag, New York), pp. 269-315, 1994; see also WO 93 / 16185 and U.S. Patent Nos. 5,571,894 and 5,587,458. See US Pat. No. 5,869,046 for a detailed discussion of Fab and F(ab')2 fragments that contain salvage receptor binding epitope residues and have increased in vivo half-lives.

[0181] Antibody fragments in which two Fabs are linked through a bis-maleimide are referred to herein as bismaleimide-(thio-Fab)2 or bis-Fab.

[0182] Diabodies are antibody fragments with two antigen-binding sites, which may be bivalent or bispecific. See, e.g., EP 404,097, WO 1993 / 01161, Hudson et al. Nat. Med. 9:129-134, 2003, and Hollinger et al. Proc. Natl. Acad. Sci. USA 90:6444-6448, 1993. Triabodies and tetrabodies are also described in Hudson et al. Nat. Med. 9:129-134, 2003.

[0183] Single-domain antibodies are antibody fragments that contain all or a portion of the heavy chain variable domain or all or a portion of the light chain variable domain of an antibody. In certain embodiments, single-domain antibodies are human single-domain antibodies (Domantis, Inc., Waltham, MA; see, e.g., U.S. Patent No. 6,248,516 B1).

[0184] Antibody fragments can be produced by a variety of techniques, including, but not limited to, proteolytic digestion of intact antibodies and production by recombinant host cells (eg, E. coli or phage), as described herein.

[0185] 3. Chimeric and humanized antibodies In certain embodiments, the antibodies provided herein are chimeric antibodies. Certain chimeric antibodies are described, for example, in U.S. Patent No. 4,816,567 and Morrison et al. Proc. Natl. Acad. Sci. USA, 81:6851-6855, 1984. In one example, a chimeric antibody comprises a non-human variable region (e.g., a variable region derived from a mouse, rat, hamster, rabbit, or non-human primate, such as a monkey) and a human constant region. In a further example, a chimeric antibody is a "class-switched" antibody whose class or subclass has been changed from that of the parent antibody. Chimeric antibodies include antigen-binding fragments thereof.

[0186] In certain embodiments, a chimeric antibody is a humanized antibody. Typically, a non-human antibody is humanized to reduce immunogenicity to humans while retaining the specificity and affinity of the parent non-human antibody. Generally, a humanized antibody comprises one or more variable domains, the HVRs, e.g., CDRs (or portions thereof), of which are derived from a non-human antibody and the FRs (or portions thereof) are derived from human antibody sequences. A humanized antibody also optionally comprises at least a portion of a human constant region. In some embodiments, some FR residues in a humanized antibody are substituted with corresponding residues from the non-human antibody (e.g., the antibody from which the HVR residues are derived), e.g., to restore or improve the specificity or affinity of the antibody.

[0187] Humanized antibodies and methods for their production are reviewed, for example, in Almagro et al. Front. Biosci. 13:1619-1633, 2008, and are described, for example, in Riechmann et al. Nature 332:323-329, 1988, Queen et al. Proc. Natl Acad. Sci. USA 86:10029-10033, 1989, U.S. Patent Nos. 5,821,337, 7,527,791, 6,982,321, and 7,087,409, Kashmiri et al. Methods 36:25-34, 2005 (describing specificity-determining region (SDR) grafting), Padlan et al. This is further described in Mol. Immunol. 28:489-498, 1991 (describing "resurfacing"), Dall'Acqua et al. Methods 36:43-60, 2005 (describing "FR shuffling"), and Osbourn et al. Methods 36:61-68, 2005, and Klimka et al. Br. J. Cancer, 83:252-260, 2000 (describing a "guided selection" approach to FR shuffling).

[0188] Human framework regions that can be used for humanization include framework regions selected using the "best-fit" method (see, e.g., Sims et al. J. Immunol. 151:2296, 1993), framework regions derived from consensus sequences of human antibodies of particular subgroups of light or heavy chain variable regions (see, e.g., Carter et al. Proc. Natl. Acad. Sci. USA, 89:4285, 1992, and Presta et al. J. Immunol. 151:2623, 1993), human mature (somatically mutated) framework regions or human germline framework regions (see, e.g., Almagro et al. Front. Biosci. 13:1619-1633, 2008), and framework regions obtained from screening of FR libraries (see, e.g., Baca et al. J. Biol. Chem. 272:10678-10684, 1997, and Rosok et al. J. Immunol. 151:2623, 1993). al. J. Biol. Chem. 271:22611-22618, 1996).

[0189] 4. Human antibodies In certain embodiments, the antibodies provided herein are human antibodies. Human antibodies can be produced using various techniques known in the art. Human antibodies are generally described in van Dijk and van de Winkel, Curr. Opin. Pharmacol. 5:368-74, 2001, and Lonberg, Curr. Opin. Immunol. 20:450-459, 2008.

[0190] Human antibodies can be prepared by administering immunogens to transgenic animals that are modified to produce intact human antibodies or intact antibodies with human variable regions in response to antigen challenge.Such animals typically contain all or part of the human immunoglobulin loci, which replace endogenous immunoglobulin loci, or are present extrachromosomally or randomly integrated into animal chromosomes.In such transgenic mice, endogenous immunoglobulin loci are generally inactivated.For a general overview of methods for obtaining human antibodies from transgenic animals, see Lonberg, Nat.Biotech.23:1117-1125,2005. See also, e.g., U.S. Patent Nos. 6,075,181 and 6,150,584, which describe XENOMOUSE™ technology, U.S. Patent No. 5,770,429, which describes HUMAB® technology, U.S. Patent No. 7,041,870, which describes KM MOUSE® technology, and U.S. Patent Application Publication No. US 2007 / 0061900, which describes VELOCIMOUSE® technology. The human variable regions from intact antibodies produced by such animals may be further modified, for example, by combining with different human constant regions.

[0191] Human antibodies can also be produced by hybridoma-based methods. Human myeloma and mouse-human heteromyeloma cell lines for the production of human monoclonal antibodies have been described (see, e.g., Kozbor J. Immunol., 133:3001, 1984; Brodeur et al. Monoclonal Antibody Production Techniques and Applications, pp. 51-63 (Marcel Dekker, Inc., New York, 1987); and Boerner et al. J. Immunol., 147:86, 1991). Human antibodies produced by human B cell hybridoma technology are also described in Li et al. Proc. Natl. Acad. Sci. USA, 103:3557-3562, 2006. Additional methods include those described, for example, in U.S. Patent No. 7,189,826 (which describes the production of monoclonal human IgM antibodies from hybridoma cell lines) and Ni, Xiandai Mianyixue, 26(4):265-268, 2006 (which describes human-human hybridomas). Human hybridoma technology (trioma technology) is also described in Vollmers and Brandlein, Histology and Histopathology, 20(3):927-937, 2005, and Vollmers and Brandlein, Methods and Findings in Experimental and Clinical Pharmacology, 27(3):185-91, 2005.

[0192] Human antibodies may be generated by isolating Fv clone variable domain sequences selected from a human-derived phage display library. Such variable domain sequences may then be combined with desired human constant domains. Techniques for selecting human antibodies from antibody libraries are described below.

[0193] 5. Library-derived antibodies Antibodies of the invention can be isolated by screening combinatorial libraries for antibodies with the desired activity(ies). For example, a variety of methods are known in the art for generating phage display libraries and screening such libraries for antibodies with the desired binding characteristics. Such methods are reviewed, for example, in Hoogenboom et al., in Methods in Molecular Biology 178:1-37 (O'Brien et al., ed., Human Press, Totowa, NJ, 2001), and are also described, for example, in McCafferty et al., Nature 348:552-554, Clackson et al., Nature 352:624-628, 1991, Marks et al., J. Mol. Biol. 222:581-597, 1992, Marks and Bradbury, in Methods in Molecular Biology 248:161-175 (Lo, ed., Human Press, Totowa, NJ, 2003), Sidhu et al., J. Mol. Biol. 338(2):299-310, 2004, Lee et al. al. J. Mol. Biol. 340(5):1073-1093, 2004, Fellouse, Proc. Natl. Acad. Sci. USA 101(34):12467-12472, 2004, and Lee et al. J. Immunol. Methods 284(1-2):119-132, 2004.

[0194] In one particular phage display method, repertoires of VH and VL genes are separately cloned by polymerase chain reaction (PCR) and randomly recombined into phage libraries, which can then be screened for antigen-binding phage, as described in Winter et al. Ann. Rev. Immunol., 12:433-455, 1994. Phages typically display antibody fragments as either single-chain Fv (scFv) fragments or Fab fragments. Libraries derived from immunized sources provide high-affinity antibodies against immunogens without the need for hybridoma construction. Alternatively, naive repertoires can be cloned (e.g., from humans) to provide a single source of antibodies against a wide range of non-self and self antigens without any immunization, as described in Griffiths et al. EMBO J, 12:725-734, 1993. Finally, naive libraries can also be generated synthetically by cloning unrearranged V gene segments from stem cells and using PCR primers containing random sequences to encode the hypervariable CDR3 regions, and achieving rearrangement in vitro, as described in Hoogenboom and Winter, J. Mol. Biol., 227:381-388, 1992. Patent publications describing human antibody phage libraries include, for example, U.S. Patent No. 5,750,373, and U.S. Patent Publication Nos. 2005 / 0079574, 2005 / 0119455, 2005 / 0266000, 2007 / 0117126, 2007 / 0160598, 2007 / 0237764, 2007 / 0292936, and 2009 / 0002360. Antibodies or antibody fragments isolated from human antibody libraries are considered human antibodies or human antibody fragments herein.

[0195] 6. Multispecific antibodies, including FcRH5 T cell-dependent bispecific (TDB) antibodies In any one of the above aspects, the anti-FcRH5 antibody provided herein is a multispecific antibody, for example, a bispecific antibody. A multispecific antibody is a monoclonal antibody that has binding specificities for at least two different sites. In certain embodiments, a bispecific antibody can bind to two different epitopes of FcRH5.

[0196] In certain embodiments, one of the binding specificities is for FcRH5 and the other is for CD3 (e.g., CD3ε or CD3γ). Such bispecific anti-FcRH5 antibodies are also referred to as FcRH5 T cell-dependent bispecific (TDB) antibodies or FcRH5 TDBs. In some cases, the second binding domain binds to an epitope of CD3 that includes amino acid residue Glu6 of CD3. In some cases, the epitope further includes one or more additional amino acid residues selected from the group consisting of Gln1, Asp2, and Met7 of CD3. In some cases, the epitope includes amino acid residues Gln1, Asp2, and Glu6 of CD3. In some cases, the epitope includes amino acid residues Gln1, Asp2, Glu6, and Met7 of CD3. In some cases, the epitope does not include amino acid residue Glu5 of CD3. In some cases, the epitope does not include amino acid residues Gly3 and Glu5 of CD3. In some instances, the epitope consists of amino acid residues Gln1, Asp2, Glu6, and Met7 of CD3.

[0197] In some other cases, the second binding domain can bind to a human CD3 polypeptide or a cynomolgus monkey CD3 polypeptide. In some cases, the human CD3 polypeptide or the cynomolgus monkey CD3 polypeptide is a human CD3ε polypeptide or a cynomolgus monkey CD3ε polypeptide, respectively. In some cases, the human CD3 polypeptide or the cynomolgus monkey CD3 polypeptide is a human CD3γ polypeptide or a cynomolgus monkey CD3γ polypeptide, respectively.

[0198] In certain cases, the second binding domain has a denaturing activity of ≦1 μM, ≦100 nM, ≦10 nM, ≦1 nM, ≦0.1 nM, ≦0.01 nM, or ≦0.001 nM (e.g., 10 -8 M or less, e.g. 10 -8 M~10 -13 M, e.g. 10 -9 M~10 -13 Dissociation constant (K D For example, in some cases, the second binding domain binds to a human CD3ε polypeptide with a K of ≦100 nM (e.g., ≦90 nM, ≦80 nM, ≦70 nM, ≦60 nM, ≦50 nM, ≦40 nM, ≦30 nM, ≦20 nM, ≦10 nM, ≦5 nM, ≦1 nM, ≦750 pM, ≦500 pM, ≦250 pM, ≦100 pM, ≦50 pM, ≦25 pM, ≦10 pM, ≦5 pM, or ≦1 pM) or less. D It binds to human CD3ε polypeptide at

[0199] In some cases, for example, the present invention provides an anti-FcRH5 antibody wherein the second binding domain comprises at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 117, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 120.

[0200] In some instances, the present invention provides an anti-FcRH5 antibody, wherein the second binding domain comprises at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 123. In some cases, the invention provides a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 133, or the sequence of SEQ ID NO: 133. and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 134, or the sequence of SEQ ID NO: 134. In some cases, the anti-FcRH5 antibody comprises a second binding domain comprising at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 125, 126, 127, and 128, respectively. In some cases, the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 133. In some cases, the second binding domain further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 129, 130, 131, and 132, respectively. In some cases, the second binding domain comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 134.In some cases, the second binding domain comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 133 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 134. Thus, in some cases, a half antibody variant of an anti-FcRH5 antibody of the invention can be paired with a half antibody variant of anti-CD3 antibody 38E4.v1 to form an FcRH5 TDB (i.e., an anti-FcRH5 / 38E4.v1 TDB).

[0201] In some instances, the present invention provides an anti-FcRH5 antibody, wherein the second binding domain comprises at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 122, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 123. In some cases, the invention provides a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 135, or the sequence of SEQ ID NO: 135. and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 136, or the sequence of SEQ ID NO: 136. In some cases, the anti-FcRH5 antibody comprises a second binding domain comprising at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 125, 126, 127, and 128, respectively. In some cases, the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 135. In some cases, the second binding domain further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 129, 130, 131, and 132, respectively. In some cases, the second binding domain comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 136.In some cases, the second binding domain comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 135 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 136. Thus, in some cases, a half antibody variant of an anti-FcRH5 antibody of the invention can be paired with a half antibody variant of anti-CD3 antibody 38E4.v1 to form an FcRH5 TDB (i.e., an anti-FcRH5 / 38E4.v1 TDB).

[0202] In some instances, the present invention provides an anti-FcRH5 antibody, wherein the second binding domain comprises at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 124. In some cases, the invention provides a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 137, or the sequence of SEQ ID NO: 137. and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 138, or the sequence of SEQ ID NO: 138. In some cases, the anti-FcRH5 antibody comprises a second binding domain comprising at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 125, 126, 127, and 128, respectively. In some cases, the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 137. In some cases, the second binding domain further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 129, 130, 131, and 132, respectively. In some cases, the second binding domain comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 138.In some cases, the second binding domain comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 137 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 138. Thus, in some cases, a half antibody variant of an anti-FcRH5 antibody of the invention can be paired with a half antibody variant of the anti-CD3 antibody 38E4.v11 to form an FcRH5 TDB (i.e., an anti-FcRH5 / 38E4.v11 TDB).

[0203] In some instances, the present invention provides an anti-FcRH5 antibody, wherein the second binding domain comprises at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 139, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 140, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 141, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 142, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 143, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 144. In some cases, the invention provides a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 153, or the sequence of SEQ ID NO: 153. and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 154, or the sequence of SEQ ID NO: 154. In some cases, the anti-FcRH5 antibody comprises a second binding domain comprising at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 145, 146, 147, and 148, respectively. In some cases, the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 153. In some cases, the second binding domain further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 149, 150, 151, and 152, respectively. In some cases, the second binding domain comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 154.In some cases, the second binding domain comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 153 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 154. Thus, in some cases, a half antibody variant of an anti-FcRH5 antibody of the invention can be paired with a half antibody variant of the anti-CD3 antibody hu40G5c to form an FcRH5 TDB (i.e., an anti-FcRH5 / hu40G5c TDB).

[0204] In some cases, for example, the present invention provides an anti-FcRH5 antibody wherein the second binding domain comprises at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 155, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 156, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 157, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 158, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 159, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 160.

[0205] In some instances, the present invention provides an anti-FcRH5 antibody, wherein the second binding domain comprises at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 155, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 162, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 157, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 158, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 159, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 160. In some cases, for example, the second binding domain comprises a VH domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of, SEQ ID NO: 172, and / or a VL domain comprising an amino acid sequence having at least 80% (e.g., 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to, or the sequence of SEQ ID NO: 173. In some cases, for example, an anti-FcRH5 antibody comprises a second binding domain comprising at least one (e.g., one, two, three, or four) of heavy chain framework regions FR-H1, FR-H2, FR-H3, and FR-H4 comprising the sequences of SEQ ID NOs: 164, 165, 166, and 167, respectively. In some cases, the second binding domain comprises a VH domain comprising the amino acid sequence of SEQ ID NO: 172. In some cases, the second binding domain further comprises at least one (e.g., one, two, three, or four) of light chain framework regions FR-L1, FR-L2, FR-L3, and FR-L4 comprising the sequences of SEQ ID NOs: 168, 169, 170, and 171, respectively. In some cases, the second binding domain comprises a VL domain comprising the amino acid sequence of SEQ ID NO: 173.In some cases, the second binding domain comprises (a) a VH domain comprising the amino acid sequence of SEQ ID NO: 172 and (b) a VL domain comprising the amino acid sequence of SEQ ID NO: 173. Thus, in some cases, a half antibody variant of an anti-FcRH5 antibody of the invention can be paired with a half antibody variant of the anti-CD3 antibody huUCHT1.v9 to form an FcRH5 TDB (i.e., an anti-FcRH5 / huUCHT1.v9 TDB).

[0206] In some cases, for example, the present invention provides an anti-FcRH5 antibody in which the binding domain that binds to FcRH5 comprises a VH domain (VH1) comprising a charged region (CR1) and a VL domain (VL1) comprising a charged region (CR2), where CR1 in VH1 forms a charge pair with CR2 in VL1. In some cases, CR1 comprises a basic amino acid residue and CR2 comprises an acidic amino acid residue. In some cases, CR1 comprises a Q39K substitution mutation (EU numbering). In some cases, CR1 consists of a Q39K substitution mutation. In some cases, CR2 comprises a Q38E substitution mutation (EU numbering). In some cases, CR2 consists of a Q38E substitution mutation. In some cases, the second binding domain that binds to CD3 comprises a VH domain (VH2) comprising a charged region (CR3) and a VL domain (VL2) comprising a charged region (CR4), where CR4 in VL2 forms a charge pair with CR3 in VH2. In some cases, CR4 comprises a basic amino acid residue, and CR3 comprises an acidic amino acid residue. In some cases, CR4 comprises a Q38K substitution mutation (EU numbering). In some cases, CR4 consists of a Q38K substitution mutation. In some cases, CR3 comprises a Q39E substitution mutation (EU numbering). In some cases, CR3 consists of a Q39E substitution mutation. In some cases, the VL1 domain is linked to a light chain constant (CL) domain (CL1), and the VH1 is linked to a first heavy chain constant (CH1) domain (CH11), where CL1 comprises a charged region (CR5), CH11 comprises a charged region (CR6), and CR5 in CL1 forms a charge pair with CR6 in CH11. In some cases, CR5 comprises a basic amino acid residue, and CR6 comprises an acidic residue. In some cases, CR5 comprises a V133K substitution mutation (EU numbering). In some cases, CR5 comprises a V133K substitution mutation. In some cases, CR6 comprises a S183E substitution mutation (EU numbering). In some cases, CR6 comprises a S183E substitution mutation.

[0207] In some cases, the present invention provides an anti-FcRH5 antibody in which the VL2 domain is linked to a CL domain (CL2), the VH2 is linked to a CH1 domain (CH12), the CL2 comprises a charged region (CR7), the CH12 comprises a charged region (CR8), and CR8 in CH12 forms a charge pair with CR7 in CL2. In some cases, CR8 comprises a basic amino acid residue and CR7 comprises an acidic amino acid residue. In some cases, CR8 comprises a S183K substitution mutation (EU numbering). In some cases, CR8 consists of a S183K substitution mutation. In some cases, CR7 comprises a V133E substitution mutation (EU numbering). In some cases, CR7 consists of a V133E substitution mutation.

[0208] In some instances, for example, the invention provides an anti-FcRH5 antibody in which a VL2 domain is linked to a CL domain (CL2), a VH2 domain is linked to a CH1 domain (CH12), and CL2 comprises one or more mutations at amino acid residues F116, L135, S174, S176, and / or T178 (EU numbering), and CH12 comprises one or more mutations at amino acid residues A141, F170, S181, S183, and / or V185 (EU numbering). In some instances, CL2 comprises one or more of the following substitution mutations: F116A, L135V, S174A, S176F, and / or T178V. In some instances, CL2 comprises the following substitution mutations: F116A, L135V, S174A, S176F, and T178V. In some cases, CH12 comprises one or more of the following substitution mutations: A141I, F170S, S181M, S183A, and / or V185A. In some cases, CH12 comprises the following substitution mutations: A141I, F170S, S181M, S183A, and V185A.

[0209] In some cases, the present invention provides an anti-FcRH5 antibody, wherein the binding domain that binds to FcRH5 comprises a VH domain (VH1) comprising a charged region (CR1) and a VL domain (VL1) comprising a charged region (CR2), wherein CR2 in VL1 forms a charge pair with CR1 in VH1. In some cases, CR2 comprises a basic amino acid residue and CR1 comprises an acidic amino acid residue. In some cases, CR2 comprises a Q38K substitution mutation (EU numbering). In some cases, CR2 consists of a Q38K substitution mutation. In some cases, CR1 comprises a Q39E substitution mutation (EU numbering). In some cases, CR1 consists of a Q39E substitution mutation. In some cases, the second binding domain that binds to CD3 comprises a VH domain (VH2) comprising a charged region (CR3) and a VL domain (VL2) comprising a charged region (CR4), wherein CR3 in VH2 forms a charge pair with CR4 in VL2. In some cases, CR3 comprises a basic amino acid residue, and CR4 comprises an acidic amino acid residue. In some cases, CR3 comprises a Q39K substitution mutation (EU numbering). In some cases, CR3 consists of a Q39K substitution mutation. In some cases, CR4 comprises a Q38E substitution mutation (EU numbering). In some cases, CR4 consists of a Q38E substitution mutation. In some cases, the VL1 domain is linked to a light chain constant (CL) domain (CL1), and the VH1 is linked to a first heavy chain constant (CH1) domain (CH11), where CL1 comprises a charged region (CR5), CH11 comprises a charged region (CR6), and CR6 in CH11 forms a charge pair with CR5 in CL1. In some cases, CR6 comprises a basic amino acid residue, and CR5 comprises an acidic amino acid residue. In some cases, CR6 comprises a S183K substitution mutation (EU numbering). In some cases, CR6 comprises a S183K substitution mutation. In some cases, CR5 comprises a V133E substitution mutation (EU numbering). In some cases, CR5 comprises a V133E substitution mutation.

[0210] In some cases, for example, the present invention provides an anti-FcRH5 antibody in which the VL2 domain is linked to a CL domain (CL2), the VH2 is linked to a CH1 domain (CH12), the CL2 comprises a charged region (CR7), the CH12 comprises a charged region (CR8), and CR7 in CL2 forms a charge pair with CR8 in CH12. In some cases, CR7 comprises a basic amino acid residue and CR8 comprises an acidic residue. In some cases, CR7 comprises a V133K substitution mutation (EU numbering). In some cases, CR7 consists of a V133K substitution mutation. In some cases, CR8 comprises a S183E substitution mutation (EU numbering). In some cases, CR8 consists of a S183E substitution mutation.

[0211] In some instances, for example, the invention provides an anti-FcRH5 antibody in which a VL2 domain is linked to a CL domain (CL2), a VH2 domain is linked to a CH1 domain (CH12), and CL2 comprises one or more mutations at amino acid residues F116, L135, S174, S176, and / or T178 (EU numbering), and CH12 comprises one or more mutations at amino acid residues A141, F170, S181, S183, and / or V185 (EU numbering). In some instances, CL2 comprises one or more of the following substitution mutations: F116A, L135V, S174A, S176F, and / or T178V. In some instances, CL2 comprises the following substitution mutations: F116A, L135V, S174A, S176F, and T178V. In some cases, CH12 comprises one or more of the following substitution mutations: A141I, F170S, S181M, S183A, and / or V185A. In some cases, CH12 comprises one or more of the following substitution mutations: A141I, F170S, S181M, S183A, and V185A. In some cases, the anti-FcRH5 antibody comprises one or more heavy chain constant domains, wherein the one or more heavy chain constant domains are selected from a first CH2 domain (CH21), a first CH3 domain (CH31), a second CH2 domain (CH22), and a second CH3 domain (CH32). In some cases, at least one of the one or more heavy chain constant domains is paired with another heavy chain constant domain. In some cases, CH31 and CH32 each include a protuberance (P1) or a cavity (C1), and P1 or C1 in CH31 can be located at C1 or P1 in CH32, respectively. In some cases, CH31 and CH32 meet at the interface between P1 and C1. In some cases, CH21 and CH22 each include a protuberance (P2) or a cavity (C2), and P2 or C2 in CH21 can be located at C2 or P2 in CH22, respectively. In some cases, CH21 and CH22 meet at the interface between P2 and C2.

[0212] In another aspect, the present invention provides an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising an anti-FcRH5 arm comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23; and and an anti-CD3 arm comprising a second binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (b) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (c) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (d) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (e) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 123, wherein the anti-FcRH5 arm and the anti-CD3 arm each comprise a N297G substitution mutation (EU numbering), the anti-FcRH5 arm comprises a T366W substitution mutation, and the anti-CD3 arm comprises T366S, L368A, and Y407V substitution mutations.In some instances, the anti-FcRH5 antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23; and an anti-FcRH5 arm comprising six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 115, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23. and an anti-CD3 arm comprising a second binding domain comprising: (a) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 116; (b) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 121; (c) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118; (d) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119; and (e) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 123, wherein the anti-FcRH5 arm and the anti-CD3 arm each comprise a N297G substitution mutation (EU numbering), the anti-FcRH5 arm comprises a T366W substitution mutation, and the anti-CD3 arm comprises T366S, L368A, and Y407V substitution mutations.

[0213] In another aspect, the present invention provides an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising an anti-FcRH5 arm comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23; and and an anti-CD3 arm comprising a second binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 121, (b) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 122, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 119, and (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 123, wherein the anti-FcRH5 arm comprises a light chain comprising Q38E and V133K substitution mutations, and a heavy chain comprising Q39K, S183E, and N297G substitution mutations, and the anti-CD3 arm comprises a light chain comprising Q38K and V133E substitution mutations, and a heavy chain comprising Q39E, S183K, and N297G substitution mutations (EU numbering).In some instances, the anti-FcRH5 antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23; and and an anti-CD3 arm comprising a second binding domain comprising (a) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 121, (b) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 122, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 119, and (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 123, wherein the anti-FcRH5 arm comprises a light chain comprising Q38E and V133K substitution mutations, and a heavy chain comprising Q39K, S183E, and N297G substitution mutations, and the anti-CD3 arm comprises a light chain comprising Q38K and V133E substitution mutations, and a heavy chain comprising Q39E, S183K, and N297G substitution mutations (EU numbering).

[0214] In another aspect, the invention provides an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising: (a) a first binding domain comprising a VH domain comprising an amino acid sequence having at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 104, or the sequence of SEQ ID NO: 104, and a VL domain comprising an amino acid sequence having at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 105, or the sequence of SEQ ID NO: 105; and an anti-FcRH5 arm, wherein the anti-FcRH5 arm comprises a light chain comprising Q38E and V133K substitution mutations, and Q39K, S183E, and N297G substitution mutations. and (b) an anti-CD3 arm comprising a second binding domain comprising a VH domain comprising an amino acid sequence having at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 133, or the sequence of SEQ ID NO: 133, and a VL domain comprising an amino acid sequence having at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 134, or the sequence of SEQ ID NO: 134, wherein the anti-CD3 arm comprises a light chain comprising Q38K and V133E substitution mutations, and a heavy chain comprising Q39E, S183K, and N297G substitution mutations (EU numbering).In some instances, the present invention provides an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising: (a) an anti-FcRH5 arm comprising a first binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 104 and a VL domain comprising the amino acid sequence of SEQ ID NO: 105, wherein the anti-FcRH5 arm comprises a light chain comprising Q38E and V133K substitution mutations, and a heavy chain comprising Q39K, S183E, and N297G substitution mutations; and (b) an anti-CD3 arm comprising a second binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 133 and a VL domain comprising the amino acid sequence of SEQ ID NO: 134, wherein the anti-CD3 arm comprises a light chain comprising Q38K and V133E substitution mutations, and a heavy chain comprising Q39E, S183K, and N297G substitution mutations (EU numbering).

[0215] In another aspect, the present invention provides an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising an anti-FcRH5 arm comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23; and and an anti-CD3 arm comprising a second binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 121, (b) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 122, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 119, and (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 123, wherein the anti-FcRH5 arm comprises a light chain comprising Q38K and V133E substitution mutations, and a heavy chain comprising Q39E, S183K, and N297G substitution mutations, and the anti-CD3 arm comprises a light chain comprising Q38E and V133K substitution mutations, and a heavy chain comprising Q39K, S183E, and N297G substitution mutations (EU numbering).In some instances, the anti-FcRH5 antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23; and and an anti-CD3 arm comprising a second binding domain comprising (a) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 121, (b) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 118, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 122, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 119, and (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 119, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 123, wherein the anti-FcRH5 arm comprises a light chain comprising Q38K and V133E substitution mutations, and a heavy chain comprising Q39E, S183K, and N297G substitution mutations, and the anti-CD3 arm comprises a light chain comprising Q38E and V133K substitution mutations, and a heavy chain comprising Q39K, S183E, and N297G substitution mutations (EU numbering).

[0216] In another aspect, the invention provides an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising: (a) a VH domain comprising an amino acid sequence having at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 104, or the sequence of SEQ ID NO: 104; and (b) a VL domain comprising an amino acid sequence having at least 90% (e.g., 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99%) sequence identity to SEQ ID NO: 105, or the sequence of SEQ ID NO: 105. and (b) an anti-FcRH5 arm comprising a first binding domain, the anti-FcRH5 arm comprising a light chain comprising Q38K and V133E substitution mutations, and a heavy chain comprising Q39E, S183K, and N297G substitution mutations; and (b) an anti-CD3 arm comprising a second binding domain, the anti-CD3 arm comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 133 and a VL domain comprising the amino acid sequence of SEQ ID NO: 134, the anti-CD3 arm comprising a light chain comprising Q38E and V133K substitution mutations, and a heavy chain comprising Q39K, S183E, and N297G substitution mutations (EU numbering). In some instances, the present invention provides an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising: (a) an anti-FcRH5 arm comprising a first binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 104 and a VL domain comprising the amino acid sequence of SEQ ID NO: 105, wherein the anti-FcRH5 arm comprises a light chain comprising Q38K and V133E substitution mutations, and a heavy chain comprising Q39E, S183K, and N297G substitution mutations; and (b) an anti-CD3 arm comprising a second binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 133 and a VL domain comprising the amino acid sequence of SEQ ID NO: 104, wherein the anti-CD3 arm comprises a light chain comprising Q38E and V133K substitution mutations, and a heavy chain comprising Q39K, S183E, and N297G substitution mutations (EU numbering).

[0217] In another aspect, the present invention provides an anti-FcRH5 antibody that binds to FcRH5 and CD3, the anti-FcRH5 antibody comprising an anti-FcRH5 arm comprising a first binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 16, and (f) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 23; and and an anti-CD3 arm comprising a second binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 118, (b) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 119, and (c) HVR-L3 comprising the amino acid sequence of SEQ ID NO: 123; and an anti-FcRH5 arm comprising a second binding domain comprising at least one, two, three, four, five, or six hypervariable regions (HVRs) selected from (a) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 118, (c) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 119, and (d) HVR-L2 comprising the amino acid sequence of SEQ ID NO: 123. The anti-CD3 arm comprises a light chain comprising Q38K, F116A, L135V, S174A, S176F, and T178V substitution mutations, and a heavy chain comprising Q39E, A141I, F170S, S181M, S183A, V185A, and N297G substitution mutations (EU numbering).In some instances, the anti-FcRH5 antibody comprises an anti-FcRH5 arm comprising a first binding domain comprising six hypervariable regions (HVRs): (a) HVR-H1 comprising the amino acid sequence of SEQ ID NO: 1, (b) HVR-H2 comprising the amino acid sequence of SEQ ID NO: 8, (c) HVR-H3 comprising the amino acid sequence of SEQ ID NO: 9, (d) HVR-L1 comprising the amino acid sequence of SEQ ID NO: 12, (e) HVR-L2 comprising the amin...

Claims

1. 1. A full-length bispecific antibody that binds to Fc receptor-like 5 (FcRH5) and cluster of differentiation 3 (CD3), the full-length bispecific antibody comprising: (a) an anti-FcRH5 arm comprising a first binding domain comprising a heavy chain variable (VH) domain comprising the amino acid sequence of SEQ ID NO: 104 and a light chain variable (VL) domain comprising the amino acid sequence of SEQ ID NO: 105; (b) an anti-CD3 arm comprising a second binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 153 and a VL domain comprising the amino acid sequence of SEQ ID NO: 154; and Including, A full-length bispecific antibody in which the anti-FcRH5 arm and the anti-CD3 arm each contain the N297G mutation (EU numbering).

2. 1. A full-length bispecific antibody that binds to Fc receptor-like 5 (FcRH5) and cluster of differentiation 3 (CD3), the full-length bispecific antibody comprising: (a) an anti-FcRH5 arm comprising a first binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 104 and a VL domain comprising the amino acid sequence of SEQ ID NO: 105; (b) an anti-CD3 arm comprising a second binding domain comprising a VH domain comprising the amino acid sequence of SEQ ID NO: 153 and a VL domain comprising the amino acid sequence of SEQ ID NO: 154; and Including, A full-length bispecific antibody, wherein the anti-FcRH5 arm comprises the N297G and T366W mutations, and the anti-CD3 arm comprises the N297G, T366S, L368A, and Y407V mutations (EU numbering).

3. 2. The full-length bispecific antibody of claim 1, wherein the anti-FcRH5 arm of the full-length bispecific antibody binds to human FcRH5 or cynomolgus monkey (cyno) FcRH5, or both.

4. The anti-FcRH5 arm of the full-length bispecific antibody binds to human FcRH5 and Ｄ : (a) 100 nM or less, (b) 10 pM to 100 nM, (c) 100 pM to 100 nM, (d) 1 nM to 20 nM, and / or (e) 1nM to 10nM The full-length bispecific antibody of claim 3 , which binds at

5. The anti-FcRH5 arm of the full-length bispecific antibody binds to cynomolgus monkey FcRH5 as follows: Ｄ : (a) 100 nM or less, (b) 10 pM to 100 nM, (c) 100 pM to 100 nM, and / or (d) 1nM to 50nM The full-length bispecific antibody of claim 4, which binds at

6. 2. The full-length bispecific antibody of claim 1, wherein the anti-FcRH5 arm of the full-length bispecific antibody comprises substitution mutations at amino acid residues L234, L235, D265, and / or P329 (EU numbering).

7. 7. The full-length bispecific antibody of claim 6, wherein the substitution mutation is selected from the group consisting of L234A, L235A, D265A, and P329G.

8. The full-length bispecific antibody of claim 1 , which is a monoclonal antibody, a humanized antibody, or a chimeric antibody.

9. The full-length bispecific antibody of claim 8 which is an IgG antibody.

10. 10. The full-length bispecific antibody of claim 1, wherein the anti-CD3 arm comprising the second binding domain is capable of binding to a human CD3 polypeptide or a cynomolgus monkey CD3 polypeptide.

11. 11. The full-length bispecific antibody of claim 10, wherein the human CD3 polypeptide or the cynomolgus CD3 polypeptide is a human CD3ε polypeptide or a cynomolgus CD3ε polypeptide, respectively, or a human CD3γ polypeptide or a cynomolgus CD3γ polypeptide, respectively.

12. The anti-CD3 arm comprising the second binding domain binds to a human CD3ε polypeptide and Ｄ : (a) 100 nM or less, and / or (b) 10 pM to 100 nM 12. The full-length bispecific antibody of claim 11 , which binds at

13. After intravenous injection, clearance of: (a) 10 ml / kg / day to 35 ml / kg / day in mice; (b) 10 ml / kg / day to 20 ml / kg / day in mice, and / or (c) 12 ml / kg / day to 16 ml / kg / day in mice The full-length bispecific antibody of any one of claims 1 to 12, comprising:

14. After intravenous injection, clearance of: (a) 20 ml / kg / day to 40 ml / kg / day in cynomolgus monkeys; (b) 25 ml / kg / day to 35 ml / kg / day in cynomolgus monkeys, and / or (c) 30 ml / kg / day to 35 ml / kg / day in cynomolgus monkeys 14. The full-length bispecific antibody of claim 13, having the following structure:

15. One or more isolated nucleic acid molecules encoding the full-length bispecific antibody of any one of claims 1 to 14.

16. A vector comprising the isolated nucleic acid of claim 15.

17. A host cell comprising the vector of claim 16.

18. 18. The host cell of claim 17, wherein the host cell is a mammalian cell or a prokaryotic cell.

19. 19. The host cell of claim 18, wherein the mammalian cell is a Chinese hamster ovary (CHO) cell or the prokaryotic cell is an E. coli cell.

20. A method for producing the full-length bispecific antibody of any one of claims 1 to 14, comprising culturing the host cell of claim 17 in a culture medium.

21. 21. The method of claim 20, further comprising recovering the full-length bispecific antibody from the host cell or culture medium.

22. An immunoconjugate comprising the full-length bispecific antibody of any one of claims 1 to 14 and a cytotoxic agent.

23. A composition comprising the full-length bispecific antibody of any one of claims 1 to 14.

24. 24. The composition of claim 23, further comprising a pharmaceutically acceptable excipient or diluent.

25. 25. The composition of claim 24, wherein the pharmaceutically acceptable excipient is a buffer, carrier, stabilizer, or preservative.

26. 26. The composition of claim 25, which is a pharmaceutical composition.

27. 24. The composition of claim 23, further comprising a PD-1 axis binding antagonist or an additional therapeutic agent.

28. A full-length bispecific antibody according to any one of claims 1 to 14 or a composition according to any one of claims 23 to 27 for use as a medicament.

29. 28. Use of a full-length bispecific antibody according to any one of claims 1 to 14 or a composition according to any one of claims 23 to 27 in the manufacture of a medicament for treating or delaying the progression of FcRH5-positive cancer in a subject.

30. Use of the full-length bispecific antibody of any one of claims 1 to 14 or the composition of any one of claims 23 to 27 in the manufacture of a medicament for enhancing immune function in a subject with FcRH5-positive cancer.

31. The use according to claim 29 or 30, wherein the FcRH5-positive cancer is a B-cell cancer.

32. 32. The use of claim 31 , wherein the B-cell cancer is selected from the group consisting of multiple myeloma (MM), chronic lymphocytic leukemia (CLL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma (FL).

33. 33. The use of claim 32, wherein the B-cell cancer is MM.

34. 30. The use according to claim 29, wherein the full-length bispecific antibody binds to (a) an FcRH5 molecule located on a target cell, and (b) a CD3 molecule located on an immune effector cell.

35. 35. The use according to claim 34, wherein the full-length bispecific antibody activates immune effector cells after binding to FcRH5 and CD3 molecules.

36. 36. The use according to claim 35, wherein the activated immune effector cells are capable of exerting a cytotoxic and / or apoptotic effect on target cells.

37. 35. The use according to claim 34, wherein the target cells are plasma cells.

38. 38. The use of claim 37, wherein the plasma cells are short-lived plasma cells or long-lived plasma cells.

39. 38. The use of claim 37, wherein the plasma cells are myeloma cells.

40. The medicament comprises a full length bispecific antibody in the following dosage: (a) 0.01 mg / kg / week to 50 mg / kg / week, (b) 0.1 mg / kg / week to 10 mg / kg / week, and / or (c) 1 mg / kg / week, 30. The use according to claim 29, comprising:

41. 30. The use of claim 29, wherein the medicament is prepared for administration of a PD-1 axis binding antagonist and / or an additional therapeutic agent.

42. 42. The use of claim 41, wherein the PD-1 axis binding antagonist and / or additional therapeutic agent is administered before, simultaneously with, or after administration of the full-length bispecific antibody.

43. 42. The use of claim 41, wherein the PD-1 axis binding antagonist is selected from the group consisting of a PD-L1 binding antagonist, a PD-1 binding antagonist, and a PD-L2 binding antagonist.

44. 44. The use of claim 43, wherein the PD-1 axis binding antagonist is a PD-L1 binding antagonist.

45. 45. The use of claim 44, wherein the PD-L1 binding antagonist is selected from the group consisting of MPDL3280A (atezolizumab), MDX-1105, MEDI4736 (durvalumab), and MSB0010718C (avelumab).

46. 46. ​​The use of claim 45, wherein the PD-L1 binding antagonist is MPDL3280A (atezolizumab).

47. The use of claim 43, wherein the PD-1 axis binding antagonist is a PD-1 binding antagonist or a PD-L2 binding antagonist.

48. 48. The use of claim 47, wherein the PD-1 binding antagonist is selected from the group consisting of MDX 1106 (nivolumab), MK-3475 (pembrolizumab), MEDI-0680 (AMP-514), PDR001, REGN2810, and BGB-108, or the PD-L2 binding antagonist is an antibody or immunoadhesin.

49. 30. The use of claim 29, wherein the medicament is prepared for administration in combination with a PD-1 axis binding antagonist, a steroid, an immunomodulatory drug (IMiD), a proteosome inhibitor (PI), or a combination thereof.

50. (i) the steroid is a glucocorticoid; (ii) the IMiD is lenalidomide, or (iii) the PI is bortezomib; 50. The use according to claim 49.

51. 51. The use of claim 50, wherein the glucocorticoid is dexamethasone.

52. 50. The use of claim 49, wherein the full-length bispecific antibody, PD-1 axis binding antagonist, steroid, IMiD, PI, or combination thereof is administered intravenously, subcutaneously, intramuscularly, topically, orally, transdermally, intraperitoneally, intraorbitally, by implantation, by inhalation, intrathecally, intracerebroventricularly, or intranasally.

53. 53. The use of claim 52, wherein the full-length bispecific antibody, PD-1 axis binding antagonist, steroid, IMiD, PI, or a combination thereof is administered intravenously or subcutaneously.

54. 30. The use of claim 29, wherein the subject is a human.

55. 1. A method for detecting FcRH5 in a biological sample from a subject, comprising: (a) contacting a biological sample with the full-length bispecific antibody of any one of claims 1 to 14 under conditions that allow binding of the full-length bispecific antibody to naturally occurring FcRH5 in the biological sample; and (b) detecting whether a complex between the full-length bispecific antibody and naturally occurring FcRH5 is formed in the biological sample; A method comprising:

56. 56. The method of claim 55, wherein the biological sample is a blood sample.

57. 57. The method of claim 56, wherein the subject is a human.

58. 15. A kit comprising the full-length bispecific antibody of any one of claims 1 to 14 and a package insert containing instructions for using the antibody to treat or delay the progression of an FcRH5-positive cancer in a subject.

59. 59. The kit of claim 58, wherein the subject is a human.

60. A kit comprising the full-length bispecific antibody of any one of claims 1 to 14 and a package insert containing instructions for using the antibody to enhance immune function in a subject with FcRH5-positive cancer.

61. 61. The kit of claim 60, wherein the subject is a human.

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