FCRH5 monospecific antibodies and derived FCRH5XCD28 bispecific antibodies and use thereof

Abstract

The present disclosure relates to human / cynomolgus cross-reactive antibody arms that bind specifically to FcRH5, which preferentially bind to membrane-bound FcRH5 (isoform c) and which do not cross-react with other FcRH family members. The present disclosure relates to bispecific antibodies which bind to human FcRH5 using the anti-FcRH5 arms described herein and bind to human CD28. The bispecific antibodies of the disclosure provide FcRH5-dependent costimulatory signal to T cells, even in the presence of soluble FcRH5, enhancing T cell mediated anti-tumor immunity against FcRH5-expressing cancers such as multiple myeloma.

Description

FCRH5 MONOSPECIFIC ANTIBODIES AND DERIVED FCRH5XCD28 BISPECIFIC ANTIBODIES AND USE THEREOFRELATED APPLICATIONS

[0001] This application claims priority to and the benefit of U.S. Provisional Application No. 63 / 704,688, filed on October 8, 2024, and U.S. Provisional Application No 63 / 729,021, filed on December 6, 2024, each of which is incorporated by reference herein in its entirety.INCORPORATION-BY-REFERENCE OF SEQUENCE LISTING

[0002] The Sequence Listing XML associated with this application is provided electronically in XML file format and is hereby incorporated by reference into the specification. The name of the XML file containing the Sequence Listing XML is “NOVI- 060_001WO_ST26_SeqList.xml”. The XML file is 88,599 bytes, created on October 7, 2025, and is being submitted electronically.FIELD

[0003] The present disclosure discloses fully human, cynomolgus cross-reactive Fc receptorhomolog 5 (FcRH5) monospecific antibodies and FcRH5XCD28 bispecific antibodies (bsAbs), which preferentially bind to membrane-bound FcRH5 (isoform c).BACKGROUND OF THE INVENTION

[0004] In recent years, novel approaches have been developed to stimulate the body’s immune cells to better attack and kill cancer cells. Examples of successful cancer immunotherapies are monoclonal antibodies capable of blocking so-called immune checkpoints. Current approved immune checkpoint inhibitors (ICI) block CTLA-4 (e.g., Ipilimumab), PD-1 (e.g., Pembrolizumab and Cemiplimab) and PD-L1 (e.g., Atezolizumab). Durable anti-tumor responses can be obtained in a range of cancer types using ICIs. Unfortunately, responses are limited to a patient subset, and many cancer types are known to be intrinsically resistant to ICI monotherapies.

[0005] T cell costimulatory bispecific antibodies are a novel class of therapeutics that can elicit an anti-tumor response, especially in combination with T cell bispecific antibodies or immune checkpoint inhibitors (ICIs). Preclinical studies have shown the benefit of adding costimulatory CD28 bsAbs for the treatment of solid tumors, enhancing the efficacy of bispecific T cell engagers or PD-(L)1 checkpoint inhibitors (Lotze, Olejniczak, and Skokos 2024). More specifically, they provide costimulatory signal 2 to T cells within the tumor microenvironment. To date, several TAAxCD28 bsAbs have been described (by Correnti et al (2018), but also in WO2019246514, W02020132066, W02020198009, WO2020127618, W02020132024, WO2021259890, W02022040482, WO2023170474 and W02024084052), with some of them being actively tested in early-phase clinical trials (ClinicalTrials.gov Identifiers NCT03972657, NCT04590326, NCT04626635, NCT05219513 or NCT05585034).

[0006] Other approved cancer immunotherapies include T cell bispecific antibodies, which bridge T cells and cancer target cells via binding a tumor-associated antigen (TAA) that is expressed on cancer cells and a CD3 receptor displayed on T cells, and chimeric antigen receptor (CAR) T cells. Despite the very good anti-tumor responses observed with treatments using T cell bispecific antibodies (TCE) or CAR T cells in hematological malignancies, most patients eventually relapse and are left with no additional therapeutic options.FCRH5

[0007] FcRH5, also known as FcRL5, IRTA2, or CD307, is a member of the Fc receptor homolog (FcRH) family of proteins. These proteins are expressed on immune cells, particularly B cells, and play a crucial role in the immune response. Among other cell types of the B cell lineage, FcRH5 is expressed on normal and malignant plasma cells and plays a role in regulating their survival and function. Studies have shown that FcRH5 expression is upregulated in multiple myeloma (MM) cells compared to normal plasma cells. This increased expression suggests that FcRH5 may contribute to the survival and proliferation of MM cells. Consequently, FcRH5 has emerged as a potential therapeutic target in MM, and enhanced and durable anti-tumor responses are seen in patients treated with a FcRH5xCD3 bsAb termed Cevostamab (Kumar et al. 2023).

[0008] The structure of FcRH5 consists of an extracellular domain (ECD), a transmembrane domain, and an intracellular domain. The extracellular domain contains 9 immunoglobulin-like domains. Of note, MM patients display high levels of soluble FcRH5 (consisting of ECD DI to D8) and preferential binding of the bsAbs to membrane-bound FcRH5 via domain 9 (D9) ishighly desirable to minimize the potential loss of efficacy due to the sink effect (i.e., binding to soluble ECD D1-D8). However, the amino acid sequence of D9 shares a high degree of identity with some of the other FcRH5 ECD domains (intramolecular similarity) and with some of the Ig-like domains present in the ECD of the other FcRH family members (intermolecular similarity), representing a challenge for drug-developers. Thus, there is a need to develop D9 specific antibodies and bispecific antibodies for the treatment of cancer expressing FcRH5 such as MM whose activity is expected to be retained in the presence of soluble FcRH5.CD28

[0009] CD28 is a key co-stimulatory receptor expressed at the surface of T lymphocyte. It belongs to a subfamily of costimulatory molecules characterized by an extracellular variable immunoglobulin-like domain. Other members in the family of molecules include CTLA-4, ICOS, PD-1, and BTLA.

[0010] In humans, CD28 is expressed at the cell surface of T lymphocyte as a disulfide-linked homodimer, and is found on approximately 80% of human CD4+ T cells and 50% of CD8+ T cells.

[0011] Despite lacking intrinsic enzymatic activity, CD28 engagement by its ligand(s) leads to specific phosphorylation and transcriptional signaling, which ultimately results in metabolic changes and in the production of key cytokines, chemokines, and survival signals that are essential for long-term expansion and differentiation of T cells.

[0012] The primary ligands for CD28 are CD80 (B7.1) and CD86 (B7.2), which are mainly expressed at the surface of professional antigen-presenting cells (APCs). CD80 and CD86 diverge in expression patterns, multimeric states, and functionality. Because CD28 and CTLA-4 are highly homologous, they compete for the same ligands. However, since CTLA-4 binds these ligands with a higher affinity than CD28, CTLA-4 competes with CD28 for ligands and ultimately suppresses T cell responses.

[0013] Several anti-CD28 monoclonal antibodies have been proposed for the therapeutic targeting of CD28. A fraction of the identified anti-CD28 antibodies, termed superagonist (SA) antibodies, were found to induce the full activation of primary resting T cells even in the absence of TCR ligation (signal 1), via the clustering of CD28 at the surface of the T cells. The first-inhuman study of one of such SA anti-CD28 antibodies, TGN1412, resulted however in severe inflammatory reactions as well as chronic organ failure in all healthy volunteers subjected to thetreatment. A cytokine storm predicted by neither in vivo nor in vitro preclinical safety studies was the cause of these adverse events.

[0014] To minimize the side effects of anti-CD28 monoclonal antibodies, B7 x anti -tumor- associated antigen (TAA) fusion proteins were proposed by Holliger et al. (Holliger et al. 1999). These were found to be equally effective but more specific compared with anti-CD28 monoclonal antibodies, i.e., a B7 x anti-CEA bispecific fusion protein can only activate T cells in the presence of CEA-expressing cells.

[0015] On the same principle, CD28 bsAbs cannot cluster CD28 at the surface of T cells on their own but require the engagement of a second target at the surface of another cell. As such, CD28 bispecific antibodies are unable to costimulate T cells on their own and require engagement of a second target at the surface of another cell.

[0016] Preclinical studies have shown the benefit of adding costimulatory TAAxCD28 bsAbs for the treatment of solid tumors, boosting the efficacy of bispecific T cell engagers or PD-(L)1 checkpoint inhibitors. Examples of agonist TAAxCD28 bsAbs are described in WO2019246514, W02020132066, W02020198009, WO2020127618, W02020132024, WO2021259890, W02022040482, WO2023170474 and W02024084052), with some of them being actively tested in early-phase clinical trials (ClinicalTrials.gov Identifiers NCT03972657, NCT04590326, NCT04626635, NCT05219513 or NCT05585034).

[0017] A need exists for compositions and methods for targeting T-cell activation useful for treating FcRH5 -positive cancers, which preferentially bind to membrane-bound FcRH5 (isoform c) Provided herein are methods and compositions addressing this need.SUMMARY OF THE INVENTION

[0018] The disclosure provides monospecific and bispecific antibodies that specifically bind to FcRH5. In addition, the disclosure provides that preferentially bind to membrane-bound FcRH5 (i.e., isoform c). In some aspects, the antibody is a bispecific antibody, or a multispecific antibody, that has at least a first antigen binding domain that binds to FcRH5; and at least a second binding domain that binds to CD28, referred to herein as FcRH5xCD28 bsAbs or CD28xFcRH5 bsAbs.

[0019] In some aspects, this disclosure provides an antibody, wherein the antibody binds to FcRH5, the antibody comprising: ai. a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of (SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; a ii: a light chain variable region having: 1. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 29; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 30; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 31; 2. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 32; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 33; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 34; 3. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 35; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 36; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 37; 4. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 38; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 39; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 40; 5. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 41; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 42; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 43; 6. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 44; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 45; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 46; 7. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 47; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 48; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 49; 8. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 50; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 51; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 52; 9. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 53; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 54; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 55; 10. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 56; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 57; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 58; 11. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 59; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 60; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 61 ; 12. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 62; a CDRL2 comprisingthe amino acid sequence of SEQ ID NO: 63; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 64; 13. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 65; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 66; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 67; or 14.a CDRL1 comprising the amino acid sequence of SEQ ID NO: 68; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 69; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 70.

[0020] In some embodiments, the antibody comprises a light chain variable region of a. part a. ii. 1. comprises the amino acid sequence of SEQ ID NO: 71; b. part a. ii. 2. comprises the amino acid sequence of SEQ ID NO: 72; c. part a. ii. 3. comprises the amino acid sequence of SEQ ID NO: 73; d. part a. ii. 4. comprises the amino acid sequence of SEQ ID NO: 74; e. part a. ii. 5. comprises the amino acid sequence of SEQ ID NO: 75; f. part a. ii. 6. comprises the amino acid sequence of SEQ ID NO: 76; g. part a. ii. 7. comprises the amino acid sequence of SEQ ID NO: 77; h. part a. ii. 8. comprises the amino acid sequence of SEQ ID NO: 78; i. part a. ii. 9. comprises the amino acid sequence of SEQ ID NO: 79; j. part a. ii. 10. comprises the amino acid sequence of SEQ ID NO: 80; k. part a. ii. 11. comprises the amino acid sequence of SEQ ID NO: 81; 1. part a. ii. 12. comprises the amino acid sequence of SEQ ID NO: 82; m. part a. ii. 13. comprises the amino acid sequence of SEQ ID NO: 83; or n. part a. ii. 14. comprises the amino acid sequence of SEQ ID NO: 84.

[0021] In some embodiments, the light chain of: a. part a. ii. 1. comprises the amino acid sequence of SEQ ID NO: 85; b. part a. ii. 2. comprises the amino acid sequence of SEQ ID NO: 86; c. part a. ii. 3. comprises the amino acid sequence of SEQ ID NO: 87; d. part a. ii. 4. comprises the amino acid sequence of SEQ ID NO: 88; e. part a. ii. 5. comprises the amino acid sequence of SEQ ID NO: 89; f. part a. ii. 6. comprises the amino acid sequence of SEQ ID NO: 90; g. part a. ii. 7. comprises the amino acid sequence of SEQ ID NO: 91; h. part a. ii. 8. comprises the amino acid sequence of SEQ ID NO: 92; i. part a. ii. 9. comprises the amino acid sequence of SEQ ID NO: 93; j. part a. ii. 10. comprises the amino acid sequence of SEQ ID NO: 94; k. part a. ii. 11. comprises the amino acid sequence of SEQ ID NO: 95; 1. part a. ii. 12. comprises the amino acid sequence of SEQ ID NO: 96; m. part a. ii. 13. comprises the amino acid sequence of SEQ ID NO: 97; or n. part a. ii. 14. comprises the amino acid sequence of SEQ ID NO: 98.

[0022] In some embodiments, the heavy chain variable region of the antibody comprises the amino acid sequence of SEQ ID NO: 10.

[0023] In some embodiments, the heavy chain comprises the amino acid sequence of SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO: 13.

[0024] In some aspects, this disclosure provides a bispecific antibody, wherein the bispecific antibody binds at least to FcRH5, the bispecific antibody comprising: a. a first antigen binding domain that binds to FcRH5; wherein the first antigen binding domain comprises: i. a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of (SEQ ID NO: 7); a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of (SEQ ID NO: 8); and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of (SEQ ID NO: 9); and ii. a first light chain variable region having: 1. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 29; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 30; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 31 ; 2. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 32; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 33; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 34; 3. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 35; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 36; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 37; 4. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 38; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 39; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 40; 5. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 41; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 42; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 43; 6. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 44; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 45; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 46; 7. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 47; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 48; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 49; 8. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 50; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 51; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 52; 9. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 53; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 54; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 55; 10. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 56; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 57; and a CDRL3 comprising the / amino acid sequence of SEQ ID NO: 58; 11. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 59; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 60; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 61; 12. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 62; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 63; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 64; 13. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 65; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 66; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 67; or 14. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 68; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 69; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 70; and b. a second antigen binding domain that binds to a second antigen (i.e., different from FcRH5), wherein the second antigen binding domain comprises: i. a second heavy chain variable region having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9. In certain embodiments, the bispecific antibody is specific for FcRH5 and CD28. In some embodiments, the bispecific antibody second antigen binding domain comprises: ii. a second light chain variable region having: 1. a CDR1 comprising the amino acid sequence of SEQ ID NO: 14; a CDR2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDR3 comprising the amino acid sequence of SEQ ID NO: 16.

[0025] In some embodiments, the bispecific antibody comprises a first light chain variable region, wherein the first light chain variable region of: a. part a. ii. 1. comprises the amino acid sequence of SEQ ID NO: 71; b. part a. ii. 2. comprises the amino acid sequence of SEQ ID NO: 72; c. part a. ii. 3. comprises the amino acid sequence of SEQ ID NO: 73; d. part a. ii. 4. comprises the amino acid sequence of SEQ ID NO: 74; e. part a. ii. 5. comprises the amino acid sequence of SEQ ID NO: 75; f. part a. ii. 6. comprises the amino acid sequence of SEQ ID NO: 76; g. part a. ii. 7. comprises the amino acid sequence of SEQ ID NO: 77; h. part a. ii. 8. comprises the amino acid sequence of SEQ ID NO: 78; i. part a. ii. 9. comprises the amino acid sequence of SEQ ID NO: 79; j. part a. ii. 10. comprises the amino acid sequence of SEQ ID NO: 80; k. part a. ii. 11. comprises the amino acid sequence of SEQ ID NO: 81; 1. part a. ii. 12. comprises the amino acid sequence of SEQ ID NO: 82; m. part a. ii. 13. comprises the amino acid sequence of SEQ ID NO: 83; or n. part a. ii. 14. comprises the amino acid sequence of SEQ ID NO: 84.

[0026] In some embodiments, the bispecific antibody comprises a first light chain, wherein the first light chain of: a. part a. ii. 1. comprises the amino acid sequence of SEQ ID NO: 85; b. part a. ii. 2. comprises the amino acid sequence of SEQ ID NO: 86; c. part a. ii. 3. comprises the amino acid sequence of SEQ ID NO: 87; d. part a. ii. 4. comprises the amino acid sequence of SEQ ID NO: 88; e. part a. ii. 5. comprises the amino acid sequence of SEQ ID NO: 89; f. part a. ii. 6. comprises the amino acid sequence of SEQ ID NO: 90; g. part a. ii. 7. comprises the amino acid sequence of SEQ ID NO: 91; h. part a. ii. 8. comprises the amino acid sequence of SEQ ID NO: 92; i. part a. ii. 9. comprises the amino acid sequence of SEQ ID NO: 93; j. part a. ii. 10. comprises the amino acid sequence of SEQ ID NO: 94; k. part a. ii. 11. comprises the amino acid sequence of SEQ ID NO: 95; 1. part a. ii. 12. comprises the amino acid sequence of SEQ ID NO: 96; m. part a. ii. 13. comprises the amino acid sequence of SEQ ID NO: 97; or n. part a. ii. 14. comprises the amino acid sequence of SEQ ID NO: 98.

[0027] In some embodiments, the second light chain variable region comprises the amino acid sequence of SEQ ID NO: 17. In some embodiments, the second light chain comprises the amino acid sequence of SEQ ID NO: 18.

[0028] In some embodiments, the first heavy chain variable region and the second heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 10.

[0029] In some embodiments, the first heavy chain and the second heavy chain comprises the amino acid sequence of SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO: 13.

[0030] In some embodiments, the first light chain is a kappa and the second light chain is a lambda. In some embodiments, the first light chain is a lambda and the second light chain is a kappa.

[0031] In some embodiments, the antibody or bispecific comprises an Fc domain comprising one or more amino acid substitutions that reduce binding to an activating Fc receptor and / or reduce effector function. In some embodiments, the amino acid substitution comprises a L234A and L235A substitution. In some embodiments, the amino acid substitution comprises a P329A, P329G or P329R substitution. In some embodiments, the antibody or bispecific antibody has an IgG isotype. In some embodiments, the antibodies or bispecific antibodies are human.

[0032] In some embodiments, the antibodies or bispecific antibodies preferentially bind membrane-bound FcRH5 (i.e., isoform c) via binding to D9. In some embodiments, the antibodies or bispecific antibodies preferentially bind membrane-bound FcRH5 (i.e., isoform c)relative to soluble FcRH5 (i.e., isoform a). In some embodiments, the antibodies or bispecific antibodies preferentially bind membrane-bound FcRH5 (i.e., isoform c) relative to soluble FcRH5 (i.e., isoform a), wherein preferentially means that the bispecific antibodies retain substantial efficacy in the presence of soluble FcRH5.

[0033] The disclosure provides a composition comprising any one of the antibodies or bispecific antibodies of the disclosure. In some embodiments, the composition comprising the antibody or bispecific antibody enables cancer-specific or tumor-specific T cell activation.

[0034] In some embodiments, the composition is a pharmaceutical composition, wherein the pharmaceutical composition comprises any one of the antibodies or bispecific antibodies disclosed herein. The disclosure provides a method of reducing the proliferation of and / or killing a cancer cell comprising contacting the cell with any one of the compositions of the disclosure. The disclosure provides a method of treating a cancer in a subject comprising administering to the subject any one of the compositions of the disclosure. In some embodiments, the cancer is a B cell malignancy. In some embodiments, the cancer is a FcRH5 cancer. In some embodiments, the cancer is a BCMA positive cancer.

[0035] In some embodiments, the antibody is a F(ab) fragment, a F(ab’)2 fragment, and Fv fragment or a single chain Fv fragment.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. Although methods and materials similar or equivalent to those described herein can be used in the practice of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are expressly incorporated by reference in their entirety. In cases of conflict, the present specification, including definitions, will control. In addition, the materials, methods, and examples described herein are illustrative only and are not intended to be limiting.

[0037] Other features and advantages of the disclosure will be apparent from and encompassed by the following detailed description and claims.BRIEF DESCRIPTION OF THE DRAWINGS

[0038] FIGs. 1A-1AB illustrate concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibodies of the disclosure to human FcRH5 full-length (huFcRH5 FL) and to truncated versions of huFcRH5, namely to domains 7, 8 and 9 (huFcRH5 D7-8-9), domains 8 and 9 (huFcRH5 D8-9) or to domain 9 only (huFcRH5-D9). An irrelevant protein (either huGPC3 or huCEA) was used as a negative control. FIG. 1A shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lB3. FIG. IB shows concentrationdependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lE6. FIG. 1C shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG AN lFl l. FIG. ID shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lB6. FIG. IE shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lC4. FIG. IF shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lH5 (AN9). FIG. 1G shows concentrationdependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_2B3. FIG. 1H shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lF9. FIG. II shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lH9 (AN13). FIG. 1J shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lE9. FIG. IK shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lG5 (AN15). FIG. IL shows concentrationdependent binding ELISA of anti-FcRH5 monoclonal antibody IgG AN l Al 1. FIG. IM shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lA7. FIG. IN shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_2E9. FIG. IO shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_2Fl l (AN19). FIG. IP shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG AN lGll. FIG. IQ shows concentrationdependent binding ELISA of anti-FcRH5 monoclonal antibody IgG AN lAl. FIG. 1R shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lB9. FIG. IS shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lE2. FIG. IT shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_2H5 (AN24). FIG. 1U shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lD12. FIG. IV shows concentrationdependent binding ELISA of anti-FcRH5 monoclonal antibody IgG AN IHl 1 (AN27). FIG.1W shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lH8. FIG. IX shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_2Gl l. FIG. 1Y shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lG9. FIG. 1Z shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_lE5. FIG. 1AA shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody IgG_AN_2F7 (AN34). FIG. 1AB shows concentration-dependent binding ELISA of anti-FcRH5 monoclonal antibody AN36.

[0039] FIGs. 2A-2F illustrate concentration-dependent binding ELISA of FcRH5xCD28 bsAbs of the disclosure. FIG. 2A shows concentration-dependent binding ELISA of FcRH5xCD28 bsAbs to human FcRH5 full-length (huFcRH5 FL). FIG. 2B shows concentrationdependent binding ELISA of FcRH5xCD28 bsAbs to a truncated version of huFcRH5 to domains 7, 8 and 9 (huFcRH5 D7-8-9). FIG. 2C shows concentration-dependent binding ELISA of FcRH5xCD28 bsAbs to a truncated version of huFcRH5 to domains 8 and 9 (huFcRH5 D8-9). FIG. 2D shows concentration- dependent binding ELISA of FcRH5xCD28 bsAbs to a truncated version of huFcRH5 to domain 9 only (huFcRH5-D9). FIG. 2E shows concentration dependent binding ELISA of FcRH5xCD28 bsAbs to human CD28 (huCD28). FIG. 2F shows concentration-dependent binding ELISA of FcRH5xCD28 bsAbs to an irrelevant protein (huCEA) as a negative control.

[0040] FIGs. 3A-3B illustrate concentration-dependent binding ELISA of FcRH5xCD28 bsAbs of the disclosure to FcRH5. FIG. 3A shows concentration-dependent binding ELISA of FcRH5xCD28 bsAbs of the disclosure to full-length FcRH5 (huFcRH5 FL). FIG. 3B shows concentration-dependent binding ELISA of FcRH5xCD28 bsAbs of the disclosure to soluble FcRH5 (sFcRH5), corresponding to domains 1 to 8 (huFcRH5 DI -8).

[0041] FIGs. 4A-4I illustrate concentration-dependent competition ELISA mediated by FcRH5 full-length (FcRH5 FL) or by FcRH5 Dl-8 (corresponding to sFcRH5). FIG. 4A shows concentration-dependent competition ELISA applied in solution to a fixed concentration of AI3AN9 / N FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. FIG. 4B shows concentration-dependent competition ELISA applied in solution to a fixed concentration of AI3AN13 / N FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. FIG. 4C shows concentration-dependent competition ELISA applied in solution to a fixed concentration ofAI3AN15 / N FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. FIG. 4D shows concentration-dependent competition ELISA applied in solution to a fixed concentration of AI3AN19 / N FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. FIG. 4E shows concentration-dependent competition ELISA applied in solution to a fixed concentration of AI3AN24 / N FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. FIG. 4F shows concentration-dependent competition ELISA applied in solution to a fixed concentration of AI3AN27 / N FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. FIG. 4G shows concentration-dependent competition ELISA applied in solution to a fixed concentration of AI3AN34 / N FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. FIG. 4H shows concentration-dependent competition ELISA applied in solution to a fixed concentration of AI3AN36 / N FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. FIG. 41 shows concentration-dependent competition ELISA applied in solution to a fixed concentration of 1G7.V85 monovalent antibody bound to immobilized FcRH5 FL.

[0042] FIGs. 5A-5B illustrate concentration-dependent binding of the FcRH5xCD28 bispecific antibodies of the disclosure to cells. FIG. 5A shows concentration-dependent binding of the FcRH5xCD28 bispecific antibodies of the disclosure to FcRH5+ and CD28+ MOLP-2 cells. FIG. 5B shows concentration-dependent binding of the FcRH5xCD28 bispecific antibodies of the disclosure to FcRH5 and CD28 double-negative J.RT3-T3.5 cells. hlgGl: isotype control.

[0043] FIG. 6 illustrates T-cell retargeted killing / lysis of MOLP-2 cells by a fixed concentration of the FcRH5xCD28 bispecific antibodies of the disclosure (16.7 nM) when combined with a dose-response (DR) of a BCMAxCD3 bsAb (Alnuctamab analog) following a 6-day incubation time. Effector cells were T cell-containing PBMCs derived from healthy donors. Effector : Target ratio (E:T) = 1:1.

[0044] FIGs. 7A-7I illustrate concentration-dependent competition ELISA by FcRH5 full- length (FcRH5 FL) or by FcRH5 DI -8 (corresponding to sFcRH5). FIG. 7A shows the concentration-dependent competition ELISA applied in solution to a fixed concentration of optimized AI3AN36 / N FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. FIG. 7B shows the concentration-dependent competition ELISA applied in solution to a fixed concentration of optimized AI3AN39 / N FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. FIG. 7C shows the concentration-dependent competition ELISA applied in solution to a fixed concentration ofoptimized AI3AN61 / N FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. FIG. 7D shows the concentration-dependent competition ELISA applied in solution to a fixed concentration of optimized AI3AN68 / N FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. FIG. 7E shows the concentration-dependent competition ELISA applied in solution to a fixed concentration of optimized AI3AN69 / N FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. FIG. 7F shows the concentration-dependent competition ELISA applied in solution to a fixed concentration of optimized AI3AN71 / N FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. FIG. 7G shows the concentration-dependent competition ELISA applied in solution to a fixed concentration of optimized AI3AN91 / N FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. FIG. 7H shows the concentration-dependent competition ELISA applied in solution to a fixed concentration of the reference FcRH5xCD28 bispecific antibody AI3xlG7.v85 / N bound to immobilized FcRH5 FL. FIG. 71 shows the concentration-dependent competition ELISA applied in solution to a fixed concentration of the reference FcRH5xCD28 bispecific antibody AI3xlOA8 / N bound to immobilized FcRH5 FL.

[0045] FIG. 8 illustrates concentration-dependent binding of the FcRH5xCD28 bispecific antibodies of the disclosure carrying an optimized anti-FcRH5 arm to FcRH5+ and CD28+ MOLP-2 cells. hlgGl: isotype control; AI3xlG7.v85 / N and AI3xl0A8 / N; FcRH5xCD28 reference bispecific antibodies.

[0046] FIG. 9 concentration dependent binding of the FcRH5xCD28 bispecific antibodies of the disclosure carrying an optimized anti-FcRH5 arm to PEAK cells transiently expressing huFcRH5. hlgGl: isotype control. AI3xlG7.v85 / N and AI3xl0A8 / N: FcRH5xCD28 reference bispecific antibodies.

[0047] FIG. 10 illustrates binding of the FcRH5xCD28 bispecific antibodies of the disclosure to human FcRHl, human FcRH2, human FcRH3, human FcRH4, human FcRH5 or cynomolgus FcRH5 transiently expressed at the surface of PEAK cells. Binding is expressed as “Factor to WT PEAK”, corresponding to the binding ratio on a target protein relative to the binding detected on WT PEAK cells (binding on transfected PEAK / binding on WT PEAK).

[0048] FIGs. 11A-11D illustrate activation and proliferation of human CD4+ and CD 8+ T cells. FIG. 11 A shows CD4+ T cell activation from 6 healthy donor PBMCs mediated by the FcRH5xCD28 bsAbs of the disclosure, following Stebbing’s assay and as assessed by quantifying the T cell activation marker CD25. FIG. 11B shows CD4+ T cell proliferation from6 healthy donor PBMCs mediated by the FcRH5xCD28 bsAbs of the disclosure, following Stebbing’s assay and as assessed by dye dilution of labelled T cells. FIG. 11C shows CD8+ T cell activation from 6 healthy donor PBMCs mediated by the FcRH5xCD28 bsAbs of the disclosure, following Stebbing’s assay and as assessed by quantifying the T cell activation marker CD25. FIG. 11D shows CD 8+ T cell proliferation from 6 healthy donor PBMCs mediated by the FcRH5xCD28 bsAbs of the disclosure, following Stebbing’s assay and as assessed by dye dilution of labelled T cells. Vehicle control: PBS; Isotype control: negative control; TGN1412 analog: positive control.

[0049] FIGs. 12A-12L illustrate T-cell retargeted killing / lysis of MOLP-2 cells by a dose range (DR) of the FcRH5xCD28 bispecific antibodies of the disclosure when combined with a fixed, suboptimal concentration of a BCMAxCD3 bsAb (Teclistamab, 0.07 nM) with an incubation time of 6 days. Effector cells were T cell-containing PBMCs derived from healthy donors. E:T = 1: 1. Killing was performed in absence or presence of soluble FcRH5 (corresponding to FcRH5 DI -8) added at either 3 or 9 pg / mL. FIG. 12A shows T-cell retargeted killing / lysis of MOLP-2 cells by the combination of a suboptimal dose of Teclistamab and a dose range (DR) of the A13AN36 / N FcRH5xCD28 bispecific antibody. FIG. 12B shows T-cell retargeted killing / lysis of MOLP-2 cells by the combination of a suboptimal dose of Teclistamab and a dose range (DR) of the A13AN39 / N FcRH5xCD28 bispecific antibody. FIG. 12C shows T-cell retargeted killing / lysis of MOLP-2 cells by the combination of a suboptimal dose of Teclistamab and a dose range (DR) of the A13AN61 / N FcRH5xCD28 bispecific antibody. FIG. 12D shows T-cell retargeted killing / lysis of MOLP-2 cells by the combination of a suboptimal dose of Teclistamab and a dose range (DR) of the A13AN68 / N FcRH5xCD28 bispecific antibody. FIG. 12E shows T-cell retargeted killing / lysis of MOLP-2 cells by the combination of a suboptimal dose of Teclistamab and a dose range (DR) of the A13AN69 / N FcRH5xCD28 bispecific antibody. FIG. 12F shows T-cell retargeted killing / lysis of MOLP-2 cells by the combination of a suboptimal dose of Teclistamab and a dose range (DR) of the A13AN71 / N FcRH5xCD28 bispecific antibody. FIG. 12G shows T-cell retargeted killing / lysis of MOLP-2 cells by the combination of a suboptimal dose of Teclistamab and a dose range (DR) of the A13AN91 / N FcRH5xCD28 bispecific antibody. FIG. 12H shows T-cell retargeted killing / lysis of MOLP-2 cells by the combination of a suboptimal dose of Teclistamab and a dose range (DR) of the AI3xlG7.v85 / N reference FcRH5xCD28 bispecific antibody. FIG. 121 shows T-cellretargeted killing / lysis of MOLP-2 cells by the combination of a suboptimal dose of Teclistamab and a dose range (DR) of the AI3xlOA8 / N reference FcRH5xCD28 bispecific antibody. FIG. 12J shows T-cell retargeted killing / lysis of MOLP-2 cells by the combination of a suboptimal dose of Teclistamab and a dose range (DR) of the FcRH5xCD28 bispecific antibodies of the disclosure in the absence of sFcRH5. FIG. 12K shows T-cell retargeted killing / lysis of MOLP- 2 cells by the combination of a suboptimal dose of Teclistamab and a dose range (DR) of the FcRH5xCD28 bispecific antibodies of the disclosure in the presence of 3 pg / mL sFcRH5. FIG. 12L shows T-cell retargeted killing / lysis of MOLP-2 cells by the combination of a suboptimal dose of Teclistamab and a dose range (DR) of the FcRH5xCD28 bispecific antibodies of the disclosure in the presence of 9 pg / mL sFcRH5. hlgGl: isotype control.

[0050] FIGs. 13A-13B illustrate T-cell retargeted killing / lysis of MOLP-2 cells across a dose range (DR) of BCMAxCD3 bsAbs when combined with a fixed concentration of AI3AN71 / N, one of the FcRH5xCD28 bispecific antibodies of the present disclosure. In FIG. 13A the CD3 bsAb was Teclistamab and AI3AN71 / N was added at 16.7 nM, in FIG. 13B the CD3 bsAb was Elranatamab and AI3AN71 / N was added at 50 nM. Effector cells were T cell-containing PBMCs derived from healthy donors. E:T = 3:1. Incubation time: 6 days. Killing was performed in the absence or presence of soluble BCMA added at 500 ng / mL.

[0051] FIGs. 14A-14D illustrate T-cell retargeted killing / lysis of MOLP-2 cells across a dose range (DR) of CD3 bsAbs (targeting either BCMA or GPRC5D) when combined with a fixed concentration (10 nM or 50 nM) of the FcH5xCD28 bispecific antibodies of the present disclosure, and with an incubation time of 6 days. Effector cells were T cell-containing PBMCs derived from healthy donors. E:T = 1 :1. In FIG. 14A the CD3 bsAb was an Alnuctamab analog (a BCMAxCD3 bsAb); in FIG. 14B the CD3 bsAb was Teclistamab (a BCMAxCD3 bsAb); in FIG. 14C the CD3 bsAb was Talquetamab (a GPRC5DxCD3 bsAb); in FIG. 14D the CD3 bsAb was Elranatamab (a BCMAxCD3 bsAb).

[0052] FIGs. 15A-15C illustrate T-cell retargeted killing / lysis of MOLP-2 cells across a dose range (DR) of CD3 bsAbs when combined with a fixed concentration (100 nM) of the FcH5xCD28 bispecific antibodies of the present disclosure. Effector cells were fresh or exhausted T cells derived from healthy donor PBMCs. E:T = 1 :2. Incubation time 6 days. In FIG. 15A the CD3 bsAb was Teclistamab; in FIG. 15B the CD3 bsAb was Elranatamab; in FIG. 15C the CD3 bsAb was Cevostamab.

[0053] FIG. 16 illustrates T-cell retargeted killing / lysis of INA-6-GFP cells induced by a fix, suboptimal dose of BCMAxCD3 bsAb (Teclistamab, 0.5 nM) when combined with a dose range (DR) of the FcH5xCD28 bispecific antibodies of the present disclosure. Effector cells were T cell-containing PBMCs derived from healthy donors. E:T = 1:1. Incubation time: 6 days.

[0054] FIG. 17A-17C illustrate T-cell retargeted killing / lysis of NCI-H929 cells across a dose range (DR) of CD3 bsAbs when combined with a fixed concentration (100 nM) of one of the FcH5xCD28 bispecific antibodies of the present disclosure (AI3AN71 / N). Effector cells were fresh or exhausted T cells derived from healthy donor PBMCs. E:T = 1 :2. Incubation time 6 days. In FIG. 17A the CD3 bsAb was Teclistamab; in FIG. 17B the CD3 bsAb was Elranatamab; in FIG. 17C the CD3 bsAb was Talquetamab.DETAILED DESCRIPTION OF THE DISCLOSURE

[0055] The therapeutic agents, compositions, methods, and kits described herein are based, inter alia, on the surprising and unexpected discovery of a new class of therapeutic agents represented by next generation antibodies targeting FcRH5 and / or FcRH5 and CD28 pathology.

[0056] The disclosed antibodies may be monospecific or bispecific. In some embodiments, the bispecific antibodies are designed to co-stimulate T cells specifically in the presence of FcRH5- positive cells. Examples of FcRH5-positive cells include but are not limited to multiple myeloma (MM) cells.

[0057] Accordingly, the present disclosure provides, inter alia, methods of treating cancer in a subject, comprising administering to the subject at least one therapeutic agent according to the present disclosure. The present disclosure also provides kits comprising at least one therapeutic agent according to the present disclosure for use in the methods described herein.Therapeutic Agents of the Present Disclosure

[0058] The present disclosure provides therapeutic agents for treating a cancer. The present disclosure also provides therapeutic agents for ameliorating one or more symptoms associated with a cancer. In some embodiments, the therapeutic agent targets FcRH5. In some embodiments, the therapeutic agent targets FcRH5 and CD28. In some embodiments, the therapeutic agent of the present disclosure preferentially binds membrane-bound FcRH5 (isoform c) relative to soluble FcRH5 (isoform a).Antibodies of the Present DisclosureANTI-FCRH5 ANTIBODIES AND BISPECIFIC ANTIBODIES

[0059] In some embodiments, a therapeutic agent of the present disclosure comprises an antibody or a fragment, variant, or multimeric version thereof. In some embodiments, a therapeutic agent of the present disclosure comprises a biantigenic (i.e., targeting two antigens) antibody, or a fragment, variant, or multimeric version thereof.

[0060] In some embodiments, a therapeutic agent of the present disclosure targets one or more epitopes of FcHR5 and / or one or more epitopes of CD28. In some embodiments, a therapeutic agent of the present disclosure targets one epitope of FcHR5 and one epitope of CD28.

[0061] In some embodiments, a therapeutic agent of the present disclosure comprises a heavy chain (HC) and a light chain (LC).

[0062] In some embodiments, the antibody is monospecific and / or monovalent. In some embodiments, the antibody is bispecific or multispecific. In some embodiments, the antibody is bivalent or multivalent. In some embodiments the antibody is bispecific or multispecific and bivalent or multivalent. In some embodiments, the antibody is bispecific and monovalent.

[0063] The disclosure relates to anti-FcRH5 antibodies. In some embodiments, the disclosure relates to monospecific anti-Fc-RH5 antibodies and / or anti-Fc-RH5 bispecific antibodies that are capable of binding membrane-bound FcRH5 (isoform c). In additional embodiments, the disclosure relates to a bispecific antibody (bsAb) capable of FcRH5-dependent T cell activation favoring tumor cell killing even in the presence of soluble FcRH5. Specifically, the disclosure is based upon bsAb co-engaging FcRH5 expressed at the surface of the target cells to mediate CD28 clustering and therefore, tumor-specific T cell activation.

[0064] The bsAbs of the disclosure are characterized by a first antigen binding domain for the monovalent co-stimulation of CD28, and a second antigen binding domain capable of binding specifically and monovalently binding to FcRH5 for the targeted delivery of the bsAb to the tumor microenvironment. The bsAbs of the disclosure are referred to herein as CD28xFcRH5 bsAbs or FcRH5xCD28 bsAbs.Heavy chain (HC)

[0065] In some aspects, the antibodies of the present disclosure comprise a common heavy chain polypeptide. In some aspects, the antibodies of the present disclosure comprise two copies of the common heavy chain polypeptide.

[0066] In some aspects, a common heavy chain polypeptide of the present disclosure comprises a heavy chain variable region (VH) and a heavy chain constant region (CH).

[0067] In some aspects, a VH comprises a CDR-H1 having an amino acid sequence of GFTFSSYA (SEQ NO: 7), a CDR-H2 having an ammo acid sequence of ISGSGGST (SEQ NO: 8) and a CDR-H3 having an amino acid sequence of AKSYGAFDY (SEQ ID NOV), as defined by the IMGT numbering system. This CDR-H “triplet” is herein referred to as the “Common Heavy Chain CDRs triplet”.

[0068] In some aspects, a VH comprises, consists essentially of, or consists of an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to the following amino acid sequence (CDRs as defined by the IMGT numbering system are underlined; herein referred to as “Common VH”): EVQLLE SGGGLVQPGGSLRLS CAASGFTFS S YAMSWVRQAPGKGLEWVSAI SGSGGSTYYADS VKGRFT I SRDNSKNTLYLQMNSLRAEDTAVYYCAKSYGAFDYWGQGTLVTVS S (SEQ ID NO:10).

[0069] In some aspects, a HC comprises, consists essentially of, or consists of an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to the amino acid sequence of SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO: 13.Light chain

[0070] In some aspects, the antibodies of the present disclosure comprise a first light chain polypeptide and a second light chain polypeptide.

[0071] In some aspects, the antibodies of the present disclosure comprise a first light chain targeting FcRH5 and a second light chain targeting CD28.

[0072] In some aspects, a light chain polypeptide of the present disclosure comprises a light chain variable region (VL) and a light chain constant region (CL).Anti-CD28 CDR triplet

[0073] In some aspects, a VL comprises a CDR-L1 having an amino acid sequence of SEQ ID NO: 14, a CDR-L2 having an amino acid sequence of SEQ ID NO: 15, and a CDR-L3 having an amino acid sequence of SEQ ID NO: 16. This CDR-L “triplet” is herein referred to as the “AI3 CDR triplet”.Anti-FcRH5 CDR triplets

[0074] In some aspects, a VL comprises a CDR-L1 having an amino acid sequence of SEQ ID NO: 29, a CDR-L2 having an amino acid sequence of SEQ ID NO: 30, and a CDR-L3 having an amino acid sequence of SEQ ID NO: 31. This CDR-L “triplet” is herein referred to as the “AN9 CDR triplet”.

[0075] In some aspects, a VL comprises a CDR-L1 having an amino acid sequence of SEQ ID NO: 32, a CDR-L2 having an amino acid sequence of SEQ ID NO: 33, and a CDR-L3 having an amino acid sequence of SEQ ID NO: 34. This CDR-L “triplet” is herein referred to as the “AN13 CDR triplet”.

[0076] In some aspects, a VL comprises a CDR-L1 having an amino acid sequence of SEQ ID NO: 35, a CDR-L2 having an amino acid sequence of SEQ ID NO: 36, and a CDR-L3 having an amino acid sequence of SEQ ID NO: 37. This CDR-L “triplet” is herein referred to as the “AN15 CDR triplet”.

[0077] In some aspects, a VL comprises a CDR-L1 having an amino acid sequence of SEQ ID NO: 38, a CDR-L2 having an amino acid sequence of SEQ ID NO: 39, and a CDR-L3 having an amino acid sequence of SEQ ID NO: 40. This CDR-L “triplet” is herein referred to as the “AN19 CDR triplet”.

[0078] In some aspects, a VL comprises a CDR-L1 having an amino acid sequence of SEQ ID NO: 41, a CDR-L2 having an amino acid sequence of SEQ ID NO: 42, and a CDR-L3 having an amino acid sequence of SEQ ID NO: 43. This CDR-L “triplet” is herein referred to as the “AN24 CDR triplet”.

[0079] In some aspects, a VL comprises a CDR-L1 having an amino acid sequence of SEQ ID NO: 44, a CDR-L2 having an amino acid sequence of SEQ ID NO: 45, and a CDR-L3 having an amino acid sequence of SEQ ID NO: 46. This CDR-L “triplet” is herein referred to as the “AN27 CDR triplet”.

[0080] In some aspects, a VL comprises a CDR-L1 having an amino acid sequence of SEQ ID NO: 47, a CDR-L2 having an amino acid sequence of SEQ ID NO: 48, and a CDR-L3 having an amino acid sequence of SEQ ID NO: 49. This CDR-L “triplet” is herein referred to as the “AN34 CDR triplet”.

[0081] In some aspects, a VL comprises a CDR-L1 having an amino acid sequence of SEQ ID NO: 50, a CDR-L2 having an amino acid sequence of SEQ ID NO: 51, and a CDR-L3having an amino acid sequence of SEQ ID NO: 52. This CDR-L “triplet” is herein referred to as the “AN36 CDR triplet”.

[0082] In some aspects, a VL comprises a CDR-L1 having an amino acid sequence of SEQ ID NO: 53, a CDR-L2 having an amino acid sequence of SEQ ID NO: 54, and a CDR-L3 having an amino acid sequence of SEQ ID NO: 55. This CDR-L “triplet” is herein referred to as the “AN39 CDR triplet”.

[0083] In some aspects, a VL comprises a CDR-L1 having an amino acid sequence of SEQ ID NO: 56, a CDR-L2 having an amino acid sequence of SEQ ID NO: 57, and a CDR-L3 having an amino acid sequence of SEQ ID NO: 58. This CDR-L “triplet” is herein referred to as the“AN61 CDR triplet”.

[0084] In some aspects, a VL comprises a CDR-L1 having an amino acid sequence of SEQ ID NO: 59, a CDR-L2 having an amino acid sequence of SEQ ID NO: 60, and a CDR-L3 having an amino acid sequence of SEQ ID NO: 61. This CDR-L “triplet” is herein referred to as the “AN68 CDR triplet”.

[0085] In some aspects, a VL comprises a CDR-L1 having an amino acid sequence of SEQ ID NO: 62, a CDR-L2 having an amino acid sequence of SEQ ID NO: 63, and a CDR-L3 having an amino acid sequence of SEQ ID NO: 64. This CDR-L “triplet” is herein referred to as the “AN69 CDR triplet”.

[0086] In some aspects, a VL comprises a CDR-L1 having an amino acid sequence of SEQ ID NO: 65, a CDR-L2 having an amino acid sequence of SEQ ID NO: 66, and a CDR-L3 having an amino acid sequence of SEQ ID NO: 67. This CDR-L “triplet” is herein referred to as the “AN71 CDR triplet”.

[0087] In some aspects, a VL comprises a CDR-L1 having an amino acid sequence of SEQ ID NO: 68, a CDR-L2 having an amino acid sequence of SEQ ID NO: 69, and a CDR-L3 having an amino acid sequence of SEQ ID NO: 70. This CDR-L “triplet” is herein referred to as the“AN91 CDR triplet”.Light chain variable region (VL) sequences

[0088] Accordingly, in some aspects, a CD28 VL comprises, consists essentially of, or consists of an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to an amino acid sequence put forth in SEQ ID NO: 17 (“AI3 VL”).

[0089] Accordingly, in some aspects, a FcRH5 VL comprises, consists essentially of, or consists of an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to an amino acid sequence put forth in SEQ ID NO: 71 (“AN9 VL”), SEQ ID NO: 72 (“AN13 VL”), SEQ ID NO: 73 (“AN15 VL”), SEQ ID NO: 74 (“AN19 VL”), SEQ ID NO: 75 (“AN24 VL”), SEQ ID NO: 76 (“AN27 VL”), SEQ ID NO: 77 (“AN34 VL”), SEQ ID NO: 78 (“AN36 VL”), SEQ ID NO: 79 (“AN39 VL”), SEQ ID NO: 80 (“AN61 VL”), SEQ ID NO: 81 (“AN68 VL”), SEQ ID NO: 82 (“AN69 VL”), SEQ ID NO: 83 (“AN71 VL”), or SEQ ID NO: 84 (“AN91 VL”).Light chain constant region (CL) sequences

[0090] In some aspects, a CL can comprise, consist essentially of, or consist of a kappa light chain sequence. In some aspects, a CL can comprise, consist essentially of, or consist of a lambda light chain sequence.

[0091] In some aspects, a CL comprises, consists essentially of, or consists of a Kappa amino acid sequence (“CL Kappa”) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to an amino acid sequence of RTVAAPSVFI FPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNS QESVTEQDSKD S TYSLS STLTLSKADYEKHKVYACEVTHQGLS S PVTKS FNRGEC (SEQ ID NO: 99).

[0092] In some aspects, a CL comprises, consists essentially of, or consists of Lambda amino acid sequence (“CL Lambda”) that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to an amino acid sequence of GQPKAAPSVTLFPPS SEELQANKATLVCLI S DFYPGAVTVAWKADS S PVKAGVETTT PSKQSN NKYAAS SYLSLTPEQWKSHRSYSCQVTHEGS TVEKTVAPTECS (SEQ ID NO: 100).Full-length light chains of the present disclosure

[0093] In some aspects, the Light Chain (LC) can comprise any one of the VLs described herein in combination with a CL described herein. In some embodiments, the CL is CL Kappa or CL Lambda. In some aspects, the CL can comprise any one of the VLs described herein in combination with an amino acid sequence that comprises, consists essentially of, or consists of SEQ ID NO: 99 or SEQ ID NO: 100. For example, SEQ ID NO: 71 may be combined with SEQ ID NO: 99 to create a AN9 Kappa LC. Additionally, SEQ ID NO: 71 may be combined with SEQ ID NO: 100 to create a AN9 Lamda LC. 1

[0094] Accordingly, in some aspects, a CD28 LC comprises, consists essentially of, or consists of an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least99% identical, or 100% identical to an amino acid sequence put forth in SEQ ID NO: 18 (“AI3 LC”).

[0095] Accordingly, in some aspects, a FcRH5 LC comprises, consists essentially of, or consists of an amino acid sequence that is at least 95%, at least 96%, at least 97%, at least 98%, at least 99% identical, or 100% identical to an amino acid sequence put forth in SEQ ID NO: 85(“AN9 LC”), SEQ ID NO: 86 (“AN13 LC”), SEQ ID NO: 87 (“AN15 LC”), SEQ ID NO: 88 (“AN19LC”), SEQ ID NO: 89 (“AN24 LC”), SEQ ID NO: 90 (“AN27 LC”), SEQ ID NO: 91 (“AN34 LC”), SEQ ID NO: 92 (“AN36 LC”), SEQ ID NO: 93 (“AN39 LC”), SEQ ID NO: 94 (“AN61 LC”), SEQ ID NO: 95 (“AN68 LC”), SEQ ID NO: 96 (“AN69 LC”), SEQ ID NO: 97 (“AN71 LC”), or SEQ ID NO: 98 (“AN91 LC”ANTI-FCRH5 ANTIBODIES

[0096] The present disclosure provides antibodies comprising two copies of a common heavy chain polypeptide as described herein, a first light chain polypeptide as described herein, and a second light chain polypeptide as described herein.

[0097] In some aspects of the antibodies described herein, one of the light chain polypeptides comprises a lambda light chain sequence (e.g., CL Lambda) and the other light chain polypeptide comprises a kappa light chain sequence (e.g., CL Kappa), referred to herein as a “kappa / lambda antibody”. In some aspects, both of the light chain polypeptides comprise a lambda light chain sequence (e.g., CL Lambda), referred to herein as a “lambda antibody”. In some aspects, both of the light chain polypeptides comprise a kappa light chain sequence (e.g. CL Kappa), referred to herein as a “kappa antibody”. For every kappa / lambda antibody, there is a corresponding cognate kappa / kappa antibody and lambda / lambda antibody.

[0098] Exemplary anti-FcHR5 antibodies of the disclosure are described below.

[0099] In some embodiments, an antibody of the present disclosure comprises a heavy chain polypeptide comprising the Common Heavy Chain CDRs triplet, and a first light chain polypeptide and second light chain polypeptide comprising the AN9 CDR triplet, AN13 CDR triplet, AN15 CDR triplet, AN19 CDR triplet, AN24 CDR triplet, AN27 CDR triplet, AN34 CDR triplet, AN36 CDR triplet, AN39 CDR triplet, AN61 CDR triplet, AN68 CDR triplet, AN69 CDR 25triplet, AN71 CDR triplet, or AN91 CDR triplet. In some embodiments, the first light chain polypeptide and the second light chain polypeptide comprise the same or different CDR triplets.

[0100] In some embodiments, an antibody of the present disclosure comprises a heavy chain polypeptide comprising, consisting of, or consisting essentially of SEQ ID NO: 10 (“Common VH”) and a first light chain polypeptide and second light chain polypeptide comprising, consisting essentially of, or consisting of SEQ ID NO: 71 ("AN9 VL"), SEQ ID NO: 72 ("AN13 VL"), SEQ ID NO: 73 ("AN15 VL"), SEQ ID NO: 74 ("AN19 VL"), SEQ ID NO: 75 ("AN24VL"), SEQ ID NO: 76 ("AN27 VL"), SEQ ID NO: 77 ("AN34 VL"), SEQ ID NO: 78 ("AN36VL"), SEQ ID NO: 79 ("AN39 VL"), SEQ ID NO: 80 ("AN61 VL"), SEQ ID NO: 81 ("AN68VL"), SEQ ID NO: 82 ("AN69 VL"), SEQ ID NO: 83 ("AN71 VL"), or SEQ ID NO: 84 ("AN91VL"). In some embodiments, the first light chain polypeptide and second light chain polypeptide further comprise, consist of, or consist essentially of SEQ ID NO: 99 (“CL Kappa”) or SEQ ID NO: 100 (“CL Lambda”). In some embodiments, the first light chain polypeptide and the second light chain polypeptide are the same or different.

[0101] In some embodiments, an antibody of the present disclosure comprises a heavy chain polypeptide comprising, consisting of, or consisting essentially of SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO: 13; and a first light chain polypeptide and second light chain polypeptide comprising, consisting essentially of, or consisting of SEQ ID NO: 85 ("AN9 LC"), SEQ ID NO: 86 ("AN13 LC"), SEQ ID NO: 87 ("AN15 LC"), SEQ ID NO: 88 ("AN19 LC"),SEQ ID NO: 89 ("AN24 LC"), SEQ ID NO: 90 ("AN27 LC"), SEQ ID NO: 91 ("AN34 LC"),SEQ ID NO: 92 ("AN36 LC"), SEQ ID NO: 93 ("AN39 LC"), SEQ ID NO: 94 ("AN61 LC"),SEQ ID NO: 95 ("AN68 LC"), SEQ ID NO: 96 ("AN69 LC"), SEQ ID NO: 97 ("AN71 LC"),SEQ ID NO: 98 ("AN91 LC"). In some embodiments, the first light chain polypeptide and the second light chain polypeptide are the same or different.

[0102] In some embodiments, the AN9 antibody has a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 29;a CDRL2 comprising the amino acid sequence of SEQ ID NO: 30; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 31.

[0103] In some embodiments, the AN13 antibody has a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 32; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 33; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 34.

[0104] In some embodiments, the AN15 antibody has a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 35; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 36; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 37.

[0105] In some embodiments, the AN19 antibody has a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 38; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 39; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 40.

[0106] In some embodiments, the AN24 antibody has a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region having a CDRL1comprising the amino acid sequence of SEQ ID NO: 41; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 42; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 43.

[0107] In some embodiments, the AN27 antibody has a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 44; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 45; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 46.

[0108] In some embodiments, the AN34 antibody has a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 47; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 48; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 49.

[0109] In some embodiments, the AN36 antibody has a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 50; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 51 ; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 52.

[0110] In some embodiments, the AN39 antibody has a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprisingthe amino acid sequence of SEQ ID NO: 9; and a light chain variable region having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 53; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 54; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 55.

[0111] In some embodiments, the AN61 antibody has a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of (SEQ ID NO: 7); a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 56; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 57; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 58.

[0112] In some embodiments, the AN68 antibody has a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 59; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 60; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 61.

[0113] In some embodiments, the AN69 antibody has a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 62; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 63; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 64.

[0114] In some embodiments, the AN71 antibody has a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acidsequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 65; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 66; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 67.

[0115] In some embodiments, the AN91 antibody has a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a light chain variable region having a CDRL1 comprising the amino acid sequence of SEQ ID NO: 68; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 69; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 70.

[0116] In some embodiments, an antibody comprises a heavy chain variable region having an amino acid sequence of SEQ ID NO: 10 and a light chain variable region having an amino acid sequence of SEQIDNO: 71 (AN9 VL), SEQIDNO: 72 (AN13 VL), SEQIDNO: 73 (AN15 VL), SEQIDNO: 74 (AN19 VL), SEQIDNO: 75 (AN24 VL), SEQIDNO: 76 (AN27 VL), SEQ ID NO: 77 (AN34 VL), SEQIDNO: 78 (AN36 VL), SEQ ID NO: 79 (AN39 VL), SEQIDNO: 80 (AN61 VL), SEQIDNO: 81 (AN68 VL), SEQ ID NO: 82 (AN69 VL), SEQ ID NO: 83 (AN71 VL), or SEQ ID NO: 84 (AN91 VL).

[0117] In some embodiments, an antibody comprises a heavy chain variable region having an amino acid sequence of SEQ ID NO: 10 and a light chain variable region having an amino acid sequence selected from: SEQ ID NO: 71 (AN9) in combination with SEQ ID NO: 99 (CL Kappa) or SEQ ID NO: 100 (CL Lambda); SEQ ID NO: 72 (AN13) in combination with SEQ ID NO: 99 or SEQIDNO: 100; SEQIDNO: 73 (AN15) in combination with SEQIDNO: 99 or SEQIDNO: 100; SEQIDNO: 74 (AN19) in combination with SEQIDNO: 99 orSEQIDNO: 100; SEQ ID NO: 75 (AN24) in combination with SEQ ID NO: 99 orSEQIDNO: 100; SEQIDNO: 76 (AN27) in combination with SEQIDNO: 99 orSEQIDNO: 100; SEQIDNO: 77 (AN34) in combination with SEQIDNO: 99 orSEQIDNO: 100; SEQIDNO: 78 (AN36) in combination with SEQ ID NO: 99 orSEQIDNO: 100; SEQIDNO: 79 combination with SEQIDNO: 99 orSEQ ID NO: 100; SEQ ID NO: 80 (AN61) in combination with SEQ ID NO: 99 orSEQ ID NO: 100; SEQ ID NO: 81 (AN68) in combination with SEQ ID NO: 99 orSEQ ID NO: 100; SEQ ID NO: 82 (AN69) in combination with SEQ ID NO: 99 orSEQ ID NO: 100; SEQ ID NO: 83 (AN71) in combination with SEQ ID NO: 99 orSEQ ID NO: 100; or SEQ ID NO: 84 (AN91) in combination with SEQ ID NO: 99 orSEQ ID NO: 100.

[0118] In some embodiments, an antibody comprises a heavy chain variable region having an amino acid sequence of SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO: 13, and a variable light chain having an amino acid sequence of SEQ ID NO: 85 (AN9 LC), SEQ ID NO: 86 (AN13 LC), SEQ ID NO: 87 (AN15 LC), SEQ ID NO: 88 (AN19 LC), SEQ ID NO: 89 (AN24 LC), SEQ ID NO: 90 (AN27 LC), SEQ ID NO: 91 (AN34 LC), SEQ ID NO: 92 (AN36 LC), SEQ ID NO: 93 (AN39 LC), SEQ ID NO: 94 (AN61 LC), SEQ ID NO: 95 (AN68 LC), SEQ ID NO: 96 (AN69 LC), SEQ ID NO: 97 (AN71 LC), or SEQ ID NO: 98 (AN91 LC).

[0119] In some embodiments of the antibodies described herein, the antibody comprises a polypeptide encoding the HC and a polypeptide encoding the LC. In some embodiments, the antibody comprises two copies of the heavy chain polypeptide. In some embodiments, the antibody comprises two copies of the light chain polypeptide. In some embodiments, the two copies of the heavy chain polypeptide are the same. In some embodiments, the two copies of the heavy chain polypeptide are different. In some embodiments, the two copies of the light chain polypeptide are the same. In some embodiments, the two copies of the light chain polypeptide are different. In some embodiments, at least a portion of the first copy of the light chain is of the kappa type and at least a portion of the second copy of the light chain is of the lambda type. In some embodiments, at least a portion of the first copy of the light chain is of the lambda type and at least a portion of the second copy of the light chain is of the kappa type. In some embodiments, at least a portion of the first and second copy of the light chain is of the lambda type. In some embodiments, at least a portion of the first and second copy of the light chain is of the kappa type.BISPECIFIC ANTIBODIES

[0120] The bsAbs antibodies according to the disclosure may be generated de novo or may be engineered from existing monospecific CD28 antibodies and FcRH5 antibodies.

[0121] The bsAbs of the disclosure can be based on any of the different antibody formats that have been previously described. In general, IgG-like formats are preferred as they provide favorable properties such as long half-life and potentially reduced immunogenicity, but any other molecular bispecific format can also be used for the disclosure.

[0122] The heavy and light chain amino acid sequences of the antibodies identified by their United States Adopted Names (US AN are available for example via the American Medical Association at https: / / www.ama-assn.org / or via the CAS registry).

[0123] Monospecific CD28 and FcRH5 binding variable domains may be selected de novo from for example a phage display library, where the phage is engineered to express human immunoglobulins or portions thereof such as Fabs, single chain variable fragments (scFv), or unpaired or paired antibody variable regions and subsequently engineered into a bispecific format. The CD28 and FcRH5 variable domains can be isolated for example from phage display libraries expressing antibody heavy and light chain variable regions as fusion proteins with bacteriophage g3 protein (scFv-g3 fusion proteins).

[0124] The antibody libraries are screened for binding CD28 antibodies and FcRH5 and the obtained positive clones are further characterized. Such phage display methods for isolating human antibodies are established in the art. See for example: U.S. Pat. Nos. 5,223,409; 5,403,484; and 5,571,698, 5,427,908, 5,580,717, 5,969,108, 6,172,197, 5,885,793; 6,521,404; 6,544,731; 6,555,313; 6,582,915 and 6,593,081. The obtained de novo variable regions binding are engineered to bispecific formats using the methods know in the art and described herein.

[0125] Additionally, bispecific antibodies of the disclosure can be made using the techniques, including those disclosed in WO 2012 / 023053, filed August 16, 2011, the contents of which are hereby incorporated by reference in their entirety. The methods described in WO 2012 / 023053 generate bispecific antibodies that are identical in structure to a human immunoglobulin. This type of molecule is composed of two copies of a unique heavy chain polypeptide, a first light chain variable region fused to a constant Kappa domain and second light chain variable region fused to a constant Lambda domain. Each combining site displays a different antigen specificity to which both the heavy and light chain contribute. The light chain variable regions can be of the Lambda or Kappa family and are preferably fused to a Lambda and Kappa constant domains, respectively. This is preferred in order to avoid the generation of non-natural polypeptide junctions.

[0126] However, it is also possible to obtain bispecific antibodies of the disclosure by fusing a Kappa light chain variable domain to a constant Lambda domain for a first specificity and / or fusing a Lambda light chain variable domain to a constant Kappa domain for the second specificity. The bispecific antibodies described in WO 2012 / 023053 are referred to as IgG KA. antibodies or “K . bodies,” a new fully human bispecific IgG format. This KA. body format allows the affinity purification of a bispecific antibody that is undistinguishable from a standard IgG molecule with characteristics that are undistinguishable from a standard monoclonal antibody and, therefore, favorable as compared to previous formats.

[0127] In addition to methods described above, bispecific antibodies of the disclosure can be generated in vitro in a cell-free environment by introducing asymmetrical mutations in the CH3 regions of two monospecific homodimeric antibodies and forming the bispecific heterodimeric antibody from two parent monospecific homodimeric antibodies in reducing conditions to allow disulfide bond isomerization according to methods described in Inti. Pat. Publ. No. WO2011 / 131746. In the methods, the first monospecific bivalent antibody and the second monospecific bivalent antibody are engineered to have certain substitutions at the CH3 domain that promoter heterodimer stability; the antibodies are incubated together under reducing conditions sufficient to allow the cysteines in the hinge region to undergo disulfide bond isomerization; thereby generating the bispecific antibody by Fab arm exchange.

[0128] Antibodies of the present disclosure have two or more antigen binding domains and are bispecific. Bispecific antibodies of the disclosure include antibodies having a full length antibody structure or partial length antibody structure such as Fab.

[0129] Exemplary anti-cell surface antibodies that may be used to engineer bispecific molecules include for example anti- tumor associate antigen antibodies know in the art, such as Pertuzumab and Trastuzumab (HER-2); Cetuximab, Necitumumab, Panitumumab and Amivantamab (EGFR); Labetuzumab and Cibisatamab (CEA); Amatuximab (mesothelin); Cordrituzumab (glypican 3); Atezolizumab, Avelumab and Durvalumab (PD-L1); Blinatumomab (CD19); Brentuximab (CD30); Daratumumab (CD38); Gemtuzumab (CD33); Tositumomab (CD22) or Obinutuzumab, Ocrelizumab, Ofatumumab, Rituximab, and Ibritumomab (CD20).

[0130] Exemplary CD28 and FcRH5 antibodies that may be used to engineer bispecific molecules include the antibodies disclosed herein. Exemplary anti-FcRH5 antibodies from whichthe FcRH5 antigen binding region can be derived from include the “AN9”, “AN13”, “AN15, “AN19”, “AN24”, AN27”, “AN34”, “AN36”, “AN39”, “AN61”, “AN68”, “AN71” or “AN91” antibody. Exemplary anti-CD28 antibodies from which the CD28 antigen binding region can be derived from include the “AI3” antibody. Table 1 shows the amino acid sequences of the regions of the antibodies of the disclosure.Table 1. Exemplary amino acid sequences of the disclosure

[0131] In some embodiments, a bispecific antibody of the present disclosure comprises a heavy chain variable region having a CDR-H1 comprising the amino acid sequence of SEQ ID NO: 7, a CDR-H2 comprising the amino acid sequence of SEQ ID NO: 8, and a CDR-H3 comprising the amino acid sequence of SEQ ID NO: 9; a first light chain variable region having a CDR-L1 comprising the amino acid sequence of SEQ ID NO: 14, a CDR-L2 comprising the amino acid sequence of SEQ ID NO: 15, and a CDR-L3 comprising the amino acid sequence of SEQ ID NO: 16; and a second light chain variable region comprising a CDR-L1, CDR-L2, and CDR-L3 comprising the amino acid sequences of SEQ ID NOs: 29, 30, and 31 (AN9 CDR triplet); SEQ ID NOs: 32, 33, and 34 (AN13 CDR triplet); SEQ ID NOs: 35, 36, and 37 (AN15 CDR triplet); SEQ ID NOs: 38, 39, and 40 (AN19 CDR triplet); SEQ ID NOs: 41, 42, and 43 (AN24 CDR triplet); SEQ ID NOs: 44, 45, and 46 (AN27 CDR triplet); SEQ ID NOs: 47, 48, and 49 (AN34 CDR triplet); SEQ ID NOs: 50, 51, and 52 (AN36 CDR triplet); SEQ ID NOs: 53, 54, and 55 (AN39 CDR triplet); SEQ ID NOs: 56, 57, and 58 (AN61 CDR triplet); SEQ ID NOs: 59, 60, and 61 (AN68 CDR triplet); SEQ ID NOs: 62, 63, and 64 (AN69 CDR triplet); SEQ ID NOs: 65, 66, and 67 (AN71 CDR triplet); or SEQ ID NOs: 68, 69, and 70 (AN91 CDR triplet).

[0132] In some embodiments, a bispecific antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 10, a first variable light chain having an amino acid sequence of SEQ ID NO: 17 (CD28VL), and a second variable light chain having an amino acid sequence of SEQ ID NO: 71 (AN9 VL), SEQ ID NO: 72 (AN13 VL), SEQ ID NO: 73 (AN15 VL), SEQ ID NO: 74 (AN19 VL), SEQ ID NO: 75 (AN24 VL), SEQ ID NO: 76 (AN27 VL),SEQ ID NO: 77 (AN34 VL), SEQ ID NO: 78 (AN36 VL), SEQ ID NO: 79 (AN39 VL), SEQ ID NO: 80 (AN61 VL), SEQ ID N0: 81 (AN68 VL), SEQ ID NO: 82 (AN69 VL), SEQ ID NO: 83 (AN71 VL), or SEQ ID NO: 84 (AN91 VL).

[0133] In some embodiments, a bispecific antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 10, a first variable light chain having an amino acid sequence of SEQ ID NO: 17 (CD28 VL) in combination with SEQ ID NO: 99 (CL Kappa) or SEQ ID NO: 100 (CL Lambda), and a second variable light chain having an amino acid sequence selected from: SEQ ID NO: 71 (AN9 VL) in combination with SEQ ID NO: 99 or SEQ ID NO: 100; SEQ ID NO: 72 (AN13 VL) in combination with SEQ ID NO: 99 or SEQ ID NO: 100; SEQ ID NO: 73 (AN15 VL) in combination with SEQ ID NO: 99 or SEQ ID NO: 100; SEQ ID NO: 74 (AN19 VL) in combination with SEQ ID NO: 99 or SEQ ID NO: 100; SEQ ID NO: 75 (AN24 VL) in combination with SEQ ID NO: 99 or SEQ ID NO: 100; SEQ ID NO: 76 (AN27 VL) in combination with SEQ ID NO: 99 or SEQ ID NO: 100; SEQ ID NO: 77 (AN34 VL) in combination with SEQ ID NO: 99 or SEQ ID NO: 100; SEQ ID NO: 78 (AN36 VL) in combination with SEQ ID NO: 99 or SEQ ID NO: 100; SEQ ID NO: 79 (AN39 VL) in combination with SEQ ID NO: 99 or SEQ ID NO: 100; SEQ ID NO: 80 (AN61 VL) in combination with SEQ ID NO: 99 or SEQ ID NO: 100; SEQ ID NO: 81 (AN68 VL) in combination with SEQ ID NO: 99 or SEQ ID NO: 100; SEQ ID NO: 82 (AN69 VL) in combination with SEQ ID NO: 99 or SEQ ID NO: 100; SEQ ID NO: 83 (AN71 VL) in combination with SEQ ID NO: 99 or SEQ ID NO: 100; or SEQ ID NO: 84 (AN91 V L) in combination with SEQ ID NO: 99 or SEQ ID NO: 100.

[0134] In some embodiments, a bispecific antibody comprises a variable heavy chain having an amino acid sequence of SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO: 13, a first variable light chain having an amino acid sequence of SEQ ID NO: 18 (CD28 LC), and a second variable light chain having an amino acid sequence of SEQ ID NO: 85 (AN9 LC), SEQ ID NO: 86 (AN13 LC), SEQ ID NO: 87 (AN15 LC), SEQ ID NO: 88 (AN19 LC), SEQ ID NO: 89 (AN24 LC), SEQ ID NO: 90 (AN27 LC), SEQ ID NO: 91 (AN34 LC), SEQ ID NO: 92 (AN36 LC), SEQ ID NO: 93 (AN39 LC), SEQ ID NO: 94 (AN61 LC), SEQ ID NO: 95 (AN68 LC), SEQ ID NO: 96 (AN69 LC), SEQ ID NO: 97 (AN71 LC), or SEQ ID NO: 98 (AN91 LC).

[0135] Table 2 provides the nomenclature used in the present disclosure. “Al” denotes anti- huCD28 arms, “AN” denotes anti-huFcRH5 arms, “ / N” denotes heavy chain with LALAPA mutation. Alternate nomenclature is shown within the parentheses.Table 2: Nomenclature and Chains Used to Generate the Panel of KX-Bodies of the Disclosure.

[0136] In some embodiments, the AI3AN9 / N bispecific antibody has a heavy chain comprising a first antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the first antigen binding domain comprises: a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a first light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 29; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 30; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 31; and a second heavy chain variable region having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9; and a second light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprisingthe amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.

[0137] In some embodiments, the AI3AN9 / N bispecific antibody has a first heavy chain variable region and a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a first light chain variable region comprising the amino acid sequence of SEQ ID NO: 71 ; and a second light chain variable region comprising the amino acid sequence of SEQ ID NO: 17.

[0138] In some embodiments, the AI3AN9 / N bispecific antibody has a first heavy chain and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the AI3AN9 / N bispecific antibody has a first light chain comprising the amino acid sequence of SEQ ID NO: 85 and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0139] In some embodiments, the AI3AN13 / N bispecific antibody has a heavy chain comprising a first antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the first antigen binding domain comprises: a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a first light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 32; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 33; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 34; and a second heavy chain variable region having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9; and a second light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.

[0140] In some embodiments, the AI3AN13 / N bispecific antibody has a first heavy chain variable region and a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a first light chain variable region comprising the amino acid sequence ofSEQ ID NO: 72; and a second light chain variable region comprising the amino acid sequence of SEQ ID NO: 17.

[0141] In some embodiments, the AI3AN13 / N bispecific antibody has a first heavy chain and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the AI3AN13 / N bispecific antibody has a first light chain comprising the amino acid sequence of SEQ ID NO: 86 and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0142] In some embodiments, the AI3AN15 / N bispecific antibody has a heavy chain comprising a first antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the first antigen binding domain comprises: a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a first light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 35; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 36; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 37; and a second heavy chain variable region having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9; and a second light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.

[0143] In some embodiments, the AI3AN15 / N bispecific antibody has a first heavy chain variable region and a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a first light chain variable region comprising the amino acid sequence of SEQ ID NO: 73; and a second light chain variable region comprising the amino acid sequence of SEQ ID NO: 17.

[0144] In some embodiments, the AI3AN15 / N bispecific antibody has a first heavy chain and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the AI3AN15 / N bispecific antibody has a first light chain comprising the aminoacid sequence of SEQ ID NO: 87 and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0145] In some embodiments, the AI3AN19 / N bispecific antibody has a heavy chain comprising a first antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the first antigen binding domain comprises: a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a first light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 38; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 39; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 40; and a second heavy chain variable region having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9; and a second light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.

[0146] In some embodiments, the AI3AN19 / N bispecific antibody has a first heavy chain variable region and a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a first light chain variable region comprising the amino acid sequence of SEQ ID NO: 74; and a second light chain variable region comprising the amino acid sequence of SEQ ID NO: 17.

[0147] In some embodiments, the AI3AN19 / N bispecific antibody has a first heavy chain and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the AI3AN19 / N bispecific antibody has a first light chain comprising the amino acid sequence of SEQ ID NO: 88 and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0148] In some embodiments, the AI3AN24 / N bispecific antibody has a heavy chain comprising a first antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the first antigen binding domain comprises: a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a first light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 41 ; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 42; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 43; and a second heavy chain variable region having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9; and a second light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.

[0149] In some embodiments, the AI3AN24 / N bispecific antibody has a first heavy chain variable region and a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a first light chain variable region comprising the amino acid sequence of SEQ ID NO: 75; and a second light chain variable region comprising the amino acid sequence of SEQ ID NO: 17.

[0150] In some embodiments, the AI3AN24 / N bispecific antibody has a first heavy chain and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the AI3AN24 / N bispecific antibody has a first light chain comprising the amino acid sequence of SEQ ID NO: 89 and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0151] In some embodiments, the AI3AN27 / N bispecific antibody has a heavy chain comprising a first antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the first antigen binding domain comprises: a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a first light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 44; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 45; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 46; and a second heavy chain variable region having a CDRH1 comprising the amino acidsequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9; and a second light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.

[0152] In some embodiments, the AI3AN27 / N bispecific antibody has a first heavy chain variable region and a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a first light chain variable region comprising the amino acid sequence of SEQ ID NO: 76; and a second light chain variable region comprising the amino acid sequence of SEQ ID NO: 17.

[0153] In some embodiments, the AI3AN27 / N bispecific antibody has a first heavy chain and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the AI3AN27 / N bispecific antibody has a first light chain comprising the amino acid sequence of SEQ ID NO: 90 and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0154] In some embodiments, the AI3AN34 / N bispecific antibody has a heavy chain comprising a first antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the first antigen binding domain comprises: a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a first light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 47; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 48; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 49; and a second heavy chain variable region having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9; and a second light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.

[0155] In some embodiments, the AI3AN34 / N bispecific antibody has a first heavy chain variable region and a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a first light chain variable region comprising the amino acid sequence of SEQ ID NO: 77; and a second light chain variable region comprising the amino acid sequence of SEQ ID NO: 17.

[0156] In some embodiments, the AI3AN34 / N bispecific antibody has a first heavy chain and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the AI3AN34 / N bispecific antibody has a first light chain comprising the amino acid sequence of SEQ ID NO: 91 and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0157] In some embodiments, the AI3AN36 / N bispecific antibody has a heavy chain comprising a first antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the first antigen binding domain comprises: a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a first light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 50; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 51; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 52; and a second heavy chain variable region having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9; and a second light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.

[0158] In some embodiments, the AI3AN36 / N bispecific antibody has a first heavy chain variable region and a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a first light chain variable region comprising the amino acid sequence of SEQ ID NO: 78; and a second light chain variable region comprising the amino acid sequence of SEQ ID NO: 17.

[0159] In some embodiments, the AI3AN36 / N bispecific antibody has a first heavy chain and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the AI3AN36 / N bispecific antibody has a first light chain comprising the amino acid sequence of SEQ ID NO: 92 and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0160] In some embodiments, the AI3AN39 / N bispecific antibody has a heavy chain comprising a first antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the first antigen binding domain comprises: a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a first light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 53; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 54; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 55; and a second heavy chain variable region having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9; and a second light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.

[0161] In some embodiments, the AI3AN39 / N bispecific antibody has a first heavy chain variable region and a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a first light chain variable region comprising the amino acid sequence of SEQ ID NO: 79; and a second light chain variable region comprising the amino acid sequence of SEQ ID NO: 17.

[0162] In some embodiments, the AI3AN39 / N bispecific antibody has a first heavy chain and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the AI3AN39 / N bispecific antibody has a first light chain comprising the amino acid sequence of SEQ ID NO: 93 and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0163] In some embodiments, the AI3AN61 / N bispecific antibody has a heavy chain comprising a first antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the first antigen binding domain comprises: a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a first light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 56; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 57; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 58; and a second heavy chain variable region having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9; and a second light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.

[0164] In some embodiments, the AI3AN61 / N bispecific antibody has a first heavy chain variable region and a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a first light chain variable region comprising the amino acid sequence of SEQ ID NO: 80; and a second light chain variable region comprising the amino acid sequence of SEQ ID NO: 17.

[0165] In some embodiments, the AI3AN61 / N bispecific antibody has a first heavy chain and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the AI3AN61 / N bispecific antibody has a first light chain comprising the amino acid sequence of SEQ ID NO: 94 and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0166] In some embodiments, the AI3AN68 / N bispecific antibody has a heavy chain comprising a first antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the first antigen binding domain comprises: a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprisingthe amino acid sequence of SEQ ID NO: 9; and a first light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 59; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 60; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 61; and a second heavy chain variable region having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9; and a second light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.

[0167] In some embodiments, the AI3AN68 / N bispecific antibody has a first heavy chain variable region and a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a first light chain variable region comprising the amino acid sequence of SEQ ID NO: 81 ; and a second light chain variable region comprising the amino acid sequence of SEQ ID NO: 17.

[0168] In some embodiments, the AI3AN68 / N bispecific antibody has a first heavy chain and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the AI3AN68 / N bispecific antibody has a first light chain comprising the amino acid sequence of SEQ ID NO: 95 and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0169] In some embodiments, the AI3AN69 / N bispecific antibody has a heavy chain comprising a first antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the first antigen binding domain comprises: a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a first light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 62; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 63; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 64; and a second heavy chain variable region having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9; and a second light chainvariable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.

[0170] In some embodiments, the AI3AN69 / N bispecific antibody has a first heavy chain variable region and a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a first light chain variable region comprising the amino acid sequence of SEQ ID NO: 82; and a second light chain variable region comprising the amino acid sequence of SEQ ID NO: 17.

[0171] In some embodiments, the AI3AN69 / N bispecific antibody has a first heavy chain and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the AI3AN69 / N bispecific antibody has a first light chain comprising the amino acid sequence of SEQ ID NO: 96 and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0172] In some embodiments, the AI3AN71 / N bispecific antibody has a heavy chain comprising a first antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the first antigen binding domain comprises: a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a first light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 65; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 66; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 67; and a second heavy chain variable region having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9; and a second light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.

[0173] In some embodiments, the AI3AN71 / N bispecific antibody has a first heavy chain variable region and a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a first light chain variable region comprising the amino acid sequence ofSEQ ID NO: 83; and a second light chain variable region comprising the amino acid sequence of SEQ ID NO: 17.

[0174] In some embodiments, the AI3AN71 / N bispecific antibody has a first heavy chain and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the AI3AN71 / N bispecific antibody has a first light chain comprising the amino acid sequence of SEQ ID NO: 97 and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.

[0175] In some embodiments, the AI3AN91 / N bispecific antibody has a heavy chain comprising a first antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the first antigen binding domain comprises: a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and a first light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 68; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 69; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 70; and a second heavy chain variable region having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9; and a second light chain variable region having: a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.

[0176] In some embodiments, the AI3AN91 / N bispecific antibody has a first heavy chain variable region and a second heavy chain variable region comprising the amino acid sequence of SEQ ID NO: 10, and a first light chain variable region comprising the amino acid sequence of SEQ ID NO: 84; and a second light chain variable region comprising the amino acid sequence of SEQ ID NO: 17.

[0177] In some embodiments, the AI3AN91 / N bispecific antibody has a first heavy chain and a second heavy chain comprising the amino acid sequence of SEQ ID NO: 13. In some embodiments, the AI3AN91 / N bispecific antibody has a first light chain comprising the aminoacid sequence of SEQ ID NO: 98 and a second light chain comprising the amino acid sequence of SEQ ID NO: 18.Compositions of the Present Disclosure

[0178] The present disclosure provides compositions for treating cancer, or one or more symptoms of cancer.PHARMACEUTICAL COMPOSITIONS

[0179] The present disclosure provides pharmaceutical compositions comprising a therapeutic agent of the present disclosure and a pharmaceutically acceptable carrier. In some embodiments the therapeutic agent is one or more antibodies of the present disclosure. In some embodiments, the one or more antibodies are one or more FcRH5 antibodies. In some embodiments, the one or more antibodies are one or more FcRH5xCD28 bispecific antibodies. In some embodiments, the one or more antibodies are one or more FcRH5 monospecific antibodies. In some embodiments, the one or more antibodies are a combination of one or more FcRH5 monospecific antibodies and one or more FcRH5xCD28 bispecific antibodies.

[0180] The antibodies of the disclosure (also referred to herein as “active compound(s)” or “therapeutic agent(s)”), and derivatives, fragments, analogs and homologs thereof, can be incorporated into composition or pharmaceutical compositions suitable for administration. Such compositions typically comprise the antibody and a pharmaceutically acceptable carrier. In some embodiments, the one or more antibodies are one or more FcRH5 monospecific antibodies and / or one or more FcRH5xCD28 bispecific antibodies.

[0181] For the antibodies described herein that comprise a kappa / lambda antibody (i.e., an antibody comprising a kappa light chain and a lambda light chain), the present disclosure provides a composition composing a plurality of kappa / lambda antibodies and their cognate kappa / kappa and lambda / lambda antibodies.

[0182] Also provided herein are compositions comprising a plurality of antibodies described herein comprising a mixture of 3 species of antibodies: (i) a first antibody species comprising a lambda light chain polypeptide, a kappa light chain polypeptide, and two copies of a common heavy chain polypeptide (ii) a second antibody species comprising two copies of the kappa light chain polypeptides, and two copies of the common heavy chain polypeptide, and (iii) a thirdantibody species comprising two copies of the lambda light chain polypeptide, and two copies of the common heavy chain polypeptide.

[0183] In some embodiments, a composition of the present disclosure comprises at least one kappa antibody described herein, or a fragment or variant thereof. In some embodiments, a composition of the present disclosure comprises at least one lambda antibody described herein, or a fragment or variant thereof. In some embodiments, a composition of the present disclosure comprises at least one kappa / lambda antibody described herein, or a fragment or variant thereof

[0184] In some embodiments, a composition of the present disclosure comprises at least one kappa antibody described herein, or a fragment or variant thereof, and at least one lambda antibody described herein, or a fragment or variant thereof.

[0185] In some embodiments, a composition of the present disclosure comprises at least one kappa antibody described herein, or a fragment or variant thereof, and at least one kappa / lambda antibody described herein, or a fragment or variant thereof.

[0186] In some embodiments, a composition of the present disclosure comprises at least one lambda antibody described herein, or a fragment or variant thereof, and at least one kappa / lambda antibody described herein, or a fragment or variant thereof.

[0187] In some embodiments, a composition of the present disclosure comprises at least one kappa antibody described herein, or a fragment or variant thereof, at least one lambda antibody described herein, or a fragment or variant thereof, and at least one kappa / lambda antibody described herein, or a fragment or variant thereof.Pharmaceutically Acceptable Carriers

[0188] A pharmaceutical composition of the disclosure is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral (e.g., inhalation), transdermal (i.e., topical), transmucosal, and rectal administration. Solutions or suspensions used for parenteral, intradermal, or subcutaneous application can include the following components: a sterile diluent such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerine, propylene glycol or other synthetic solvents; antibacterial agents such as benzyl alcohol or methyl parabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid (EDTA); buffers such as acetates, citrates or phosphates, and agents for the adjustment of tonicity such as sodium chloride or dextrose. The pH can be adjustedwith acids or bases, such as hydrochloric acid or sodium hydroxide. The parenteral preparation can be enclosed in ampoules, disposable syringes or multiple dose vials made of glass or plastic.

[0189] Pharmaceutical compositions suitable for injectable use include sterile aqueous solutions (where water soluble) or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, N.J.) or phosphate buffered saline (PBS). In all cases, the composition must be sterile and should be fluid to the extent that easy syringeability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. Prevention of the action of microorganisms can be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, polyalcohols such as manitol, sorbitol, sodium chloride in the composition. Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent which delays absorption, for example, aluminum monostearate and gelatin.

[0190] Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by filtered sterilization. Generally, dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, methods of preparation are vacuum drying and freeze-drying that yields a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

[0191] Oral compositions generally include an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form oftablets, troches, or capsules. Oral compositions can also be prepared using a fluid carrier for use as a mouthwash, wherein the compound in the fluid carrier is applied orally and swished and expectorated or swallowed. Pharmaceutically compatible binding agents, and / or adjuvant materials can be included as part of the composition. The tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: a binder such as microcrystalline cellulose, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as magnesium stearate or Sterotes; a glidant such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or a flavoring agent such as peppermint, methyl salicylate, or orange flavoring.

[0192] For administration by inhalation, the compounds are delivered in the form of an aerosol spray from pressured container or dispenser which contains a suitable propellant, e.g., a gas such as carbon dioxide, or a nebulizer.

[0193] Systemic administration can also be by transmucosal or transdermal means. For transmucosal or transdermal administration, penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art, and include, for example, for transmucosal administration, detergents, bile salts, and fusidic acid derivatives. Transmucosal administration can be accomplished through the use of nasal sprays or suppositories. For transdermal administration, the active compounds are formulated into ointments, salves, gels, or creams as generally known in the art.

[0194] The compounds can also be prepared in the form of suppositories (e.g., with conventional suppository bases such as cocoa butter and other glycerides) or retention enemas for rectal delivery.

[0195] In one embodiment, the active compounds are prepared with carriers that will protect the compound against rapid elimination from the body, such as a controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Methods for preparation of such formulations will be apparent to those skilled in the art. The materials can also be obtained commercially from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to infected cells with monoclonal antibodies to viral antigens) can also be used aspharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Patent No. 4,522,811.

[0196] It is especially advantageous to formulate oral or parenteral compositions in dosage unit form for ease of administration and uniformity of dosage. Dosage unit form as used herein refers to physically discrete units suited as unitary dosages for the subject to be treated; each unit containing a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for the dosage unit forms of the disclosure are dictated by and directly dependent on the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and the limitations inherent in the art of compounding such an active compound for the treatment of individuals.Methods of the Present Disclosure

[0197] The present disclosure provides methods for treating a medical condition in a subject.METHODS OF USE AND TREATMENT

[0198] The present disclosure provides methods for treating cancer in a subject comprising administering to the subject at least one amount of at least one therapeutic agent, therapeutic formulation, or composition described herein.

[0199] The present disclosure provides methods for preventing cancer in a subject comprising administering to the subject at least one amount of at least one therapeutic agent, formulation, or composition described herein.

[0200] The present disclosure provides methods for slowing the progression of cancer in a subject comprising administering to the subject at least one amount of at least one therapeutic agent, formulation, or composition described herein.

[0201] The present disclosure provides methods for treating, ameliorating, or preventing one or more symptoms associated with cancer in a subject comprising administering to the subject at least one amount of at least one therapeutic agent or composition described herein.

[0202] The present disclosure provides a therapeutic agent of the present disclosure for use in a method for treating cancer in a subject, the method comprising administering to the subject at least one amount of the at least one therapeutic agent. bU

[0203] The present disclosure provides a therapeutic agent of the present disclosure for use in a method for preventing cancer in a subject, the method comprising administering to the subject at least one amount of the therapeutic agent.

[0204] The present disclosure provides a therapeutic agent of the present disclosure for use in a method for slowing the progression of cancer in a subject, the method comprising administering to the subject at least one amount of the therapeutic agent.

[0205] The present disclosure provides a therapeutic agent of the present disclosure for use in a method for treating, ameliorating, or preventing one or more symptoms associated with a cancer in a subject, the method comprising administering to the subject at least one amount of the therapeutic agent.

[0206] The present disclosure provides the use of a therapeutic agent of the present disclosure in the manufacture of a medicament for treating cancer in a subject.

[0207] The present disclosure provides the use of a therapeutic agent of the present disclosure in the manufacture of a medicament for preventing cancer in a subject.

[0208] The present disclosure provides the use of a therapeutic agent of the present disclosure in the manufacture of a medicament for slowing the progression of cancer in a subject.

[0209] The present disclosure provides the use of a therapeutic agent of the present disclosure in the manufacture of a medicament methods for treating, ameliorating, or preventing one or more symptoms associated with cancer in a subject.

[0210] In some embodiments, the therapeutic agent of the present disclosure is a monospecific antibody. In some embodiments, the therapeutic agent of the present disclosure is a FcRH5 monospecific antibody. In some embodiments, the therapeutic agent of the present disclosure is a bispecific antibody. In some embodiments, the bispecific antibody is a FcRH5xCD28 bispecific antibody.

[0211] The therapeutic agent or composition of the present disclosure may be used alone or in combination with any suitable agent or conventional treatment regime. In some embodiments, the suitable agent or conventional treatment regime is a chemotherapeutic. In some embodiments, the suitable agent or conventional treatment regime is one or more T cell engagers (TCE) antibodies. Non-limiting examples of suitable agents include Alnuctamab, Elranatamab, Teclistamab, Talquetamab, and Cevostamab.

[0212] In each of the embodiments of the treatment methods described herein, the antibody of the present disclosure or fragment thereof is delivered in a manner consistent with conventional methodologies associated with management of the disease or disorder for which treatment is sought. In accordance with the disclosure herein, at least one amount of the antibody or fragment thereof is administered to a patient in need of such treatment for a time and under conditions sufficient to prevent or treat the disease or disorder.

[0213] Therapeutic formulations of the disclosure, which include one or more bsAbs of the disclosure, are used to treat or alleviate a symptom associated with a cancer, such as, by way of non-limiting example, leukemias, lymphomas, breast cancer, colon cancer, ovarian cancer, bladder cancer, prostate cancer, glioma, lung & bronchial cancer, colorectal cancer, pancreatic cancer, esophageal cancer, liver cancer, urinary bladder cancer, kidney and renal pelvis cancer, oral cavity & pharynx cancer, uterine corpus cancer, and / or melanoma. In some embodiments, the cancer is a B cell malignancy.

[0214] In some embodiments, the antibodies of the present disclosure are formulated or coadministered in combination with T cell engagers (TCE) antibodies. In some embodiments, the TCE antibodies are developed for treating multiple myeloma (e.g., Teclistamab, Alnuctamab, Talquetamab, or variants thereof). In some embodiments, the antibodies of the present disclosure are formulated or co-administered in combination with T cell engagers (TCE) antibodies, wherein there is a synergistic tumor and / or cancer cell-killing effect.

[0215] In certain embodiments, the therapeutic formulations, or uses thereof, which include the bsAbs of the disclosure, are used to treat or alleviate a symptom associated with multiple myeloma. The present disclosure also provides methods of treating or alleviating a symptom associated with a cancer. A therapeutic regimen is carried out by identifying a subject, e.g., a human patient suffering from (or at risk of developing) a cancer, using standard methods.

[0216] Efficaciousness of treatment is determined in association with any known method for diagnosing or treating the particular immune-related disorder or cancer. Alleviation of one or more symptoms of the immune-related disorder or cancer indicates that the antibody confers a clinical benefit.

[0217] In some aspects of the methods and uses of the present disclosure, an amount of a therapeutic agent, therapeutic formulation, or composition described herein can be a therapeutically effective amount.Subjects

[0218] In some aspects, a subject to be treated using the methods or kits of the present disclosure is a mammal. In some aspects, the mammal is a human.

[0219] In some aspects, the subject is a juvenile subject. In some aspects, the subject is an adult subject.

[0220] In some aspects, the human is at least about 18, at least about 20 years old, at least about 21, at least about 25 years old, at least about 30 years old, at least about 35 years old, at least about 40 years old, at least about 45 years old, at least about 50 years old, at least about 55 years old, at least about 60 years old, or at least about 61 years old, or at least about 62 years old, or at least about 63 years old, or at least about 64 years old, or at least about 65 years old, or at least about 66 years old, or at least about 67 years old, or at least about 68 years old, or at least about 69 years old, or at least about 70 years old, or at least about 71 years old, or at least about 72 years old, or at least about 73 years old, or at least about 74 years old, or at least about 75 years old, or at least about 76 years old, or at least about 77 years old, or at least about 78 years old, or at least about 79 years old, or at least about 80 years old, or at least about 81 years old, or at least about 82 years old, or at least about 83 years old, or at least about 84 years old, or at least about 85 years old, or at least about 86 years old, or at least about 87 years old, or at least about 88 years old, or at least about 89 years old, or at least about 90 years old, or at least about 91 years old, or at least about 92 years old, or at least about 93 years old, or at least about 94 years old, or at least about 95 years old, or at least about 96 years old, or at least about 97 years old, or at least about 98 years old, or at least about 99 years old, or at least about 100 years old.

[0221] In some aspects, the subject is male. In some aspects, the subject is female.

[0222] In some aspects, the subject has cancer.

[0223] In some embodiments, the cancer is a blood cancer. In some embodiments, the cancer is a B cell malignancy. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is a leukemia, a lymphoma, breast cancer, colon cancer, ovarian cancer, bladder cancer, prostate cancer, glioma, lung & bronchial cancer, colorectal cancer, pancreatic cancer, esophageal cancer, liver cancer, urinary bladder cancer, kidney and renal pelvis cancer, oral cavity & pharynx cancer, uterine corpus cancer, and / or melanoma.Kits of the Present Disclosure

[0224] Present disclosure provides kits for use in the methods described herein.

[0225] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration.

[0226] The present disclosure provides kits comprising at least one amount of a composition of the present disclosure and instructions for use. The instructions can be written instructions. A kit of the present disclosure can be used for any method described herein. In some embodiments, the instructions describe methods of treating cancer in a subject. In some embodiments, the instructions describe methods of slowing the progression of cancer in a subject. In some embodiments, the instructions describe methods of treating, ameliorating, or preventing one or more symptoms associated with cancer in a subject.

[0227] In some embodiments, the at least one amount of a composition of the present disclosure is presented in unit-dose or multi-dose containers, for example, sealed ampoules and vials (including amber vials), and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, water, immediately prior to use. In some embodiments, the at least one amount of a composition of the present disclosure is cryopreserved or frozen for transportation and storage and thawed prior to use.

[0228] In some embodiments, the unit dose comprises about 1 mL, about 2 mL, about 5 mL, about 7 mL, about 10 mL, about 15 mL, about 20 mL, about 25 mL, about 30 mL, about 35 mL, about 40 mL, about 45 mL, about 50 mL, about 60 mL, about 70 mL, about 80 mL, or about 100 mL of a composition of the present disclosure. In some embodiments, the unit dose comprises about 30 mL of a composition of the present disclosure.

[0229] In some embodiments, the unit dose comprises 1 mL, 2 mL, 5 mL, 7 mL, 10 mL, about 15 mL, 20 mL, 25 mL, 30 mL, 35 mL, 40 mL, 45 mL, 50 mL, 60 mL, 70 mL, 80 mL, or 100 mL of a composition of the present disclosure. In some embodiments, the unit dose comprises 30 mL of a composition of the present disclosure.

[0230] In some embodiments, the unit dose comprises between 1 mL and 100 mL, 5 mL and 70 mL, 10 mL and 50 mL, 20 mL to 40 mL, or 25 mL to 30 mL of a composition of the present disclosure.DEFINITIONS

[0231] As used herein, including the appended claims, the singular forms of words such as "a," "an," and "the," include their corresponding plural references unless the context clearly dictates otherwise.

[0232] As used herein, “TGN1412”, refers to a superagonistic (SA) anti-huCD28 antibody in a human IgG4 isotype as described in W02006050949. A TGN1412 analog was produced in house comprising a heavy chain and a light chain with the amino acid sequences of SEQ ID NOs: 1 and 2, respectively.

[0233] As used herein, “Alnuctamab” refers to a BCMAxCD3 bsAb in the 2+1 format based on the VLs and VHs disclosed in US 12053466B2. An Alnuctamab analog was produced in house comprising the amino acid sequences of SEQ ID NOs: 3, 4, 5, 6.

[0234] As used herein, “Teclistamab” refers to a human BCMAxCD3 bsAb in the 1+1 format sold under the brand name Tecvayli, used for the treatment of relapsed and refractory multiple myeloma. Teclistamab is available on the market and was thus purchased.

[0235] As used herein, “Talquetamab” refers to a human GPRC5DxCD3 bsAb in the 1+1 format sold under the brand name Talvey, used for the treatment of relapsed and refractory multiple myeloma. Talquetamab is available on the market and was thus purchased.

[0236] As used herein, “AI3” refers to a K . body compatible (common dummy heavy chain) anti-human CD28 agonist antibody arm that is human / cyno cross-reactive. It was originally described in WO2023170474 (which is hereby incorporated by reference in its entirety). AI3 comprises as variable heavy (VH) and variable light (VL) the amino acid sequences of SEQ ID NOs: 10 and 17, respectively.

[0237] As used herein, “ / N”, refers to a set of mutations (Leu234Ala + Leu235Ala + Pro329Ala) (i.e., LALAPA) introduced in the human IgGl Fc portion of a given antibody to abrogate Fc-mediated effector function.

[0238] As used herein, “1G7.V85” refers to an anti-FcRH5 antibody arm described in W02016205520 to be FcRH5 specific, cynomolgus cross-reactive, and capable of binding to an isoform c-specific region of the extracellular domain of FcRH5c comprising domain 9. 1G7.V85 comprises as a variable heavy (VH) chain and a variable light (VL) chain, the amino acid sequences of SEQ ID NOs: 19 and 20, respectively.

[0239] As used herein, “10A8” refers to a non-isoform selective anti-FcRH5 antibody arm that binds to FcRH5 domains D4-5. 10A8 comprises as a variable heavy (VH) chain and a variable light (VL) chain, the amino acid sequences of SEQ ID NOs: 21 and 22, respectively.

[0240] As used herein, “AI3xlG7.v85 / N” refers to a FcRH5xCD28 bsAb produced by pairing the anti-CD28 arm AI3 mentioned above to the anti-FcRH5 arm 1G7.V85 mentioned above using the CrossMAb / Knobs-Into-Hole technologies. It encompasses the / N mutations described above and comprises the amino acid sequences of SEQ ID NOs: 23, 24, 25 and 26.

[0241] As used herein, “1G7.V85 monovalent” refers to the 1G7.V85 anti-FcRH5 arm paired to an irrelevant antibody arm to generate a monovalent antibody.

[0242] As used herein, “AI3xlOA8 / N” refers to a FcRH5xCD28 bsAb produced by pairing the anti-CD28 arm AI3 mentioned above to the anti-FcRH5 arm 10A8 mentioned above using the CrossMAb / Knobs-Into-Hole technologies. It encompasses the / N mutations described above and comprises the amino acid sequences of SEQ ID NOs: 23, 24, 27 and 28.

[0243] "Affinity'' refers to the strength of the sum total 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 indicated otherwise, as used herein, "binding affinity" refers to intrinsic binding affinity which reflects a 1: 1 interaction between members of a binding pair (e.g., antibody and antigen). The affinity of a molecule X for its partner Y can generally be represented by the dissociation constant (KD). Affinity can be measured by common methods known in the art, including KinExA and Biacore.

[0244] As used herein, the term "antibody" includes, but is not limited to, monoclonal antibodies, polyclonal antibodies, multispecific antibodies (e.g., bispecific antibodies), fully human antibodies, and chimeric antibodies.

[0245] "Full length antibody" as used herein refers to an antibody having two full length antibody heavy chains and two full length antibody light chains. A full length antibody heavy chain (HC) consists of well known heavy chain variable and constant domains VH, CHI, CH2, and CH3. A full length antibody light chain (LC) consists of well known light chain variable and constant domains VL and CL. The full length antibody may be lacking the C-terminal lysine (K) in either one or both heavy chains.

[0246] Full length bispecific antibodies of the disclosure may be generated for example using Fab arm exchange (or half molecule exchange) between two monospecific bivalent antibodiesby introducing substitutions at the heavy chain CH3 interface in each half molecule to favor heterodimer formation of two antibody half molecules having distinct specificity either in vitro in cell-free environment or using co-expression. The Fab arm exchange reaction is the result of a disulfide-bond isomerization reaction and dissociation-association of CH3 domains. The heavy-chain disulfide bonds in the hinge regions of the parent monospecific antibodies are reduced. The resulting free cysteines of one of the parent monospecific antibodies form an inter heavy-chain disulfide bond with cysteine residues of a second parent monospecific antibody molecule and simultaneously CH3 domains of the parent antibodies release and reform by dissociation-association. The CH3 domains of the Fab arms may be engineered to favor heterodimerization over homodimerization. The resulting product is a bispecific antibody having two Fab arms or half molecules which each bind a distinct epitope.

[0247] "Homodimerization" as used herein refers to an interaction of two heavy chains having identical CH3 amino acid sequences. "Homodimer" as used herein refers to an antibody having two heavy chains with identical CH3 amino acid sequences.

[0248] "Heterodimerization" as used herein refers to an interaction of two heavy chains having non-identical CH3 amino acid sequences. "Heterodimer" as used herein refers to an antibody having two heavy chains with non-identical CH3 amino acid sequences.

[0249] The "knob-in-hole" strategy (see, e.g., PCT Inti. Publ. No. WO 2006 / 028936) may be used to generate full length bispecific antibodies. Briefly, selected amino acids forming the interface of the CH3 domains in human IgG can be mutated at positions affecting CH3 domain interactions to promote heterodimer formation. An amino acid with a small side chain (hole) is introduced into a heavy chain of an antibody specifically binding a first antigen and an amino acid with a large side chain (knob) is introduced into a heavy chain of an antibody specifically binding a second antigen. After co-expression of the two antibodies, a heterodimer is formed as a result of the preferential interaction of the heavy chain with a "hole" with the heavy chain with a "knob". Exemplary CH3 substitution pairs forming a knob and a hole are (expressed as modified position in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain): T366Y / F405A, T366W / F405W, F405W / Y407A, T394W / Y407T, T394S / Y407A, T366W / T394S, F405W / T394S andT366W / T366S L368 A_Y407V.

[0250] Other strategies such as promoting heavy chain heterodimerization using electrostatic interactions by substituting positively charged residues at one CH3 surface and negatively charged residues at a second CH3 surface may be used, as described in US Pat. Publ. No. US2010 / 0015133; US Pat. Publ. No. US2009 / 0182127; US Pat. Publ. No. US2010 / 028637 or US Pat. Publ. No. US2011 / 0123532. In other strategies, heterodimerization may be promoted by following substitutions (expressed as modified position in the first CH3 domain of the first heavy chain / modified position in the second CH3 domain of the second heavy chain): L351Y_F405A_Y407V / T394W, T366I_K392M_T394W / F405A_Y407V,T366L_K392M_T394W / F405A_Y407V, L351 Y_Y407A / T366A_K409F,L351Y_Y407A / T366V_K409F, Y407A / T366A_K409F, orT350V_L351Y_F405A_Y407V / T350V_T366L_K392L_T394W as described in U.S. Pat. Publ. No. US2012 / 0149876 or U.S. Pat. Publ. No. US2013 / 0195849.

[0251] As used herein, unless otherwise indicated, "antigen-binding fragment" refers to antigen-binding fragments of antibodies, i.e. antibody fragments that retain the ability to bind to the antigen bound by the full-length antibody, e.g. fragments that retain one or more CDR regions. Examples of antibody binding fragments include, but are not limited to, Fab, Fab', F(ab')2, Fv fragments and individual antibody heavy chains or light chains, and individual heavy chain or light chain variable regions.

[0252] A "Fab fragment" is comprised of one light chain and the CHI and variable regions of one heavy chain. The heavy chain of a Fab molecule cannot form a disulfide bond with another heavy chain molecule. A "Fab fragment" can be the product of papain cleavage of an antibody.

[0253] The term "Fab-arm" or "half molecule" refers to one heavy chain-light chain pair that specifically binds an antigen.

[0254] A "Fc" region contains two heavy chain fragments comprising the CH2 and CH3 domains of an antibody. The two heavy chain fragments are held together by two or more disulfide bonds and by hydrophobic interactions of the CH3 domains.

[0255] A "Fab' fragment" contains one light chain and a portion or fragment of one heavy chain that contains the VH domain and the CHI domain and also the region between the CHI and CH2 domains, such that an interchain disulfide bond can be formed between the two heavy chains of two Fab' fragments to form a F(ab')2 molecule.

[0256] A "F(ab')2 fragment" contains two light chains and two heavy chains containing a portion of the constant region between the CHI and CH2 domains, such that an interchain disulfide bond is formed between the two heavy chains. A F(ab')2 fragment thus is composed of two Fab' fragments that are held together by a disulfide bond between the two heavy chains. An "F(ab')2 fragment" can be the product of pepsin cleavage of an antibody. The "Fv region" comprises the variable regions from both the heavy and light chains but lacks the constant regions.

[0257] “Isolated antibody" refers to the purification status and in such context means the molecule is substantially free of other biological molecules such as nucleic acids, proteins, lipids, carbohydrates, or other material such as cellular debris and growth media. Generally, the term "isolated" is not intended to refer to a complete absence of such material or to an absence of water, buffers, or salts, unless they are present in amounts that substantially interfere with experimental or therapeutic use of the binding compound as described herein.

[0258] The term "monoclonal antibody", as used herein, refers to a population of substantially homogeneous antibodies, i.e., the antibody molecules comprising the population are identical in amino acid sequence except for possible naturally occurring mutations that may be present in minor amounts. In contrast, conventional (polyclonal) antibody preparations typically include a multitude of different antibodies having different amino acid sequences in their variable domains that are often specific for different epitopes. The modifier "monoclonal" indicates the character of the antibody as being obtained from a substantially homogeneous population of antibodies, and is not to be construed as requiring production of the antibody by any particular method. For example, the monoclonal antibodies to be used in accordance with the present disclosure may be made by the hybridoma method first described by Kohler et al. (1975) Nature 256: 495, or may be made by recombinant DNA methods (see, e.g., U.S. Pat. No. 4,816,567). The "monoclonal antibodies" may also be isolated from phage antibody libraries using the techniques described in Clackson et al. (1991) Nature 352: 624-628 and Marks et al. (1991) J. Mol. Biol. 222: 581-597, for example. See also Presta (2005) J. Allergy Clin. Immunol. 116:731.

[0259] The term "fully human antibody" refers to an antibody that comprises human immunoglobulin protein sequences only. A fully human antibody may contain murine carbohydrate chains if produced in a mouse, in a mouse cell, or in a hybridoma derived from a mouse cell. Similarly, "mouse antibody" refers to an antibody that comprises mouseimmunoglobulin sequences only. Alternatively, a fully human antibody may contain rat carbohydrate chains if produced in a rat, in a rat cell, or in a hybridoma derived from a rat cell. Similarly, "rat antibody" refers to an antibody that comprises rat immunoglobulin sequences only.

[0260] In general, the basic "antibody" structural unit comprises a tetramer. In a monospecific antibody, each tetramer includes two identical pairs of polypeptide chains, each pair having one "light" (about 25 kDa) and one "heavy" chain (about 50-70 kDa). The amino-terminal portion of each chain includes a "variable region" or "variable domain" of about 100 to 110 or more amino acids primarily responsible for antigen recognition. The carboxy-terminal portion of the heavy chain may define a constant region primarily responsible for effector function.

[0261] Typically, human constant light chains are classified as kappa and lambda light chains. Furthermore, human constant heavy chains are typically classified as mu, delta, gamma, alpha, or epsilon, and define the antibody's isotype as IgM, IgD, IgG, IgA, and IgE, respectively. Subtypes of these IgG include, for example, IgGl and IgG4.

[0262] "Variable region," "variable domain, " "V region," or "V chain" as used herein means the segment of IgG chains which is variable in sequence between different antibodies. A "variable region" of an antibody refers to the variable region of the antibody light chain or the variable region of the antibody heavy chain, either alone or in combination. The variable region of the heavy chain may be referred to as "VH." The variable region of the light chain may be referred to as "VL." Typically, the variable regions of both the heavy and light chains comprise three hypervariable regions, also called complementarity determining regions (CDRs), which are located within relatively conserved framework regions (FR). The CDRs are usually aligned by the framework regions, enabling binding to a specific epitope. In general, from N-terminal to C- terminal, both light and heavy chains variable domains comprise FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The assignment of amino acids to each domain is, generally, in accordance with the definitions of Sequences of Proteins of Immunological Interest, Kabat, et al.; National Institutes of Health, Bethesda, Md.; 5th ed.; NIH Publ. No. 91-3242 (1991); Kabat (1978) Adv. Prot. Chem. 32:1-75; Kabat, et al., (1977) J. Biol. Chem. 252:6609-6616; Chothia, et al., (1987) J Mol. Biol. 196:901-917 or Chothia, et al., (1989) Nature 342:878-883.

[0263] A "CDR" refers to one of three hypervariable regions (Hl, H2, or H3) within the nonframework region of the antibody VH beta-sheet framework, or one of three hypervariable regions(LI, L2, or L3) within the non-framework region of the antibody VL beta-sheet framework. Accordingly, CDRs are variable region sequences interspersed within the framework region sequences. CDR regions are well known to those skilled in the art and have been defined by, for example, Kabat as the regions of most hypervariability within the antibody variable domains. CDR region sequences also have been defined structurally by Chothia as those residues that are not part of the conserved beta-sheet framework, and thus are able to adapt to different conformation. Both terminologies are well recognized in the art. CDR region sequences have also been defined by AbM, Contact, and IMGT. The positions of CDRs within a canonical antibody variable region have been determined by comparison of numerous structures (Al- Lazikani et al., 1997, J. Mol. Biol. 273:927-48; Morea etal., 2000, Methods 20:267-79). Because the number of residues within a hypervariable region varies in different antibodies, additional residues relative to the canonical positions are conventionally numbered with a, b, c and so forth next to the residue number in the canonical variable region numbering scheme (ALLazikani et al., supra). Such nomenclature is similarly well known to those skilled in the art. Correspondence between the numbering system, including, for example, the Kabat numbering and the IMGT unique numbering system, is well known to one skilled in the art. In some embodiments, the CDRs are as defined by the Kabat numbering system. In other embodiments, the CDRs are as defined by the IMGT numbering system. In yet other embodiments, the CDRs are as defined by the AbM numbering system. In still other embodiments, the CDRs are as defined by the Chothia numbering system. In yet other embodiments, the CDRs are as defined by the Contact numbering system.

[0264] Sequence identity refers to the degree to which the amino acids of two polypeptides are the same at equivalent positions when the two sequences are optimally aligned.

[0265] Sequence similarity includes identical residues and non-identical, biochemically related amino acids. Biochemically related amino acids that share similar properties and may be interchangeable are discussed above.

[0266] "Conservatively modified variants" or "conservative substitution" refers to substitutions of amino acids in a protein with other amino acids having similar characteristics (e.g. charge, side-chain size, hydrophobicity / hydrophilicity, backbone conformation and rigidity, etc.), such that the changes can frequently be made without altering the biological activity of the protein. Those of skill in this art recognize that, in general, single amino acid substitutions innon-essential regions of a polypeptide do not substantially alter biological activity (see, e.g., Watson et al. (1987) Molecular Biology of the Gene, The Benjamin / Cummings Pub. Co., p. 224 (4th Ed.)). In addition, substitutions of structurally or functionally similar amino acids are less likely to disrupt biological activity.

[0267] The term "epitope," as used herein, refers to an area or region on an antigen to which an antibody or antigen-binding fragment binds. Binding of an antibody or antigen-binding fragment thereof disclosed herein to an epitope means that the antibody or antigen-binding fragment thereof binds to one or more amino acid residues within the epitope.

[0268] "Isolated" nucleic acid molecule or polynucleotide means a DNA or RNA, e.g., of genomic, mRNA, cDNA, or synthetic origin or some combination thereof which is not associated with all or a portion of a polynucleotide in which the isolated polynucleotide is found in nature, or is linked to a polynucleotide to which it is not linked in nature. For purposes of this disclosure, it should be understood that "a polynucleotide comprising" (or the like) a particular nucleotide sequence does not encompass intact chromosomes. Isolated polynucleotides "comprising" specified nucleic acid sequences may include, in addition to the specified sequences, coding sequences for up to ten or even up to twenty or more other proteins or portions or fragments thereof or may include operably linked regulatory sequences that control expression of the coding region of the recited nucleic acid sequences, and / or may include vector sequences.

[0269] The phrase "control sequences" refers to polynucleotide sequences necessary or helpful for the expression of an operably linked coding sequence in a particular host organism. The control sequences that are suitable for prokaryotes, for example, include a promoter, optionally an operator sequence, and a ribosome binding site. Eukaryotic cells are known to use promoters, polyadenylation signals, and enhancers. In an embodiment of the disclosure, the polynucleotide is operably linked to a promoter such as a viral promoter, a CMV promoter, an SV40 promoter or a non-viral promoter or an elongation factor (EF)-l promotor; and / or an intron.

[0270] A nucleic acid is "operably linked" when it is placed into a functional relationship with another polynucleotide. For example, DNA for a pre-sequence or secretory leader is operably linked to DNA for a polypeptide if it is expressed as a pre-protein that participates in the secretion of the polypeptide; a promoter or enhancer is operably linked to a coding sequence if it affects the transcription of the sequence; or a ribosome binding site is operably linked to a coding sequence if it is positioned so as to facilitate translation. Generally, but not always, "operablylinked" means that the polynucleotide sequences being linked are contiguous, and, in the case of a secretory leader, contiguous and in reading phase. However, enhancers do not have to be contiguous. Linking is accomplished by ligation at convenient restriction sites. If such sites do not exist, the synthetic oligonucleotide adaptors or linkers are used in accordance with conventional practice.

[0271] As used herein, the expressions "cell," "cell line," and "cell culture" are used interchangeably and all such designations include progeny. Thus, the words "transformants" and "transformed cells" include the primary subject cell and cultures derived therefrom without regard for the number of transfers. It is also understood that not all progeny will have precisely identical DNA content, due to deliberate or inadvertent mutations. Mutant progeny that have the same function or biological activity as screened for in the originally transformed cell are included. Where distinct designations are intended, it will be clear from the context.

[0272] Host cells include eukaryotic and prokaryotic host cells, including mammalian cells. Host cells include, inter aha, Chinese hamster ovary (CHO) cells, NSO, SP2 cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2), A549 cells, 3T3 cells and HEK-293 cells. Mammalian host cells include human, mouse, rat, dog, monkey, pig, goat, bovine, horse and hamster cells. Other cell lines that may be used are insect cell lines (e.g., Spodoptera frugiperda or Tri chop lusia ni), amphibian cells, bacterial cells, plant cells and fungal cells. Fungal cells include yeast and filamentous fungus cells including, for example, Pichia pastoris, Pichia finlandica, Pichia trehalophia, Pichia koclamae, Pichia membranaefaciens, Pichia minuta (Ogataea minuta, Pichia lindnen), Pichia opuntiae, Pichia thermotolerans, Pichia salictaria, Pichia guercuum, Pichia pijperi, Pichia stiptis, Pichia methanolica, Pichia sp., Saccharomyces cerevisiae, Saccharomyces sp., Hansenula polymorpha, Kluyveromyces sp., Kluyveromyces lactis, Candida albicans, Aspergillus nidulans, Aspergillus niger, Aspergillus oryzae, Trichoderma reesei, Chrysosporium lucknowense, Fusarium sp., Fusarium gramineum, Fusarium venenatum, Physcomitrella patens and Neurospora crassa. Pichia sp., any Saccharomyces sp., Hansenula polymorpha, any Kluyveromyces sp., Candida albicans, any Aspergillus sp., Trichoderma reesei, Chrysosporium lucknowense, any Fusarium sp., Yarrowia lipolytica, and Neurospora crassa. The present disclosure includes any host cell (e.g., a CHO cell or Pichia cell, e.g., Pichia pastoris) containing1an anti-ILT4 antibody or antigen-binding fragment thereof or containing a polynucleotide encoding such an antibody or fragment or containing a vector that contains the polynucleotide.

[0273] "Treat" or "treating" means to administer antibodies or antigen-binding fragments thereof of the present disclosure, to a subject having one or more symptoms of a disease for which the antibodies and antigen-binding fragments are effective, e.g., in the treatment of a subject having cancer or an infectious disease, or being suspected of having cancer or infectious disease, for which the agent has therapeutic activity. Typically, the antibody or fragment is administered in an "effective amount" or "effective dose" or “therapeutically effective amount” or “therapeutically effective dose” which will alleviate one or more symptoms (e.g., of cancer or infectious disease) in the treated subject or population, whether by inducing the regression or elimination of such symptoms or by inhibiting the progression of such symptom(s), e.g., cancer symptoms such as tumor growth or metastasis, by any clinically measurable degree. The effective amount of the antibody or fragment may vary according to factors such as the disease stage, age, and weight of the patient, and the ability of the drug to elicit a desired response in the subject.

[0274] As used herein, the term “pharmaceutically acceptable carrier” is intended to include any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, compatible with pharmaceutical administration. Suitable carriers are described in the most recent edition of Remington’s Pharmaceutical Sciences, a standard reference text in the field, which is incorporated herein by reference. Preferred examples of such carriers or diluents include, but are not limited to, water, saline, ringer’s solutions, dextrose solution, and 5% human serum albumin. Liposomes and non-aqueous vehicles such as fixed oils may also be used. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the compositions is contemplated. Supplementary active compounds can also be incorporated into the compositions.EXAMPLESExample 1: Cloning, Expression and Purification of Recombinant FcRH5 Variants

[0275] The sequence corresponding to the complete extracellular domain (ECD) of human FcRH5 (huFcRH5 FL, corresponding to domains 1 to 9 (DI -9)) was synthesized and subcloned into a suitable mammalian expression vector. The vector was modified to introduce an Avitag™ (Avidity, Denver Colo.) and a hexa-histidine tag at the C-terminus. Additionally, truncated forms of human FcRH5 were generated by expressing only parts of the FcRH5 ECD. Namely FcRH5 extracellular domains 7, 8 and 9 (FcRH5 D7-8-9); FcRH5 extracellular domains 8 and 9 (FcRH5 D8-9); FcRH5 extracellular domain 9 only (FcRH5 D9); tandem FcRH5 extracellular domain 9 (FcRH5 D9-D9); FcRH5 extracellular domains 1 to 8 (FcRH5 Dl-8). Vectors encoding for the full-length version of human FcRH 1, 2, 3, 4, 5 and cynomolgus FcRH5 were generated for expression at the cell surface of PEAK and / or CHO cells. Similarly, vectors encoding the truncated versions of human FcRH5 D7-8 and D9 were generated for expression at the cell surface of PEAK and / or CHO cells.

[0276] Plasmids mentioned above were then transfected into HEK293 cells using polyethylenimine for transient expression of the desired recombinant proteins.

[0277] Purification of recombinant soluble protein was carried out by IMAC (Immobilized Metal Ion Affinity Chromatography).Example 2: Phage Display Selection of FcRH5 Fvs Using Human scFv Libraries Containing Fixed Variable heavy domain

[0278] General procedures for construction and handling of human scFv libraries displayed on M13 bacteriophage are described in Vaughan et al., (Nat. Biotech. 1996, 14:309-314), hereby incorporated by reference in its entirety. The libraries for selection and screening encode scFv that all share the same VH domain and are solely diversified in the VL domain. Methods for the generation of fixed VH libraries and their use for the identification and assembly of bispecific antibodies are described in US20120184716 and W02012023053, each of which is hereby incorporated by reference in its entirety. The procedures to identify scFv binding to human FcRH5 (huFcRH5) are described below. Selections were performed in solution with biotinylated huFcRH5 protein (complete ECD or truncated versions, described below). Selection strategies included up to 4 rounds of selections on the recombinant proteins.

[0279] Protein Selections

[0280] Aliquots of scFv phage libraries were blocked with PBS containing 2% (w / v) skimmed milk. Blocked phages were first deselected on streptavidin / neutravidin magnetic beads (Dynabeads™ MyOne™ Streptavidin T1 Magnetic Beads or Sera-Mag SpeedBeads Neutravidin™ Coated Magnetic Particles) then pre- incubated with 100 nM, 10 nM or 1 nM of biotinylated recombinant human FcRH5 variants. The following human recombinant proteins were used in selections: full-length extracellular domain of FcRH5 (FcRH5 FL, corresponding to domains 1 to 9 (Dl-9)); FcRH5 extracellular domains 7, 8 and 9 (D7-8-9); FcRH5 extracellular domains 8 and 9 (D8-9); FcRH5 extracellular domain 9 only (D9); tandem FcRH5 extracellular domain 9 (D9-D9). FcRH5 extracellular domains 1 to 8 (DI -8, corresponding to the soluble FcRH5 isoform) was used as counterselection reagent. The phage + antigen mix was then captured by blocked magnetic beads (the same kind used for the deselection) and washed five times with PBS / 0.1% Tween® 20 and twice with PBS only. Phages were eluted with 1 mg / mL Trypsin and, after the addition of AEBSF to block trypsin activity, directly added to exponentially growing TGI cells. An aliquot of the infected TGI was serial diluted to titer the selection outputs. Outputs were then rescued and used for the next round of selection.Example 3: Screening for scFv Binding / Non-binding to human FcRH5

[0281] Screening of scFvs for binding to FcRH5 was tested by ELISA using various biotinylated human FcRH5 proteins. Neutravidin-coated plates were blocked with 1% casein in PBS. Biotinylated FcRH5 variants (described above in Example 2) were captured at 5 nM or 1.5 nM. An irrelevant protein was similarly coated and used as negative control. Dilution of freshly prepared periplasmic extracts containing the selected scFvs were applied to the plates and detected using a combination of mouse anti-c-myc antibody and donkey anti-mouse IgG HRP antibody. The OD at 450 nm generated following the addition of TMB was measured using a microplate spectrophotometer. Hits were classified as specific binders if unable to bind to the irrelevant protein and if the OD450 on huFcRH5-FL or huFcRH5-D9 was at least 3 times higher than the background OD450.

[0282] Positive and specific hits were sequenced following DNA extraction from single clones.Example 4: Fixed VH Candidates Reformatting into IgG and Transient Expression inMammalian Cells

[0283] After screening and sequencing, scFv candidates with the desired binding properties were reformatted into IgG and expressed by transient transfection in PEAK cells. The VH and VL sequences of selected scFv were amplified with specific oligonucleotides and cloned into an expression vector containing the heavy and light chain constant regions. The expression vectors were verified by sequencing and transfected into mammalian cells using Lipofectamine 2000 (Thermo Fisher Scientific) according to manufacturer's instructions. Briefly, 4x106PEAK cells were cultured in T75 flasks in 25 ml culture media containing fetal bovine serum. Transfected cells were cultured for 5-6 days at 37°C, IgG production was quantified using an Octet RED96 instrument. The supernatant was harvested for IgG purification on FcXL affinity resin (Thermo Fisher Scientific) according to manufacturer's instructions. Briefly, supernatants from transfected cells were incubated overnight at 4°C with an appropriate amount of FcXL resin. After resin wash with PBS, samples were loaded on Amicon Pro column and the IgG consequently eluted in 50 mM Glycine pH 3.5. The eluted IgG fraction was then dialyzed by Amicon 50kDa against Histidine NaCl pH 6.0 buffer and the IgG content was quantified by absorption at 280 nm. Purity and IgG integrity were verified by electrophoresis using an Agilent Bioanalyzer 2100 according to manufacturer’s instructions (Agilent Technologies).Example 5: Binding of anti-FcRH5 mAbs to recombinant target proteins by ELISA

[0284] The binding capacity of the anti-FcRH5 antibody arms of the disclosure, tested as bivalent mAbs, was assessed by ELISA using a panel of recombinant FcRH5 protein variants.

[0285] 50 pL of biotinylated huFcRH5 FL, of huFcRH5 D7-8-9, of huFcRH5 D8-9, of huFcRH5 D9 or of an irrelevant protein (either huGPC3 or huCEA) were coated at 0.5 pg / mL on pre-blocked 96 streptawell black plates (Greiner, 655997) for 30 min at RT. Plates were washed 3 times with PBS / Tween (0.05%) and 50 pL of serial dilution of antibodies in PBS / BSA (2%) / Tween (0.05%) were added and incubated for 1 h at RT. Plates were washed again with PBS / Tween (0.05%) before being incubated 1 h at RT with 50 pL of goat anti-human IgG Fc- HRP (Jackson ImmunoResearch, 109-035-098, 1:5000 diluted). After 3 washes with PBS / Tween (0.05%), 50 pL of Amplex Red solution were added and plates were incubated 20 min in thedark. Fluorescence signal was measured using a Synergy HT (BioTek) microplate reader (530 / 590 nm). FIGs. 1A-1AB show the binding profile of a given candidate on all tested proteins. Candidates with different binding profiles were obtained. Based on the profiles, candidates could be grouped into D1-D6 binders (e.g. AN_1B3), D7 binders (e.g. AN_1E6 and AN_1A1), D8 binders (e.g. AN_2F11 and AN_2F7) or D9 binders (e.g. AN_2H5 and AN36).Example 6: Expression and Purification of Bispecific Antibodies Carrying a Lambda and a Kappa Light Chain

[0286] The simultaneous expression of one heavy chain and two light chains in the same cell can lead to the assembly of three different antibodies. Simultaneous expression can be achieved in different ways such as that the transfection of multiple vectors expressing one of the chains to be co-expressed or by using vectors that drive multiple gene expression.

[0287] Here, the two light chains were cloned into the vector pNovi KHA. that was previously generated to allow for the co-expression of one heavy chain, one Kappa light chain and one Lambda light chain as described in US20120184716 and W02012023053, each of which is hereby incorporated by reference in its entirety. The expression of the three genes is driven by human cytomegalovirus promoters (hCMV) and the vector also contains a glutamine synthetase gene (GS) that enables the selection and establishment of stable cell lines. The common VH and the VL genes of the anti-CD28 IgG and of the anti-FcRH5 IgG were cloned in the vector pNovi KHX, for transient expression in mammalian cells. Expi293 cells were cultured in suspension in an appropriate Erlenmeyer flask with suitable number of cells and culture medium volume. Plasmid DNA was transfected into Expi293 cells using PEI. Antibody concentration in the supernatant of transfected cells was measured during the production using an Octet RED96. According to antibody concentration, supernatants were harvested 5 to 7 days after transfection and clarified by filtration after addition of diatomaceous earth (Sartorius). The purification was based on a three-step purification process. First, the Captures elect™ FcXL affinity matrix (Thermo Fisher Scientific) was washed with PBS and then added in the clarified supernatant. After incubation overnight at +4°C and 15 rpm, supernatants were centrifuged at 850 g for 10 min, flow through was stored and resin were washed twice with PBS. Then, the resin was transferred on Amicon Pro columns and a solution containing 50 mM glycine at pH 3.5 was usedfor elution. Several elution fractions were generated, neutralized with Tris-HCl pH 7.4 and pooled. The pool containing total human IgGs (the bispecific and the two monospecific antibodies) was quantified using a Nanodrop spectrophotometer (NanoDrop Technologies). A small aliquot was stored for further analysis and the remaining sample was incubated for 30 min at RT and 15 rpm with the appropriate volume of Captures elect™ KappaXP affinity matrix (Thermo Fisher Scientific). Resin recovery and wash, elution and neutralization steps were performed as described above. The last affinity purification step was performed using the CaptureSelect™ LambdaXP affinity matrix (Thermo Fisher Scientific) applying the same process as for the kappa purification step. Alternatively, the purification was based on a two-step purification process, where only the CaptureSelect™ KappaXP affinity matrix and the CaptureSelect™ LambdaXP affinity matrix were used. All elution fractions were pooled and desalted against Histidine-NaCl pH 6.0 formulation buffer using 50 kDa Amicon Ultra centrifugal filter units (Merck Millipore). The final product was quantified using the Nanodrop.

[0288] Purified bispecific antibodies were analyzed by electrophoresis in denaturing and reducing conditions using an Agilent 2100 Bioanalyzer with the Protein 80 kit as described by the manufacturer (Agilent Technologies). The aggregate level was determined by SEC-UPLC. Bispecific sample purity was assessed by isoelectric focusing. Samples to be used in vivo were tested for endotoxin contamination using the Limulus Amebocyte Lysate test (LAL; Charles River Laboratories).Example 7: in vitro Characterization of FcRH5xCD28 Bispecific Antibodies

[0289] Binding of FcRH5xCD28 bsAbs of the disclosure to FcRH5 was tested by ELISA using various biotinylated huFcRH5 proteins. Additionally, binding to recombinant huCD28 was also assessed to confirm binding to CD28 via the anti-CD28 binding arm. Binding to recombinant huCEA was determined to exclude non-specific candidates.

[0290] Neutravidin-coated plates were blocked with PBS / BSA (2%) / Tween (0.05%). Biotinylated huFcRH5 variants (described above in Example 2) were captured at 5 nM or 1.5 nM. Dilutions of FcRH5xCD28 bsAbs were applied to the plates and detected using a goat antihuman IgG Fc-HRP (Jackson ImmunoResearch, 109-035-098, 1:5000 diluted). The OD at 450 nm generated following the addition of TMB was measured using a microplatespectrophotometer. The binding of all FcRH5xCD28 bsAbs to each recombinant protein is shown in FIGs. 2A-2F. As expected, all FcRH5xCD28 bsAbs bound similarly to huCD28, since they all carry the same anti-CD28 arm. Low background on the irrelevant protein was detected for all but one candidate (AI3AN9 / N). Binding signals to the different FcRH5 proteins differed from one candidate to another, with candidate AI3 AN36 / N resulting in high binding to the D9 domain of FcRH5, thus suggesting preferential binding of the membrane-bound form of FcRH5.

[0291] The binding of FcRH5xCD28 bsAbs to the recombinant truncated version of FcRH5 corresponding to the soluble form of FcRH5 (sFcRH5, that is, the domains DI to D8) was tested and compared to the binding to the full length FcRH5 (FcRH5 FL; corresponding to domains DI to D9) as described above. Results are expressed as small dose-responses (antibodies were tested at 10, 0.1 and 0.01 pg / mL). The FcRH5xCD28 bsAbs of the disclosure showed similar binding to FcRH5 FL, but differential binding to sFcRH5, with limited binding to FcRH5 Dl-8 for candidates AI3AN19 / N, AI3AN24 / N and AI3AN36 / N at the highest tested concentration and no / low binding at the lower concentrations (FIGs. 3A-3B). As comparison, the anti-FcRH5 arm 1G7.V85 disclosed in WO2016205520, tested as monovalent antibody, displayed strong binding to sFcRH5 at all doses tested.

[0292] To assess how soluble FcRH5 (sFcRH5) impacted binding of the FcRH5xCD28 bsAbs of the disclosure to membrane-bound FcRH5, a competition ELISA assay was developed.

[0293] Neutravidin-coated plates were blocked with PBS / BSA (2%) / Tween (0.05%). Full- length biotinylated huFcRH5 (huFcRH5 FL) was captured at 10 nM. A fixed concentration of the FcRH5xCD28 bsAbs was applied to the plates. After washing off the excess of unbound antibodies, a dose range of either FcRH5 FL or FcRH5 Dl-8 was applied in solution, to serve as a decoy for FcRH5xCD28 bsAb bound to immobilized FcRH5 FL. The amount of antibody remaining in the well was detected using a goat anti-human IgG Fc-HRP (Jackson ImmunoResearch, 109-035-098, 1:5000 diluted). The OD at 450 nm generated following the addition of TMB was measured using a microplate spectrophotometer. The competition induced by FcRH5 FL or FcRH5 Dl-8 for all FcRH5xCD28 bsAbs is shown in FIGs. 4A-4I. As expected, all candidates were competed by FcRH5 FL, as determined by the decrease in the fluorescence observed with increasing concentrations of the competitor in solution. Most of the candidates were also competed by FcRH5 Dl-8, except for candidates AI3AN24 / N and AI3AN36 / N, whichwere not competed by FcRH5 DI -8, suggesting preferential binding of these candidates to the membrane-bound FcRH5 by binding it via the D9 domain.

[0294] Binding of FcRH5xCD28 bsAbs to CD28 and FcRH5 double positive MOLP-2 cells or to CD28 and FcRH5 double negative J.RT3-T3.5 cells was assessed by flow cytometry to demonstrate the specific binding of FcRH5xCD28 bsAb to target cells.

[0295] Cells were harvested, checked for viability and counted. 200’000 cells were incubated for 15 minutes at 4°C with increasing concentrations of the antibodies diluted in FACS buffer (PBS 2% BSA, 0.1% NaN3). Cells were washed twice with cold FACS buffer and re-incubated for further 15 minutes at 4°C with a suitable anti-human IgG secondary antibody. Cells were washed twice with cold FACS buffer and resuspended in FACS buffer with a compatible viability marker. Binding of antibodies to living cells was measured by flow cytometry using a Cytoflex Platform (Beckman Coulter). Data was analyzed with FlowJo™ vlO software (BD Life Sciences) and dose-response binding curves were drawn using GraphPad Prism 10 software.

[0296] The various candidates displayed a different binding profile on MOLP-2 cells, possibly reflecting differences in the binding affinity to FcRH5 of the various anti-FcRH5 binding arms (FIG. 5A). Without wishing to be bound by theory, the absence of binding to J.RT3-T3.5 cells suggests specific binding of the selected targets by the FcRH5xCD28 bsAbs of the disclosure (FIG. 5B)Example 8: T-cell Dependent Cellular Cytotoxicity (TDCC) Mediated by FcRH5xCD28 Bispecific Antibodies

[0297] The T-cell dependent cellular cytotoxicity (TDCC) of FcRH5 -positive tumor cell lines induced by the FcRH5xCD28 bsAbs of the present disclosure was assessed in combination with several T cell engagers (TCE) developed for multiple myeloma using human PBMCs as source of effector cells.

[0298] Target cells were washed and plated in 96-well plates at the desired seeding concentration. PBMCs were isolated from buffy coats derived from healthy human donors using SepMate™ Tubes (Stemcell Technologies) with Lymphoprep™ buffer (Stemcell Technologies). For the TDCC assay, PBMCs were added to target cells at final E:T ratio of 10:1, 3: 1, 1:1 or 1 :3 as specified in the figure legend. The assay could be run either with a dose range (DR) of TCEand a fixed dose of the FcRH5xCD28 antibodies of the disclosure (with the fixed concentration mentioned in the figure legends) or vice versa, that is, with a DR of FcRH5xCD28 bsAb applied to a fixed, suboptimal concentration of TCE. Target cell killing is assessed after either 24h, 48h, 72h or 6 days of incubation at 37°C, 5% CO2 by quantifying the LDH released into the medium by apoptotic / necrotic cells (Cytotoxicity Detection KitPLUS (LDH), Roche). Maximal LDH release (= 100% lysis) was obtained by incubating target cells with the lysis solution provided with the kit. Spontaneous LDH release (= 0% lysis) refers to target cells co-incubated with effector cells without any antibody added. TDCC curves were plotted using GraphPad Prism 10.

[0299] FIG. 6 shows how a fixed dose of FcRH5xCD28 bsAbs (16.7 nM) synergized with a DR of Alnuctamab analog to kill FcRH5 and BCMA double positive MOLP-2 target cells. Synergy resulted in both a lower EC50 and a higher overall killing at the maximum concentration tested. Importantly, no killing is induced by the FcRH5xCD28 bsAbs (AI3 AN 15 / N, AI3 AN24 / N, AI3AN27 / N, AI3AN34 / N, AI3AN36 / N) of the disclosure in the absence of Alnuctamab analog, highlighting the importance of primary T cell stimulation (signal 1) for the activity of FcRH5xCD28 bsAbs.Example 9: Affinity Maturation and Optimization of anti-FcRH5 Antibody Arms (Lead Optimization, LO)

[0300] Antibodies identified during the screening process described in Example 3 were considered for affinity maturation to increase their affinity, potency and specificity. All these antibodies share the same variable heavy chain but have different variable light chains. Lead optimization was carried out on candidate AN36 (lambda germline IGLV1-40 according to the IMGT nomenclature). Phage libraries displaying scFv variants were generated by introducing diversity into the CDR1, CDR2 and CDR3 of the variable light chain region while the heavy chain variable region is kept unmodified. Different diversification strategies were used to generate libraries for each candidate, where either the CDRL1+CDRL2 or the CDRL3 only were diversified by oligonucleotide-directed mutagenesis of the parental sequence using degenerated oligonucleotides. CDRL1 is diversified in 0 to 5 amino acid positions, CDRL2 in 0 to 3 amino acid positions while CDRL3 in 0 to 6 amino acid positions.

[0301] These libraries were used for one single round of phage display selection as described in Example 2 using 100 nM of FcRH5 FL or FcRH5 D9 as target. Next, the diversity present in the output of this phage display selection round was cloned into a yeast display compatible vector to continue the lead optimization process using yeast display. For a typical round of yeast display, 5E6 yeast cells were centrifuged, washed once with PBS BSA 0.1% and incubated for 15-30 min with 100, 10 or 1 nM of the desired target protein in PBS BSA 0.1%. For counterselections, 150 nM of protein were applied. Cells were then centrifuged, washed once with PBS BSA 0.1% and resuspended with detection antibodies (detection of scFvs with an anti-HA-PE (Miltenyi Biotec, #130-120-717, diluted 1:100); detection of the target with Steptavidin-Cy5 (Invitrogen, #438316, diluted 1:200)) for 15-20 min. After a last washing step, resuspended cells were read for flow cytometry analysis and sorting using a CytoFlex SRT (Beckman Coulter). Cells displaying the desired profile (target detection vs. scFv expression) were sorted and amplified, thus completing a yeast display round. After 3-6 rounds, variants were screened for the capacity to bind to FcRH5 FL, FcRH5 D9 or FcRH5 Dl-8 using the assay described in Example 3. Positive clones were reformatted directly as FcRH5xCD28 bsAbs as described in Example 6.

[0302] Subsequently, a second wave of lead optimization (LO2) was carried out for AN36- derived candidates, where the diversity obtained after 1 or 3 rounds of selections of lead optimization 1 (LO1) was combined to generate new yeast display libraries containing diversity in all light chain’s CDRs (CDRL1 + CDRL2 + CDRL3). To further improve selectivity for membrane-bound FcRH5, during LO2, tandem FcRH5 extracellular domain 9 (D9-D9) was widely used alongside the FcRH5 FL protein as recombinant target, while FcRH5 extracellular domains 1 to 8 (Dl-8, corresponding to the soluble FcRH5 isoform) was used as counterselection reagent (either as soluble, non-immobilized, competitor or in dedicated deselection rounds). Yeast cell sortings were carried out as described above. Variants were then screened for the capacity to bind to FcRH5 FL, FcRH5 D9 and FcRH5 Dl-8 using the assay described in Example 3. Positive clones were reformatted directly as FcRH5xCD28 bsAbs as described in Example 6.Example 10: in vitro Characterization of Lead Optimized FcRH5xCD28 BispecificAntibodies

[0303] The affinities of a panel of affinity-matured FcRH5xCD28 bsAbs for FcRH5 from human and cynomolgus species were determined by biolayer interferometry on an OctetRED96 using commercially available recombinant proteins (FC5-H52H3 and FC5-C52H3 for human and cynomolgus FcRH5, both from AcroBiosystems). The affinity of candidates was determined during two independent experimental runs and results are shown in Table 3. Affinities range from 4 to 36 nM for human FcRH5. Similar results were obtained on cynomolgus FcRH5, confirming the full cross-reactivity of these candidates between human and cynomolgus targets.Table 3: Affinity of optimized FcRH5xCD28 bsAbs for human and cynomolgus FcRH5KD (nM) ± SD (nM) (n=2)

[0304] To assess how soluble FcRH5 (sFcRH5) impacted binding of the optimized FcRH5xCD28 bsAbs of the disclosure to membrane-bound FcRH5, optimized candidates were assessed using the competition ELISA assay described in Example 7.

[0305] Without wishing to be bound by theory, none of the LO variants tested was competed by FcRH5 DI -8, suggesting preferential binding of these LO candidates to the membrane-bound FcRH5 by binding it via the D9 domain (FIGs. 7A-7I).

[0306] Binding of optimized FcRH5xCD28 bsAbs to CD28 and FcRH5 double positive MOLP-2 cells was assessed by flow cytometry as described in Example 7.

[0307] The various candidates, AI3AN36 / N, AI3AN39 / N, AI3AN61 / N, AI3AN68 / N, AI3AN69 / N, AI3AN71 / N, andAI3AN91 / N, displayed a different binding profile on MOLP-2 cells, overall reflecting different degree of affinity maturation relative to the parental AN36 anti- FcRH5 arm (FIG. 8).

[0308] Because MM cells typically express CD28, to assess the binding of the anti-FcRH5 antibody arms present in the FcRH5xCD28 bsAbs of the disclosure in the absence of the coengagement of CD28, a different approach was used.

[0309] PEAK cells were transiently transfected with a vector encoding for the full length FcRH5 protein and then used to assess the monovalent binding of FcRH5xCD28 bsAbs to FcRH5 expressed at the cell surface of PEAK cells. Non-transfected PEAK cells were used as negative control. Flow cytometry staining and acquisition were performed as detailed in Example 7.

[0310] The various candidates, AI3AN36 / N, AI3AN39 / N, AI3AN61 / N, AI3AN68 / N, AI3AN69 / N, AI3AN71 / N, and AI3AN91 / N, displayed a different binding profile on PEAK huFcRH5 cells, overall reflecting different degree of affinity maturation relative to the parental AN36 anti-FcRH5 arm (FIG. 9).Example 11: Binding of FcRH5xCD28 bsAbs to cells transfected with different members of the FcRH family or with cynomolgus FcRH5

[0311] The specificity and cynomolgus cross-reactivity of the anti-FcRH5 antibody arms of the disclosure, tested as part of FcRH5xCD28 bsAbs, were assessed by flow cytometry using PEAK cells transfected with different members of the human FcRH family or with cynomolgus FcRH5.

[0312] Vectors encoding the full-length version of human FcRH 1, 2, 3, 4, 5 or cynomolgus FcRH5 were used to express these proteins at the surface of PEAK cells. Non-transfected PEAK cells were used as negative control. The Mean Fluorescence Intensity (MFI) values obtained when applying an antibody concentration of 30 pg / mL on transfected cells expressing any given FcRH were divided by the values obtained on WT PEAK cells, generating “Factors to PEAK WT” (FIG. 10).

[0313] All optimized FcRH5xCD28 bsAbs resulted in factor to PEAK WT for human and cynomolgus FcRH5 above 10, confirming strong binding to the desired target independently of its origin (human or cynomolgus). The factor to PEAK WT below 2 for FcRHl to FcRH4 obtained for most candidates excluded significant binding to other FcRH family members, thus minimizing the risk of targeting undesired cell populations.Example 12: Wet Plate Coating T Cell Activation and Proliferation Assay (Stebbing’s assay)

[0314] The anti-CD28 arm used to generate FcRH5xCD28 bsAbs was previously shown not to be a superagonistic anti-CD28 antibody arm, neither as CD28 bivalent mAb nor as monovalent TAAxCD28 bsAb (WO2023170474). To confirm its lack of superagonist activity in the context of FcRH5xCD28 bsAbs, the capacity to induce T cell activation or proliferation in the absence of signal 1 was assessed using a wet coating Stebbings’ assay.

[0315] 96-well polypropylene plates were coated overnight at 4°C with 100 pl of PBS containing 10 pg / ml of antibodies (wet coating). Following the wet coating procedure, plates were washed twice with PBS. In parallel, PBMCs isolated from buffy coat obtained from healthy donors were stained with CellTrace Violet Cell Proliferation Kit (ThermoFischer Scientific) according to the manufacturer’s instructions. 100’000 stained PBMC cells were added to the 96- well plate in a final volume of 200 uL / well and incubated at 37°C + 5% CO2 for 6 days. Cells were then harvested and stained for flow cytometry assessment using anti-CD4-APC (ThermoFischer, 17-0049-41) and anti-CD8-PerCP-Cy5.5 (BioLegend, 301032). The activation rate of living CD4+ and CD8+ T cells was calculated by measuring the level or cell surface expression of the T cell activation marker CD25 by flow cytometry using a CytoFLEX (Beckman Coulter). Similarly, the proliferation rate of living CD4+ and CD8+ T cells was calculated by measuring the levels of CellTrace Violet staining by flow cytometry using a CytoFLEX (Beckman Coulter). Results were evaluated by FlowJo software. An analog of the CD28 SA antibody TGN1412 served as positive control, while the background activation state and proliferation rate of T cells was determined in the absence of any antibody (PBS only) or in presence of an isotype control.

[0316] As expected, the FcRH5xCD28 bsAbs of the disclosure resulted in no / very limited T cell proliferation in line with that induced by PBS or the isotype control antibody. Conversely, TGN1412 analog induced strong T cell activation and proliferation of both CD4 and CD8 T cells with all 6 PBMS donor tested (FIGs. 11A-11D).Example 13: TDCC Mediated by Optimized FcRH5xCD28 Bispecific Antibodies

[0317] The T-cell dependent cellular cytotoxicity (TDCC) of FcRH5 -positive tumor cell lines induced by the optimized FcRH5xCD28 bispecific antibodies of the present disclosure was assessed as described in Example 8, with the notable difference that soluble FcRH5 was added at different concentrations (0, 3 or 9 pg / mL) to mimic conditions present in MM patients, where soluble FcRH5 could interfere with the activity of FcRH5 -targeted therapies.

[0318] FIGs. 12A-12L show the specific lysis of MOLP-2 target cells obtained with a fixed, suboptimal concentration of Teclistamab (BCMAxCD3, tested at 0.07 nM) combined with a DR of FcRH5xCD28 bsAbs of the disclosure in presence of 0, 3 or 9 pg / mL of sFcRH5. In the absence of sFcRH5, most candidates synergized equally well with Teclistamab to induce the killing of MOLP-2 cells. Each bsAb was however differently affected by the addition of sFcRH5, depending on its affinity and specificity for membrane-bound FcRH5. For each candidate, the percentage of inhibition in presence of sFcRH5 relative to the condition in the absence of sFcRH5 was calculated for an antibody concentration of 28.6 nM (Table 4).Table 4: Percentage of inhibition of FcRH5xCD28 activity mediated by soluble FcRH5 inTDCC assay

[0319] Of the candidates tested, AI3AN39 / N and AI3AN61 / N were the ones most affected by increasing concentrations of sFcRH5, with a reduction greater than 70% in term of maximal specific lysis observed at a FcRH5xCD28 bsAb concentration of 28.6 nM when 9 pg / mL of sFcRH5 were added to the plate. Even in the presence of 3 pg / mL of sFcRH5, these candidates lost around 33% of their killing potential. Of note, the FcRH5xCD28 bsAb carrying the 1 G7.V85targeting arm was also heavily affected by the addition of 3 and 9 pg / mL of sFcRH5, with a reduction of activity of -41.9% and -74.1%, respectively. At the other end of the spectrum, candidate AI3AN71 / N displayed a reduction in terms of specific lysis as low as 4.1% and 22.1% in presence of 3 and 9 pg / mL of sFcRH5, respectively. Along with candidate AI3AN71 / N, candidates AI3AN36 / N (-9.0% and -20.9%), AI3AN68 / N (-3.0% and -37.0%), AI3AN69 / N (- 8.8% and -30.3%), and AI3AN91 / N (-11.5% and -22.1%) demonstrated a minor decrease in activity in the presence of sFcRH5. This suggests these candidates may retain substantial efficacy even in patients with elevated levels of soluble FcRH5, offering potential therapeutic advantages in such clinical settings.

[0320] The T-cell dependent cellular cytotoxicity (TDCC) of FcRH5 -positive tumor cell lines induced by the optimized FcRH5xCD28 bispecific antibodies of the present disclosure was further assessed in combination with Teclistamab (a BCMAxCD3 bsAbs) in the presence of soluble BCMA (sBCMA, added at 500 ng / mL) to mimic conditions present in MM patients, where sBCMA could interfere with the activity of BCMA-targeted therapies. This represents a known resistance mechanism to BCMA-targeted TCEs in MM patients.

[0321] FIG. 13 shows how a fixed dose (16.7 nM or 50 nM) of AI3AN71 / N, one of the FcRH5xCD28 bsAbs of the disclosure, mitigated Teclistamab (Fig. 13A) and Elranatamab (Fig. 13B) activity loss induced by sBCMA as determined by quantifying the killing of FcRH5 and BCMA double positive MOLP-2 target cells. The addition of FcRH5xCD28 bsAbs partially (Fig. 13A), completely (Fig. 13B) restored the activity of BCMA-targeting TCEs reduced by soluble BCMA, potentially overcoming a known resistance mechanism to TCEs in MM patients. The observed synergy resulted in both a lower EC50 and a higher overall killing at the maximum concentration tested. Importantly, no killing is induced by AI3AN71 / N in the absence of TCEs.

[0322] The possibility to combine the FcRH5xCD28 bsAbs of the present disclosure with TCE targeting different MM cell surface markers was explored in T-cell dependent cellular cytotoxicity (TDCC) assays where T cell activation signal 1 was provided by different TCEs in development or approved for MM.

[0323] FIG. 14 shows how a fixed dose of FcRH5xCD28 bsAbs (10 nM or 50 nM) synergized across a DR of Alnuctamab analog (FIG. 14A), Teclistamab (FIG. 14B), Talquetamab (FIG. 14C) and Elranatamab (FIG. 14D) to kill FcRH5, BCMA and GPRC5D triple positive MOLP- 2 target cells. The measured synergy resulted in both a lower EC50 and a higher overall killingat the maximum concentration tested. This data suggests that the FcRH5xCD28 bsAbs of the disclosure can synergize with T cell engagers targeting different MM markers (e.g. BCMA and GPRC5D).

[0324] T cell activation signal 2 provided by the FcRH5xCD28 bsAbs of the present disclosure could help restore the activity of exhausted T cells induced by TCE treatments. It is indeed known in the field that excessive and continuous stimulation by TCEs via CD3 can lead to T-cell exhaustion, characterized by impaired T-cell function and diminished anti -turn or efficacy, a condition that might be prevented if signal 2 is provided alongside signal 1.

[0325] The TDCC of FcRH5-positive tumor cell lines induced by the optimized FcRH5xCD28 bispecific antibodies of the present disclosure was thus assessed using in vitro exhausted T cells. The procedure detailed in Example 8 was followed, with the notable difference that as effector cells purified T cells were used instead of PBMC. These could be used as fresh T cells (not subjected to the exhaustion protocol) or as exhausted T cells. To induce exhaustion, purified T cells were cultured in flasks pre-coated with 10 ug / mL of anti CD3 mAb Clone OKT-3. Every 2-3 days T cells were recovered, counted and reseeded into new, anti-CD3 mAb pre-coated flasks. After 4 cycles of exhaustion, T cells were seeded with target cells at a E:T ratio of 1 :2 and cultured in presence of a DR of TCE to which 100 nM of either an isotype control (hlgGl) or AI3AN71 / N were added.

[0326] FIG. 15 shows how a fixed dose of FcRH5xCD28 bsAbs counteracts the reduction / loss of activity of Teclistamab (FIG. 15A), Elranatamab (FIG. 15B) and Cevostamab (FIG. 15C) due to the presence of exhausted T cells. While the killing of the MOLP-2 target cells induced by the TCE alone is greatly reduced when exhausted T cells are used, the killing induced by the combination of TCE and AI3AN71 / N in presence of exhausted cells remains at least as potent as that observed with the TCE alone when fresh T cells are used. Without wishing to be bound by theory, this suggests that adding the FcRH5xCD28 bsAbs of the present invention to approved TCEs may prevent the onset of resistance due to T cell exhaustion in MM patients. Additionally, synergy is observed between a FcRH5xCD28 bsAb of the disclosure (AI3AN71 / N) and FcRH5- targeted TCE Cevostamab (FIG. 15C), independent of the kind of T cells used (fresh vs. exhausted), suggesting that AI3AN71 / N and Cevostamab do not fully compete for FcRH5, even if they were both developed to target the membrane-bound isoform of FcRH5. Without wishing to be bound by theory, this also suggests that the FcRH5xCD28 bsAb of the disclosure may alsobe combined with TCE targeting the same TAA (i.e. FcRH5) to enhance the anti-tumor activity of the TCE-based treatment.

[0327] To confirm that the activity observed with the FcRH5xCD28 bsAbs of the present invention is not cell line specific, and thus not limited to MOLP-2 cells, other MM cells lines were tested, and namely the INA-6 and the NCI-H929 cell lines.

[0328] The TDCC of FcRH5 -positive INA-6 MM cells induced by a dose range of the optimized FcRH5xCD28 bispecific antibodies of the present disclosure was assessed in combination with a fixed dose of a TCE. INA-6-GFP cells were seeded at an E:T ratio of 1: 1 with PBMCs derived from healthy human donors and cultured for 6 days in presence of Teclistamab. The proliferation / killing of MM cells was followed by Incucyte. The killing was determined by imaging: the area covered by viable MM cells in each well was compared to that of cells grown in the absence of TCE and eventually expressed as a percentage of killing.

[0329] FIG. 16 shows how a dose response in terms of killing is induced by a dose range of FcRH5xCD28 bsAbs of the present disclosure when combined with a fixed, suboptimal concentration of Teclistamab (0.5 nM). Addition of an isotype control (hlgGl) does not enhance the killing induced by Teclistamab. Without wishing to be bound by theory, this data suggests that the killing of MM cells induced by TCEs may be enhanced by FcRH5xCD28 bsAbs on any FcRH5 -positive MM cells.

[0330] For NCI-H929, the TDCC of FcRH5 -positive NCI-H929 MM cells induced by a dose range of different TCEs combined with a fixed dose [100 nM] of AI3AN71 / N was assessed by Incucyte. For this, NCI-H929-GFP cells were seeded at an E:T ratio of 1:2 with T cells derived from healthy human donors and cultured for 6 days. Either fresh or exhausted T cells were used. Exhausted T cells were generated as detailed above. The killing was determined by imaging: the area covered by viable MM cells in each well was compared to that of cells grown in the absence of TCE and eventually expressed as a percentage of killing.

[0331] FIG. 17 shows how a fixed dose of AI3AN71 / N counteracts the reduction of activity of Teclistamab (FIG. 17A), Elranatamab (FIG. 17B) and Talquetamab (FIG. 17C) due to the use of exhausted T cells as effector cells. While the killing of NCI-H929 by the TCEs alone is greatly reduced when exhausted T cells are used, the maximal killing induced by the combination of TCEs and AI3AN71 / N in presence of exhausted T cells remains the same as that observed with the TCE alone when fresh T cells are used. Without wishing to be bound by theory, this datagenerated with a different cell line than MOLP-2 reinforces the idea that the addition of FcRH5xCD28 bsAbs of the present invention to approved TCEs may prevent the onset of resistance due to T cell exhaustion in MM patients.Other EmbodimentsEmbodiment 1. An antibody, comprising: a. an antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the antigen binding domain comprises: i. a heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and ii. a light chain variable region having:1. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 29; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 30; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 31;2. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 32; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 33; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 34;3. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 35; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 36; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 37;4. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 38; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 39; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 40;a CDRL1 comprising the amino acid sequence of SEQ ID NO: 41; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 42; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 43; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 44; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 45; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 46; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 47; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 48; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 49; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 50; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 51; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 52; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 53; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 54; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 55; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 56; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 57; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 58; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 59; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 60; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 61; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 62; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 63;and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 64;13. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 65; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 66; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 67; or14. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 68; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 69; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 70.Embodiment 2. The antibody of embodiment 1 , wherein the light chain variable region of: a. part a. ii. 1. comprises the amino acid sequence of SEQ ID NO: 71; b. part a. ii. 2. comprises the amino acid sequence of SEQ ID NO: 72; c. part a. ii. 3. comprises the amino acid sequence of SEQ ID NO: 73; d. part a. ii. 4. comprises the amino acid sequence of SEQ ID NO: 74; e. part a. ii. 5. comprises the amino acid sequence of SEQ ID NO: 75; f. part a. ii. 6. comprises the amino acid sequence of SEQ ID NO: 76; g. part a. ii. 7. comprises the amino acid sequence of SEQ ID NO: 77; h. part a. ii. 8. comprises the amino acid sequence of SEQ ID NO: 78; i. part a. ii. 9. comprises the amino acid sequence of SEQ ID NO: 79; j. part a. ii. 10. comprises the amino acid sequence of SEQ ID NO: 80; k. part a. ii. 11. comprises the amino acid sequence of SEQ ID NO: 81; l. part a. ii. 12. comprises the amino acid sequence of SEQ ID NO: 82; m. part a. ii. 13. comprises the amino acid sequence of SEQ ID NO: 83; or n. part a. ii. 14. comprises the amino acid sequence of SEQ ID NO: 84.Embodiment 3. The antibody of embodiment 1, wherein the light chain of: a. part a. ii. 1. comprises the amino acid sequence of SEQ ID NO: 85; b. part a. ii. 2. comprises the amino acid sequence of SEQ ID NO: 86;c. part a. ii. 3. comprises the amino acid sequence of SEQ ID NO: 87; d. part a. ii. 4. comprises the amino acid sequence of SEQ ID NO: 88; e. part a. ii. 5. comprises the amino acid sequence of SEQ ID NO: 89; f. part a. ii. 6. comprises the amino acid sequence of SEQ ID NO: 90; g. part a. ii. 7. comprises the amino acid sequence of SEQ ID NO: 91 ; h. part a. ii. 8. comprises the amino acid sequence of SEQ ID NO: 92; i. part a. ii. 9. comprises the amino acid sequence of SEQ ID NO: 93; j. part a. ii. 10. comprises the amino acid sequence of SEQ ID NO: 94; k. part a. ii. 11. comprises the amino acid sequence of SEQ ID NO: 95; l. part a. ii. 12. comprises the amino acid sequence of SEQ ID NO: 96; m. part a. ii. 13. comprises the amino acid sequence of SEQ ID NO: 97; or n. part a. ii. 14. comprises the amino acid sequence of SEQ ID NO: 98.Embodiment 4. A bispecific antibody, comprising: a. a first antigen binding domain that binds to Fc receptor-homolog 5 (FcRH5); wherein the first antigen binding domain comprises: i. a first heavy chain variable region having a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and ii. a first light chain variable region having:1. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 29; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 30; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 31;2. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 32; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 33; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 34;3. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 35; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 36; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 37;a CDRL1 comprising the amino acid sequence of SEQ ID NO: 38; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 39; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 40; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 41; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 42; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 43; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 44; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 45; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 46; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 47; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 48; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 49; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 50; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 51; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 52; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 53; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 54; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 55; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 56; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 57; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 58; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 59; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 60; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 61; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 62; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 63; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 64; a CDRL1 comprising the amino acid sequence of SEQ ID NO: 65; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 66; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 67; or14. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 68; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 69; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 70; and b. a second antigen binding domain that binds a second antigen, wherein the second antigen binding domain comprises: ii. a second heavy chain variable region having a CDRH1 comprising the amino acid sequence of SEQ ID NO: 7; a CDRH2 comprising the amino acid sequence of SEQ ID NO: 8; and a CDRH3 comprising the amino acid sequence of SEQ ID NO: 9.Embodiment 5. The bispecific antibody of embodiment 4, wherein the first light chain variable region of: a. part a. ii. 1. comprises the amino acid sequence of SEQ ID NO: 71; b. part a. ii. 2. comprises the amino acid sequence of SEQ ID NO: 72; c. part a. ii. 3. comprises the amino acid sequence of SEQ ID NO: 73; d. part a. ii. 4. comprises the amino acid sequence of SEQ ID NO: 74; e. part a. ii. 5. comprises the amino acid sequence of SEQ ID NO: 75; f. part a. ii. 6. comprises the amino acid sequence of SEQ ID NO: 76; g. part a. ii. 7. comprises the amino acid sequence of SEQ ID NO: 77; h. part a. ii. 8. comprises the amino acid sequence of SEQ ID NO: 78; i. part a. ii. 9. comprises the amino acid sequence of SEQ ID NO: 79; j. part a. ii. 10. comprises the amino acid sequence of SEQ ID NO: 80; k. part a. ii. 11. comprises the amino acid sequence of SEQ ID NO: 81; l. part a. ii. 12. comprises the amino acid sequence of SEQ ID NO: 82; m. part a. ii. 13. comprises the amino acid sequence of SEQ ID NO: 83; or n. part a. ii. 14. comprises the amino acid sequence of SEQ ID NO: 84.Embodiment 6. The bispecific antibody of embodiment 4, wherein the first light chain of: a. part a. ii. 1. comprises the amino acid sequence of SEQ ID NO: 85; b. part a. ii. 2. comprises the amino acid sequence of SEQ ID NO: 86; c. part a. ii. 3. comprises the amino acid sequence of SEQ ID NO: 87;d. part a. ii. 4. comprises the amino acid sequence of SEQ ID NO: 88; e. part a. ii. 5. comprises the amino acid sequence of SEQ ID NO: 89; f. part a. ii. 6. comprises the amino acid sequence of SEQ ID NO: 90; g. part a. ii. 7. comprises the amino acid sequence of SEQ ID NO: 91 ; h. part a. ii. 8. comprises the amino acid sequence of SEQ ID NO: 92; i. part a. ii. 9. comprises the amino acid sequence of SEQ ID NO: 93; j. part a. ii. 10. comprises the amino acid sequence of SEQ ID NO: 94; k. part a. ii. 11. comprises the amino acid sequence of SEQ ID NO: 95; l. part a. ii. 12. comprises the amino acid sequence of SEQ ID NO: 96; m. part a. ii. 13. comprises the amino acid sequence of SEQ ID NO: 97; or n. part a. ii. 14. comprises the amino acid sequence of SEQ ID NO: 98.Embodiment 7. The bispecific antibody of embodiment 4, wherein the second antigen is CD28.Embodiment 8. The bispecific antibody of embodiment 4, wherein the second antigen binding domain comprises: ii. a second light chain variable region having:1. a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.Embodiment 9. The bispecific antibody of embodiment 8, wherein the second light chain variable region comprises the amino acid sequence of SEQ ID NO: 17.Embodiment 10. The bispecific antibody of embodiment 8, wherein the second light chain comprises the amino acid sequence of SEQ ID NO: 18.Embodiment 11. The antibody of embodiment 1 , wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 10.Embodiment 12. The bispecific antibody of embodiment 4, wherein the first heavy chain variable region and the second heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 10.Embodiment 13. The antibody of embodiment 1 , wherein the heavy chain comprises the amino acid sequence of SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO: 13.Embodiment 14. The bispecific antibody of embodiment 4, wherein the first heavy chain and the second heavy chain comprises the amino acid sequence of SEQ ID NO: 11, SEQ ID NO: 12, or SEQ ID NO: 13.Embodiment 15. The bispecific antibody of embodiment 4, wherein the first light chain is a kappa and the second light chain is a lambda or wherein the first light chain is a lambda and the second light chain is a kappa.Embodiment 16. The antibody of embodiment 1, wherein the antibody includes a F(ab) fragment, a F(ab’)2 fragment, and Fv fragment or a single chain Fv fragment.Embodiment 17. A method of treating cancer in a subject comprising administering to the subject a composition comprising the antibody of embodiment 1.Embodiment 18. The method of embodiment 17, wherein the cancer is a B cell malignancy.Embodiment 19. A method of treating cancer in a subject comprising administering to the subject a composition comprising the bispecific antibody of embodiment 4.Embodiment 20. The method of embodiment 19, wherein the cancer is a B cell malignancy.

Claims

What is Claimed is:

1. An antibody, comprising: i. a heavy chain variable region comprising a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and ii. a light chain variable region comprising: a) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 29; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 30; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 31; b) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 32; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 33; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 34; c) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 35; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 36; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 37; d) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 38; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 39; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 40; e) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 41 ; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 42; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 43; f) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 44; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 45; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 46; g) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 47; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 48; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 49;h) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 50; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 51; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 52; i) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 53; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 54; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 55; j) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 56; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 57; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 58; k) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 59; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 60; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 61; l) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 62; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 63; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 64; m) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 65; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 66; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 67; or n) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 68; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 69; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 70.

2. The antibody of claim 1, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 10.

3. The antibody of claim 1 or claim 2, wherein the heavy chain comprises the amino acid sequence of one of SEQ ID NOs: 11-13.

4. The antibody of any one of claims 1-3, wherein the light chain variable region comprises the amino acid sequence of one of SEQ ID NOs: 71-84.

5. The antibody of any one of claims 1-4, wherein the light chain comprises the amino acid sequence of one of SEQ ID NOs: 85-98.

6. The antibody of any one of claims 1-5, wherein the light chain variable region comprises a CDRL1 comprising the amino acid sequence of SEQ ID NO: 65; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 66; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 67.

7. The antibody of any one of claims 1-6, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 83.

8. The antibody of any one of claims 1-7, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 97.

9. The antibody of any one of claims 1-5, wherein the light chain variable region comprises a CDRL1 comprising the amino acid sequence of SEQ ID NO: 59; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 60; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 61.

10. The antibody of any one of claims 1-5 or 9, wherein the light chain variable region comprises the amino acid sequence of SEQ ID NO: 81.

11. The antibody of any one of claims 1-7, 9, or 10, wherein the light chain comprises the amino acid sequence of SEQ ID NO: 95.

12. The antibody of any one of claims 1-11, wherein the antibody binds to Fc receptorhomolog 5 (FcRH5).

13. The antibody of claim 12, wherein the antibody preferentially binds membrane-bound FcRH5 (isoform c) relative to soluble FcRH5 (isoform a).

14. An antibody, comprising: i. a heavy chain variable region comprising a complementarity determining region 1 (CDRH1) comprising the amino acid sequence of SEQ ID NO: 7; a complementarity determining region 2 (CDRH2) comprising the amino acid sequence of SEQ ID NO: 8; and a complementarity determining region 3 (CDRH3) comprising the amino acid sequence of SEQ ID NO: 9; and ii. a first light chain variable region comprising: a) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 29; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 30; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 31; b) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 32; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 33; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 34; c) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 35; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 36; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 37; d) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 38; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 39; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 40; e) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 41; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 42; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 43; f) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 44; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 45; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 46; g) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 47; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 48; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 49; h) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 50; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 51; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 52;i) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 53; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 54; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 55; j) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 56; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 57; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 58; k) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 59; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 60; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 61; l) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 62; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 63; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 64; m) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 65; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 66; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 67; or n) a CDRL1 comprising the amino acid sequence of SEQ ID NO: 68; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 69; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 70; and iii. a second light chain variable region comprising a CDRL1 comprising the amino acid sequence of SEQ ID NO: 14; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 15; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 16.

15. The antibody of claim 14, wherein the antibody comprises two copies of the heavy chain variable region.

16. The antibody of claim 14 or claim 15, wherein the heavy chain variable region comprises the amino acid sequence of SEQ ID NO: 10.

17. The antibody of any one of claims 14-16, wherein the heavy chain comprises the amino acid sequence of one of SEQ ID NOs: 11-13.

18. The antibody of any one of claims 14-17, wherein the first light chain variable region comprises the amino acid sequence of one of SEQ ID NOs: 71-84.

19. The antibody of any one of claims 14-18, wherein the first light chain comprises the amino acid sequence of one of SEQ ID NOs: 85-98.

20. The antibody of any one of claims 14-19, wherein the first light chain variable region comprises a CDRL1 comprising the amino acid sequence of SEQ ID NO: 65; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 66; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 67.

21. The antibody of any one of claims 14-20, wherein the first light chain variable region comprises the amino acid sequence of SEQ ID NO: 83.

22. The antibody of any one of claims 14-21, wherein the first light chain comprises the amino acid sequence of SEQ ID NO: 97.

23. The antibody of any one of claims 14-19, wherein the first light chain variable region comprises a CDRL1 comprising the amino acid sequence of SEQ ID NO: 59; a CDRL2 comprising the amino acid sequence of SEQ ID NO: 60; and a CDRL3 comprising the amino acid sequence of SEQ ID NO: 61.

24. The antibody of any one of claims 14-19 or 23, wherein the first light chain variable region comprises the amino acid sequence of SEQ ID NO: 81.

25. The antibody of any one of claims 14-29, 23, or 24 wherein the first light chain comprises the amino acid sequence of SEQ ID NO: 95.

26. The antibody of any one of claims 14-25, wherein the second light chain variable region comprises the amino acid sequence of SEQ ID NO: 17.

27. The antibody of any one of claims 14-26, wherein the second light chain comprises the amino acid sequence of SEQ ID NO: 18.

28. The antibody of any one of claims 14-27, wherein a) at least a portion of the first light chain is of the kappa type and at least a portion of the second light chain is of the lambda type; or b) at least a portion of the first light chain is of the lambda type and at least a portion of the second light chain is of the kappa type.

29. The antibody of any one of claims 14-28, wherein the antibody is a bispecific antibody.

30. The antibody of claim 29, wherein the antibody binds to FcRH5 and / or CD28, preferably wherein the antibody simultaneously binds to FcRH5 and CD28.

31. The bispecific antibody of claim 30, wherein the antibody preferentially binds membrane-bound FcRH5 (isoform c) relative to soluble FcRH5 (isoform a).

32. The antibody of any one of claims 1-31, wherein the antibody comprises a F(ab) fragment, a F(ab’)2 fragment, a Fv fragment, or a single chain Fv fragment.

33. The antibody of any one of claims 1-32, wherein the antibody is a human antibody.

34. The antibody of any one of claims 1-33, wherein the antibody is an IgGl antibody or an IgG4 antibody.

35. The antibody of any one of claims 1-34, wherein the antibody has a LALA mutation or a LALAPA mutation.

36. A pharmaceutical composition comprising: i) the antibody of any one of claims 1-35, and ii) at least one pharmaceutically acceptable carrier.

37. A method of treating cancer in a subject comprising administering to the subject at least one amount of the antibody of any one of claims 1-35 or the pharmaceutical composition of claim 36.

38. A method of slowing the progression of cancer in a subject comprising administering to the subject at least one amount of the antibody of any one of claims 1-35 or the pharmaceutical composition of claim 36.

39. A method for treating, ameliorating, or preventing one or more symptoms associated with cancer in a subject comprising administering to the subject at least one amount of the antibody of any one of claims 1-35 or the pharmaceutical composition of claim 36.

40. The method of any one of claims 37-39, wherein the cancer is blood cancer.

41. The method of claim 40, wherein the blood cancer is a B-cell malignancy, preferably wherein the B-cell malignancy is multiple myeloma.

42. The method of any one of claims 37-41, wherein the cancer is a FcRH5 positive cancer.

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