Multispecific immune cell engager

Abstract

Provided herein, in certain aspects, are multispecific binder molecules able to bind tumor associated antigens and engage immune cells. The multispecific binder molecules comprise a combination of GPRC5D, BCMA, CD38, SLAMF7, FcRH5, and CD3 binding modalities. Also provided here are methods for use of the multispecific binder molecules for inducing an immune response against tumor cells and for use in the treatment of hematological cancers.

Description

MULTISPECIFIC IMMUNE CELL ENGAGERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 578,298, filed on August 23, 2023, and U.S. Provisional Patent Application No. 63 / 561,447, filed on March 05, 2024, both of which are incorporated by reference herein in their entireties.TECHNICAL FIELD

[0002] The disclosure provided herein relates to multispecific binder molecules that bind to a combination of the proteins: B-cell maturation antigen (BCMA), G-protein coupled receptor, class C, group 5, member D (GPRC5D), CD38 molecule (CD38), SLAM family member 7 (SLAMF7), Fc receptor like 5 (FCRL5) - also known as FcRH5, and / or cluster determinant 3 (CD3), and methods for use of these multispecific binder molecules.BACKGROUND

[0003] Hematological tumor cells from some cancers are known to express certain cell surface markers at a higher protein level than in non-malignant cells. These cell surface markers can be termed tumor associated antigens, as an elevated level of expression of one or more of these markers is often indicative of a tumor cell phenotype. Targeted therapeutics aiming to stimulate immune cell recognition of hematological tumor cells and induce a directed cytotoxic response is a promising approach to develop novel treatments for a variety of hematological cancers. Targeted therapeutics may engage immune cells such as T cells, NK cells, and / or NKT cells and bring these cells in proximity to hematological tumor cells expressing an abnormally high level of one or more tumor associated antigens. Stimulation of these immune cells can lead to a targeted cytotoxic response directed specifically against the tumor cells expressing elevated levels of the one or more tumor associated antigens selected to identify malignant cells.

[0004] Multiple myeloma accounts for approximately 10% of hematological cancers in the United States and the treatment burden for patients diagnosed with multiple myeloma is extensive. Certain cells surface markers including BCMA are known to be overexpressed in multiple myeloma cells from a majority of patients. Strategies using an immune cell engager to bring T cells in proximity to BCMA+ multiple myeloma cells have met with some clinical success. However, many subjects receiving this type of treatment still do not reach a satisfactory clinical outcome or suffer from a relapse of cancer. Improvements are needed to effectively target multiple myeloma cells and induce immune responses directed against these tumor cells in order to achieve better clinical outcomes in patients.SUMMARY OF THE DISCLOSURE

[0005] Described herein, in some aspects, are multispecific binder molecules comprising three distinct tumor antigen binding moieties (a-c) comprising: a) a TNFRSF17 (BCMA) binding moiety, b) a GPRC5D binding moiety, and c) a FcRH5 binding moiety; and d) an immune cell engager. In some embodiments, the immune cell engager comprises a T cell binding moiety, an NK cell binding moiety, or an NKT cell binding moiety. In some embodiments, the immune cell engager comprises a T cell binding moiety. In some embodiments, the T cell binding moiety comprises a CD3 binding moiety. In some embodiments of the multispecific binder molecule described herein, at least one of the three distinct tumor antigen binding moieties is an antibody or antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment thereof is a human antibody, a humanized antibody, or antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment thereof comprises a chimeric antibody, a monoclonal antibody, a monovalent Fab’, a divalent Fab2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), a camelid antibody, or antigen binding fragment thereof. In some embodiments, the multispecific binder molecule described herein comprises a first immunoglobulin chain constant region and a second immunoglobulin chain constant region. In some embodiments, the TNFRSF17 (BCMA) binding moiety and the GPRC5D binding moiety are linked to the first immunoglobulin chain constant region, and wherein the CD3 binding moiety and the FcRH5 binding moiety are linked to the second immunoglobulin chain constant region. In some embodiments, the TNFRSF17 (BCMA) binding moiety and the CD3 binding moiety are linked to the first immunoglobulin chain constant region, and wherein the GPRC5D binding moiety and the FcRH5 binding moiety are linked to the second immunoglobulin chain constant region. In some embodiments, the TNFRSF17 (BCMA) binding moiety and the FcRH5 binding moiety are linked to the first immunoglobulin chain constant region, and wherein the GPRC5D binding moiety and the CD3 binding moiety are linked to the second immunoglobulin chain constant region. In some embodiments, the a) TNFRSF17 (BCMA) binding moiety, b) GPRC5D binding moiety, c) FcRH5 binding moiety, and d) CD3 binding moiety, comprise an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises Fab’, scFv, IgG-scFv, nanobody, mini-antibody, minibody, scFv-CH3 KiH, or scFv-KiH. In some embodiments, the first or second immunoglobulin chain constant region comprises a heavy chain constant region of IgGl, IgG2, and IgG4, or a variant thereof. In some embodiments, the first or second immunoglobulin chain constant regions form a IgGl heavy chain or a variant thereof. In some embodiments, the TNFRSF17 (BCMA) binding moiety is coupled to the N- terminus of the IgGl heavy chain or a variant thereof. In some embodiments, the TNFRSF17(BCMA) binding moiety is coupled to the C-terminus of the IgGl heavy chain or a variant thereof. In some embodiments, the GPRC5D binding moiety is coupled to the N-terminus of the IgGl heavy chain or a variant thereof. In some embodiments, the GPRC5D binding moiety is coupled to the C-terminus of the IgGl heavy chain or a variant thereof. In some embodiments, the FcRH5 binding moiety is coupled to the N-terminus of the IgGl heavy chain or a variant thereof. In some embodiments, the FcRH5 binding moiety is coupled to the C-terminus of the IgGl heavy chain or a variant thereof. In some embodiments, the CD3 binding moiety is coupled to the N-terminus of the IgGl heavy chain or a variant thereof. In some embodiments, the CD3 binding moiety is coupled to the C-terminus of the IgGl heavy chain or a variant thereof. In some embodiments, the IgGl heavy chain comprises a mutation that reduces FcyR binding. In some embodiments, the mutation comprises N297A mutation. In some embodiments of the multispecific binder molecule described herein, at least one of the three distinct tumor antigen binding moieties is coupled to an immunoglobulin kappa light chain domain. In some embodiments of the multispecific binder molecule described herein, at least one of the three distinct tumor antigen binding moieties is coupled to an immunoglobulin lambda light chain domain. In some embodiments, one of the three distinct tumor antigen binding moieties is coupled to an immunoglobulin lambda light chain domain and another of the three distinct tumor antigen binding moieties is coupled to an immunoglobulin kappa light chain domain. In some embodiments, the TNFRSF17 (BCMA) binding moiety is derived from Teclistamab, AMG 701, Alnuctamab, Belantamab mafodotin, Elranatamab, Linvoseltamab, ABBV-383, HPN217, ISB 2001, GSK287916, MEDI2228, TNB-383B, REGN545, or AMG 420. In some embodiments, the GPRC5D binding moiety is derived from Talquetamab or RG6234. In some embodiments, the FcRH5 binding moiety is derived from Cevostamab or DFRF4539A. In some embodiments, the CD3 binding moiety is derived from AMG 701, Alnuctamab, Elranatamab, Linvoseltamab, Teclistamab, ABBV-383, HPN217, XmAb969, ISB 1347, Talquetamab, RG6234, Cevostamab, SAR442257, F182112, or ISB 2001.

[0006] Described herein, in some aspects, are methods for inducing an immune response against a tumor cell, the methods comprising contacting the tumor cell with a multispecific binder molecule described herein. In some embodiments, the contacting induces proximity between the tumor cell and one or more immune effector cells. In some embodiments, the contacting supports formation of a cytolytic immunological synapse between the tumor cell and one or more immune effector cells. In some embodiments, the one or more immune effector cells comprise one or more activated T cells. In some embodiments, the one or more activated T cells release primary cytokines that induce the activation of other immune cell types wherein the other immune cell types comprise macrophages, dendritic cells, monocytes, NK cells, or anycombination thereof. In some embodiments, the other immune cell types produce elevated levels of secondary cytokines, wherein the secondary cytokines comprise IL6, IL 10, IL5, or any combination thereof. In some embodiments, the one or more immune effector cells induce apoptosis in a target tumor cell. In some embodiments, the one or more immune effector cells induce pyroptosis in a target tumor cell. In some embodiments, the one or more immune effector cells release one or more cytotoxic proteases of the granzyme family following the contacting. In some embodiments, the one or more immune effector cells release one or more cytotoxic proteases of the granzyme family following the contacting the one or more cytotoxic proteases of the granzyme family comprise Granzyme B (GrB). In some embodiments, the one or more immune effector cells one or more lytic proteins following the contacting. In some embodiments, the one or more lytic proteins comprise perforin. In some embodiments, the contacting engages a T cell receptor (TCR) on one or more T cells. In some embodiments, the one or more T cells comprise naive T cells, helper T cells, cytotoxic T cells, or any combination thereof. In some embodiments, the one or more T cells receive a co-stimulatory signal resulting in T cell proliferation, differentiation, and survival. In some embodiments, the contacting induces co-stimulation independent polyclonal T-cell activation. In some embodiments, the tumor cell is a multiple myeloma tumor cell.

[0007] Described herein, in some aspects, are methods for treating a cancer in a subject in need thereof, the methods comprising administering a therapeutically effective amount of a multispecific binder molecule described herein. In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is myeloma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the therapeutically effective amount reduces a risk of the subject developing cytokine release syndrome (CRS) following the administering.INCORPORATION BY REFERENCE

[0008] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.BRIEF DESCRIPTION OF THE DRAWINGS

[0009] The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

[0010] FIG. 1 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. One modified heavy chain is configured from N- terminal to C-terminal as: i) Binding arm A heavy chain variable region (VH), ii) a first constant Ig domain of a heavy chain (CHI), iii) a second constant Ig domain of a heavy chain (CH2), iv) a mutated third Ig domain of a heavy chain (CH3) comprising KiH knob substitutions, v) Binding arm C VH, and vi) CHI. A second modified heavy chain is configured from N-terminal to C-terminal as: i) Binding arm B VH, ii) CHI, iii) CH2 iv) a mutated CH3 comprising KiH hole substitutions, v) Binding arm D VH, and vi) CHI. A first light chain is configured from N- terminal to C-terminal as: i) Binding arm A light chain variable region (VL). and ii) a constant Ig domain of a light chain (CL - K set 1 or CL - K set 2). Paired Binding arm A VH and Binding arm A VL form a first binding moiety. A second light chain is configured from N-terminal to C- terminal as: i) Binding arm B VL and ii) CL - K set 1 or CL - K set 2. Paired Binding arm B VH and Binding arm B VL form a second binding moiety. A third light chain is configured from N- terminal to C-terminal as: i) Binding arm C VL and ii) CL - K set 1 or CL - K set 2. Paired Binding arm C VH and Binding arm C VL form a third binding moiety. A fourth light chain is configured from N-terminal to C-terminal as: i) Binding arm D VL, and ii) CL - K set 1 or CL - K set 2. Paired Binding arm D VH and Binding arm D VL form a fourth binding moiety.

[0011] FIG. 2 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. Paired Binding arm A VH and Binding arm A VL form a BCMA binding moiety. Paired Binding arm B VH and Binding arm B VL form a GPRC5D binding moiety. Paired Binding arm C VH and Binding arm C VL form an FcRH5 binding moiety. Paired Binding arm D VH and Binding arm D VL form a CD3 binding moiety.

[0012] FIG. 3 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. Two light chains are paired with each of two modified heavy chains with the respective VH and VL regions arranged to form a BCMA binding moiety, a GPRC5D binding moiety, a CD3 binding moiety, and a CD38 binding moiety.

[0013] FIG. 4 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. Two light chains are paired with each of two modifiedheavy chains with the respective VH and VL regions arranged to form a BCMA binding moiety, a GPRC5D binding moiety, a CD3 binding moiety, and a SLAMF7 binding moiety.

[0014] FIG. 5 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. Two light chains are paired with each of two modified heavy chains with the respective VH and VL regions arranged to form a SLAMF7 binding moiety, a GPRC5D binding moiety, a CD3 binding moiety, and a CD38 binding moiety.

[0015] FIG. 6 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. Two light chains are paired with each of two modified heavy chains with the respective VH and VL regions arranged to form a BCMA binding moiety, a SLAMF7 binding moiety, a CD3 binding moiety, and a CD38 binding moiety.

[0016] FIG. 7 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. Two light chains are paired with each of two modified heavy chains with the respective VH and VL regions arranged to form a BCMA binding moiety in binding arm A, a CD3 binding moiety in binding arm B, a FcRH5 binding moiety in binding arm C, and a GPRC5D binding moiety in binding arm D.

[0017] FIG. 8 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. Two light chains are paired with each of two modified heavy chains with the respective VH and VL regions arranged to form a BCMA binding moiety in binding arm A, a CD3 binding moiety in binding arm B, a GPRC5D binding moiety in binding arm C, and a FcRH5 binding moiety in binding arm D.

[0018] FIG. 9 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. Two light chains are paired with each of two modified heavy chains with the respective VH and VL regions arranged to form a FcRH5 binding moiety in binding arm A, a CD3 binding moiety in binding arm B, a GPRC5D binding moiety in binding arm C, and a BCMA binding moiety in binding arm D.

[0019] FIG. 10 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. Two light chains are paired with each of two modified heavy chains with the respective VH and VL regions arranged to form a FcRH5 binding moiety in binding arm A, a CD3 binding moiety in binding arm B, a BCMA binding moiety in binding arm C, and a GPRC5D binding moiety in binding arm D.

[0020] FIG. 11 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. Two light chains are paired with each of two modified heavy chains with the respective VH and VL regions arranged to form a GPRC5D binding moiety in binding arm A, a CD3 binding moiety in binding arm B, a FcRH5 binding moiety in binding arm C, and a BCMA binding moiety in binding arm D.

[0021] FIG. 12 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. Two light chains are paired with each of two modified heavy chains with the respective VH and VL regions arranged to form a GPRC5D binding moiety in binding arm A, a CD3 binding moiety in binding arm B, a BCMA binding moiety in binding arm C, and a FcRH5 binding moiety in binding arm D.DETAILED DESCRIPTION

[0022] Cancers originating in the blood and bone marrow make up a significant portion of diseases in which there is either an unmet medical need or treatment options offering limited success. Multiple myeloma (MM) is the second most common hematological malignancy in the United States accounting for approximately 10% of hematological cancers. Multiple myeloma is characterized by uncontrolled clonal expansion of neoplastic plasma cells in and outside of the bone marrow (BM). These neoplastic plasma cells undergo excessive proliferation while surrounded by a permissive and protective tumor microenvironment. A dependence of MM plasma cells on BM microenvironment cells, each of which express different sets of cell surface receptors and adhesion molecules, has been demonstrated indicating a critical role for cross-talk involving receptors and adhesion in establishing and maintaining the permissive and protective role of BM microenvironment in MM progression. CD38, BCMA, and SLAMF7 are highly expressed in MM plasma cells pointing to their utility as selective targets for delivering therapeutics to malignant cells. BCMA is expressed at significantly higher levels in MM plasma cells than in healthy plasma cells, but is not expressed in other hematological cells types. CD38 and SLAMF7, while being highly expressed in MM plasma cells, also maintain expression in other immune cell types including immune effector cells and other hematopoietic cell lineages. GPRC5D is another marker strongly expressed in MM plasma cells, and restricted to expression among immune cell types to plasma cells. FcRH5 is expressed exclusively in B cell lineages and expression of FcRH5 is retained in plasma cells, including MM plasma cells. This expression pattern for FcRH5 makes it a promising candidate to use for tumor antigen targeting in MM and other hematological malignancies derived from B cell lineages.

[0023] Chemotherapy, stem cell transplant, or gene therapy are currently used where treatment in a subject is indicated in myeloma with symptoms. Yet, the majority of patients treated for multiple myeloma, including those having undergone either autologous hematopoietic stem-cell transplantation (auto-SCT) or allogeneic hematopoietic stem-cell transplantation, do suffer relapse after initial treatment. Relapse within the first 18 months of initial multiple myeloma diagnosis is considered to be functional high-risk multiple myeloma. Treatment options for relapsed disease can include retreatment using the original treatment modality, use of a differenttreatment modality, or a first or second auto-SCT. As relapsed multiple myeloma progresses, the disease can become refractory to one or more formerly effective treatments. This stage of multiple myeloma is referred to as relap sed / refractory multiple myeloma (RRMM).

[0024] Immunotherapeutic approaches to elicit or amplify an immune response are classified as activation immunotherapies and can be effective as therapeutics for cancer. Immune effector cells such as lymphocytes, macrophages, natural killer (NK) cells, and cytotoxic T lymphocytes participate in the defense against cancer by targeting abnormal antigens expressed on the surface of tumor cells. Compositions and methods to activate immune responses in these cells to target tumor cells can provide an effective therapy for various cancers.

[0025] Treatment modalities currently used to treat RRMM in patients include dexamethasone, proteasome inhibitors, nuclear export inhibitors, immunomodulatory drugs such as thalidomide or pomalidomide, or antibody treatments. Yet, despite recent advances in the treatment of MM, acute forms of MM remain almost incurable for the majority of patients since treatment-resistant clones eventually emerge and evolve leading to a low 5-year overall survival (OS) of about 50%. Clinical outcomes for subjects with RRMM are poor due to the diminishing performance and the gradual decreased durability of response with successive lines of MM therapy. High risk patients suffer shorter survival times, partly due to weakened immune systems. Immunotherapy has provided improved response rate, patient survival, and a favorable safety profile offering hope of significant long term treatment efficacy and durability for patients suffering from MM. An obstacle to effective immunotherapy is the immunosuppressive nature of the BM microenvironment. Malignant MM cells interact with surrounding BM accessory cells, including BM stromal cells, osteoclasts, regulatory T cells, regulatory B cells, myeloid-derived suppressor cells, tumor-associated macrophages, and plasmacytoid dendritic cells within the BM microenvironment. These surrounding BM accessory cells promote the growth and chemoresistance of MM plasma cells and also promote tumor cells immune escape, inhibiting tumor-specific T effector cells, inducing T-cell anergy, and increasing regulatory T cell numbers, fostering an immunosuppressive BM microenvironment. Therapies aimed at targeting specific MM antigens and also reversing or overcoming the immunosuppressive BM microenvironment provide a path to developing more effective therapies. Clinical success using anti-BCMA CAR-T cell therapy has demonstrated a significance of and a need to develop improved T cell-directing immunotherapies. The choice of tumor antigen(s) that is targeted is critical in effectiveness of a T cell-directing immunotherapy.

[0026] Described herein are multispecific binder molecules targeting tumor associated antigens which can be used in novel treatments for MM. A multispecific binder molecule targeted to at least three MM tumor antigens and having an immune cell engager component, offers a novelapproach to immunotherapy in MM. The multispecific binder molecule can bring an immune effector cell or immune effector cells in proximity to a pre-malignant or malignant MM cell. The multispecific binder molecule can simultaneously bind to a pre-malignant or malignant MM cell and an immune effector cell, creating an immune synapse between the two cells. This interaction encourages T cell activation, promotes tumor cell lysis, enhances T cell proliferation, or any combination thereof. The cytotoxic effect of this treatment involves polyclonal T cell responses. The multispecific binder molecule modulates general T cell function, such as differentiation of naive T cells to T cells with memory phenotypes (e.g., central memory and effector memory T cells) which contributes to improved occurrence of minimal residual disease (MRD) negativity in treated patients.

[0027] Multi specific binder molecules described herein and methods for use thereof target at least three tumor associated antigens selected from GPRC5D, BCMA, CD38, FcRH5 and SLAMF7 to effective target cancerous plasma cells, including pre-malignant and malignant plasma cells. The multispecific binder molecule additionally has an immune cell engager which comprises either a T cell binding moiety, an NK cell binding moiety, and / or an NKT cell binding moiety. The immune cell engager component of the multispecific binder molecule allows for binding to immune cells which can then elicit an immune response and the tumor associated antigen binding moieties allow for binding to pre-malignant and / or malignant plasma cells. Contacting a pre-malignant or a malignant plasma cell with the multispecific binding molecule can bring cytotoxic immune cells, which may be activated, in close proximity thereby eliciting a targeted immune response against pre-malignant and / or malignant plasma cells. Administering the multispecific binding molecule to a subject in need thereof can similarly induce a targeted immune response against pre-malignant and / or malignant plasma cells present in the subject. In some embodiments, the multispecific binder molecule has specific binding affinity for at least two tumor associated antigens and at least one T cell binding moiety, NK cell binding moiety, or NKT cell binding moiety. In some embodiments, the multispecific binder molecule has specific binding affinity for at least three tumor associated antigens and at least one T cell binding moiety, NK cell binding moiety, or NKT cell binding moiety. In some instances, the multispecific binder molecule having specific binding affinity for at least three tumor associated antigens and at least one T cell binding moiety, NK cell binding moiety, or NKT cell binding moiety is referred to as a tetraspecific binder molecule or a tetraspecific binding molecule.

[0028] Disclosed herein, in certain aspects, are multispecific binding molecules that bind to a combination of the targets: B-cell maturation antigen (BCM A), G-protein coupled receptor, class C, group 5, member D (GPRC5D), CD38 molecule (CD38), Fc receptor-homolog 5(FcRH5), SLAM family member 7 (SLAMF7), and / or cluster determinant 3 (CD3). In some aspects, the combination of targets comprise an amino acid sequence and / or a carbohydrate, lipid, or other chemical entity of BCMA, GPRC5D, CD38, FcRH5, SLAMF7, and / or CD3. In some embodiments, the targets comprise one or more antigens comprising a portion of a target molecule that is able to be bound by an adaptive immune molecule such as an antibody or antigen-binding fragment thereof, B-cell receptor, or T-cell receptor. Disclosed herein, in certain aspects, are multispecific binding molecules that bind to a combination of the antigens: B-cell maturation antigen (BCMA), G-protein coupled receptor, class C, group 5, member D (GPRC5D), CD38 molecule (CD38), Fc receptor-homolog 5 (FcRH5), SLAM family member 7 (SLAMF7), and / or cluster determinant 3 (CD3 ). In some aspects, also disclosed herein are methods used for inducing an immune response against a tumor cells by contacting the tumor cell with a multispecific binding molecule described herein. In some aspects, also disclosed herein are methods for treating a cancer in a subject in need thereof by administering a therapeutically effective amount of a multispecific binding molecule described herein.

[0029] G protein-coupled receptor class C group 5 member D (GPRC5D) is a cell surface receptor exhibiting highly variable levels of expression in patients with MM. Low levels of GPRC5D are found in normal tissues. High levels of GPRC5D mRNA are positively correlated with high plasma cell count in the BM of MM patients indicating its utility as an MM-associated antigen. Human GPRC5D is described in the NCBI Gene database under Gene ID: 55507 and in the UniProt database under Entry: Q9NZD1. GPRC5D can be expressed in high quantities in plasma B cells. GPRC5D can be expressed in high quantities in malignant plasma B cells. GPRC5D can be expressed in memory B-cells. GPRC5D can be expressed in class switched memory B cells. GPRC5D can be expressed in exhausted memory B cells. GPRC5D can be expressed in plasmablasts. GPRC5D can be expressed in peripheral blood mononuclear cells (PBMCs). In some embodiments, GPRC5D expression serves as a marker for plasma B cells. In some embodiments of multispecific binder molecules described herein, GPRC5D is a tumor associated antigen to which the multispecific binder molecule binds.

[0030] BCMA encodes a member of the TNF-receptor superfamily and is preferentially expressed in mature B lymphocytes including plasma cells. BCMA specifically binds to the signaling ligand BAFF (TNFSF13B) and this signaling event can lead to NF-kappaB and MAPK8 / JNK activation. BCMA can be expressed in high quantities in plasma B cells. BCMA can be expressed in high quantities in malignant plasma B cells. BCMA can be expressed in germinal center B cells. BCMA can be expressed in memory B cells. BCMA can be expressed in naive B cells. BCMA can be expressed in class switched memory B cells. BCMA can be expressed in exhausted memory B cells. BCMA can be expressed in plasmablasts. BCMA canbe expressed in plasmacytoid dendritic cells. BCMA can be expressed in PBMCs. In some embodiments, BCMA expression serves as a marker for plasma B cells. Human BCMA (TNFRSF17) is described in the NCBI Gene database under Gene ID: 608 and in the UniProt database under Entry: Q02223. In some embodiments of multispecific binder molecules described herein, BCMA is a tumor associated antigen to which the multispecific binder molecule binds.

[0031] Fc receptor-homolog 5 (FcRH5) is a single-pass type I membrane protein containing 8 immunoglobulin-like C2-type domains that is exclusively expressed in B cell lineages. Two membrane-bound isoforms of FcRH5 protein and one soluble isoform of FcRH5 protein have been identified. FcRH5, also known as FCRL5 or CD307, has elevated expression in MM cells as compared to normal B cells or non-cancerous plasma cells. High levels of soluble FcRH5 has been in detected in serum from patients with MM, chronic lymphocytic leukemia (CLL), and mantle cell lymphoma (MCL). In some embodiments, FcRH5 serves as a marker for plasma B cells. FcRH5 can be expressed in high quantities in plasma B cells. FcRH5 can be expressed in high quantities in malignant plasma B cells. FcRH5 can be expressed in germinal center B cells. FcRH5 can be expressed in memory B cells. FcRH5 can be expressed in class switched memory B cells. FcRH5 can be expressed in exhausted memory B cells. Human FcRH5 is described in the NCBI Gene database under Gene ID: 83416 and in the UniProt database under Entry: Q96RD9. In some embodiments of multispecific binder molecules described herein, FcRH5 is a tumor associated antigen to which the multispecific binder molecule binds.

[0032] Cyclic ADP ribose hydrolase is a transmembrane glycoprotein also known as CD38. CD38 is widely expressed in lymphoid and myeloid cell lineages. For example, CD38 is expressed by T cell precursors such as CD4+CD8+ double-positive thymocytes, in a subset of memory T cells, in CD4+ / CD45RA+ naive T cells, and CD38 is a marker for activated T cells. Among CD8+ T cells, CD38 is strongly expressed during period of chronic infection. CD38 expression is modulated during different stages of B cell differentiation being expressed at high levels on BM B cell precursors and then downregulated in mature B cells. CD38 is then expressed at high levels in terminally differentiated plasma cells. CD38 is also strongly expressed in several pathological cells including chronic lymphocytic leukemia cells and on malignant MM cells. Detailed analysis of CD38 expression within the BM microenvironment has indicated that only plasma cell types express high levels of CD38 demonstrating its utility as a specific antigen to target plasma cells. CD38 can be expressed in plasmablasts at a high level of expression. CD38 can be expressed in NK cells at a high level of expression. CD38 can be expressed in memory B cells. CD38 can be expressed in naive B cells. CD38 can be expressed in plasmacytoid dendritic cells. CD38 can be expressed in exhausted memory B cells. HumanCD38 is described in the NCBI Gene database under Gene ID: 952 and in the UniProt database under Entry: P28907. In some embodiments of multispecific binder molecules described herein, CD38 is a tumor associated antigen to which the multispecific binder molecule binds. In some embodiments of multispecific binder molecules described herein, a CD38 binding moiety is an immune cell engager comprising an NK cell binding moiety. In some embodiments of multispecific binder molecules described herein, a CD38 binding moiety is an immune cell engager comprising a T cell binding moiety. In some embodiments of multispecific binder molecules described herein, a CD38 binding moiety is an immune cell engager comprising an NKT cell binding moiety.

[0033] The SLAM family member 7 (SLAMF7), also known as CD319 or CS1, is a robustly expressed marker of normal plasma cells and malignant MM plasma cells. SLAMF7 plays roles in several cell functions including maintaining plasma cell survival, cell adhesion, and NK cell and CD8+ T cell-mediated cytotoxicity. In NK cells, SLAMF7 functions as a positive regulatory of NK cell activation. Primary myeloma cells and human-derived multiple myeloma cell lines express higher levels of SLAMF7 than normal cells. SLAMF7 has a demonstrated role in mediating proliferation of MM cells. High levels of soluble SLAMF7 protein and elevated SLAMF7 mRNA levels in purified plasma cells have been documented in subjects affected by monoclonal gammopathies across the entire clinical spectrum, (e.g., monoclonal gammopathy of undetermined significance (MGUS), smoldering MM, active MM, and RRMM). In recently diagnosed MM patients, increased soluble SLAMF7 was found to be positively associated with active MM and was further increased in the most aggressive presentations of the disease. SLAMF7 can be expressed at a high level in plasma B cells. SLAMF7 can be expressed at a high level in malignant plasma B cells. SLAMF7 can be expressed in classical, non-classical, and intermediate monocytes. SLAMF7 can be expressed in a variety of T cells including Gamma-Delta T cells, mucosal-associated invariant T cells, memory CD4+ T cells, memory CD8+ T cells, central memory CD8+ T cells, effector memory CD8+ T cells, naive CD4+ T cells, naive CD8+ T cells, or terminal effector memory CD4+ T cells, or any combination thereof. SLAMF7 can be expressed in plasmacytoid dendritic cells. SLAMF7 can be expressed in myeloid dendritic cells. SLAMF7 can be expressed in NK cells. SLAMF7 can be expressed in plasmablasts. SLAMF7 can be expressed in PBMCs. Human SLAMF7 is described in the NCBI Gene database under Gene ID: 57823 and in the UniProt database under Entry: Q9NQ25. In some embodiments of multispecific binder molecules described herein, SLAMF7 is a tumor associated antigen to which the multispecific binder molecule binds. In some embodiments of multispecific binder molecules described herein, a SLAMF7 binding moiety is an immune cell engager comprising an NK cell binding moiety. In some embodiments of multispecific bindermolecules described herein, a SLAMF7 binding moiety is an immune cell engager comprising a T cell binding moiety. In some embodiments of multispecific binder molecules described herein, a SLAMF7 binding moiety is an immune cell engager comprising an NKT cell binding moiety.

[0034] Cluster of differentiation 3 (CD3) is a protein complex and T cell co-receptor. The protein complex contains a CD3y chain, a CD35 chain, and two CD3s chains. These chains in the protein complex associate with the T-cell receptor (TCR) and the CD3 zeta chain in order to generate an activation signal in T lymphocytes. Together, the CD3 zeta chain, the TCR, and the other CD3 chains in the protein complex constitute the TCR complex. The CD3 complex serves as a T cell co-receptor that associates noncovalently with TCR. CD3y, CD35, and CD3s are highly related immunoglobulin superfamily cell-surface proteins each having a single extracellular immunoglobulin domain. CD3 is initially expressed in the cytoplasm of prolymphocytes. CD3 is bound to the plasma membrane of all mature T-cells, and virtually no other cell types indicating its specificity for use as an immune cell engager target. The CD3 protein complex is a defining feature of the T cell lineage, making binders that bind to CD3 a T cell marker. CD35 (CD3D) can be expressed in regulatory T cells, mucosal-associated invariant T cells, naive CD4+ T cells, delta gamma T cells, memory CD4+ T cells, terminal effector memory CD4+ T cells, naive CD8+ T cells, central memory CD8+ T cells, effector memory CD8+ T cells, terminal effector memory CD8+ T cells, naive regulatory T cells, memory regulatory T cells, activated T cells, or cytotoxic T cells, or any combination thereof. CD3D can be expressed in NKT cells. CD3D can be expressed in NK cells. CD3s (CD3E) can be expressed in regulatory T cells, mucosal-associated invariant T cells, naive CD4+ T cells, delta gamma T cells, memory CD4+ T cells, naive CD8+ T cells, memory CD4+ T cells, terminal effector memory CD4+ T cells, central memory CD8+ T cells, effector memory CD8+ T cells, terminal effector memory CD8+ T cells, naive regulatory T cells, memory regulatory T cells, activated T cells, or cytotoxic T cells, or any combination thereof. CD3E can be expressed in NKT cells. CD3E can be expressed in NK cells. CD3E can be expressed in PBMCs. CD3y (CD3G) can be expressed in regulatory T cells, mucosal-associated invariant T cells, naive CD4+ T cells, delta gamma T cells, memory CD4+ T cells, naive CD8+ T cells, memory CD4+ T cells, terminal effector memory CD4+ T cells, central memory CD8+ T cells, effector memory CD8+ T cells, terminal effector memory CD8+ T cells, naive regulatory T cells, memory regulatory T cells, activated T cells, or cytotoxic T cells, or any combination thereof. CD3G can be expressed in NKT cells. CD3G can be expressed in NK cells. CD3G can be expressed in PBMCs. CD3 zeta (CD247) can be expressed in regulatory T cells, mucosal-associated invariant T cells, naive CD4+ T cells, delta gamma T cells, memory CD4+ T cells, naive CD8+ T cells, memory CD4+ T cells, terminal effector memory CD4+ T cells, central memory CD8+ T cells, effector memoryCD8+ T cells, terminal effector memory CD8+ T cells, naive regulatory T cells, memory regulatory T cells, activated T cells, or cytotoxic T cells, or any combination thereof. CD247 can be expressed in NKT cells. CD247 can be expressed in NK cells. CD247 can be expressed in PBMCs. CD247 can be expressed in intermediate monocytes. Human CD3y is described in the NCBI Gene database under Gene ID: 917 and in the UniProt database under Entry: P09693. Human CD35 is described in the NCBI Gene database under Gene ID: 915 and in the UniProt database under Entry: P04234. Human CD3s is described in the NCBI Gene database under Gene ID: 916 and in the UniProt database under Entry: P07766. Human CD3 zeta (CD247) is described in the NCBI Gene database under Gene ID: 919 and in the UniProt database under Entry: P20963. In some embodiments of multispecific binder molecules described herein, one or more sites within the CD3 receptor complex are targets to which the multispecific binder molecule binds. In some embodiments, by binding to the CD3 receptor complex or by binding to one of the elements comprising the CD3 receptor complex, the multispecific binder molecule functions as an immune cell engager. In some embodiments, the immune cell engager comprises a T cell binding moiety, an NK cell binding moiety, or an NKT cell binding moiety, or any combination thereof. In some embodiments, the T cell binding moiety, the NK cell binding moiety, the NKT cell binding moiety, or any combination thereof binds to CD3 or binds to one of the elements comprising the CD3 receptor complex.Antibody-Based Multi-Specific Binders

[0035] In some aspects, the multispecific binder molecule comprises an antibody-based multispecific binder. In some aspects, the multispecific binder is an antibody-based multispecific binder. In some aspects, the antibody-based multispecific binder comprises a binding moiety. In some aspects, the antibody-based multispecific binder comprises at least one, at least two, at least three, or at least four antibody-based binding moieties. In some embodiments, at least one antibody -based binding moiety binds to a tumor associated antigen. In some embodiments, at least one, at least two, at least three, or at least four antibody -based binding moieties bind to one or more tumor associated antigens. In some embodiments, at least three antibody -based binding moieties bind to three distinct tumor antigens. In some embodiments, each of at least one, at least two, at least three, or at least four antibody-based binding moieties bind to a different tumor associated antigen. In some instances, the tumor associated antigen is GPRC5D. In some instances, the tumor associated antigen is BCMA. In some instances, the tumor associated antigen is FcRH5. In some instances, the tumor associated antigen is CD38. In some instances, the tumor associated antigen is SLAMF7. In some instances, the tumor associated antigen is an extracellular portion of GPRC5D, BCMA, FcRH5, CD38, or SLAMF7. In some instances, thetumor associated antigen is present on the surface of a plasma cell. In some instances, the tumor associated antigen is present on the surface of a pre-malignant plasma cell. In some instances, the tumor associated antigen is present on the surface of a malignant plasma cell. In some instances, the tumor associated antigen is present in the blood of the subject. In some instances, the tumor associated antigen is present in a serum sample taken from the subject. In some instances, the tumor associated antigen is present in a BM aspirate from the subject. In some instances, the tumor associated antigen is present in a BM biopsy from the subject. In some instances, at least one antibody-based binding moiety binds to an immune cell. In some instances, at least one antibody-based binding moiety binds to an immune effector cell. In some instances, at least one antibody-based binding moiety binds to a T cell. In some instances, at least one antibody-based binding moiety binds to an NK cell. In some instances, at least one antibody -based binding moiety binds to an NKT cell. In some instances, at least one antibodybased binding moiety binds to a T cell, an NK cell, an NKT cell, or any combination thereof. In some instances, the at least one antibody -based binding moiety that binds to an immune cell functions as an immune cell engager. In some instances, the immune cell engager comprises a CD3 binding moiety. In some instances, the immune cell engager binds to one or more components of the CD3 co-receptor.

[0036] In some aspects, the multispecific binder molecule comprises at least three binding moieties selected from the group consisting of a GPRC5D-binding moiety, a BCMA-binding moiety, an FcRH5-binding moiety, a CD38-binding moiety, a SLAMF7-binding moiety, and a CD3-binding moiety. In some embodiments, the multispecific binder molecule comprises at least four binding moieties selected from the group consisting of a GPRC5D-binding moiety, a BCMA-binding moiety, an FcRH5-binding moiety, a CD38-binding moiety, a SLAMF7-binding moiety, and a CD3-binding moiety. In some embodiments, at least one of the at least three binding moieties is an antibody or antigen binding fragment thereof. In some embodiments, at least one of the at least four binding moieties is an antibody or antigen binding fragment thereof. In some embodiments, at least two of the at least three binding moieties are antibodies or antigen binding fragments thereof. In some embodiments, at least two of the at least four binding moieties are antibodies or antigen binding fragments thereof. In some embodiments, three of the at least three binding moieties are antibodies or antigen binding fragments thereof. In some embodiments, at least three of the at least four binding moieties are antibodies or antigen binding fragments thereof. In some embodiments, four of the at least four binding moieties are antibodies or antigen binding fragments thereof. In some embodiments, the multispecific binder molecule comprises one or more antibody-based binders and one or more non-antibody based binders.

[0037] In some aspects, the multispecific binder molecule comprises at least one antibody-based multispecific binder. In some aspects, the multispecific binder molecule comprises at least one antibody-based binder. In some aspects, the multispecific binder molecule comprises at least two or at least three antibody -based binders that bind different tumor associated antigens. In some embodiments, the multispecific binder molecule comprises an immune cell engager. In some embodiments, one or more antibody -based binders function as an immune cell engager. In some embodiments, the immune cell engager comprises a T cell binding moiety, an NK cell binding moiety, or an NKT cell binding moiety, an any combination thereof. In some embodiments, the immune cell engager comprises a T cell binding moiety. In some embodiments, the multispecific binder molecule comprises at least two antibody-based binding moieties that bind to different tumor associated antigens and at least one antibody -based immune cell binder. In some embodiments, the multispecific binder molecule comprises at least three antibody-based binding moieties that bind to different tumor associated antigens and at least one antibody -based immune cell binder. In some aspects, the antibody-based multispecific binder molecule comprises a GPRC5D binding moiety. GPRC5D is a tumor associated antigen in several forms of tumors or cancers. In some instances, GPRC5D is a tumor associated antigen for a hematological cancer. In some instances, GPRC5D is a myeloma tumor associated antigen. In some instances, GPRC5D is a multiple myeloma tumor associated antigen. In some embodiments, the antibodybased GPRC5D binding moiety of the multispecific binder molecule binds to a tumor associated antigen.

[0038] In some aspects, the antibody-based multispecific binder molecule comprises a BCMA binding moiety. BCMA is a tumor associated antigen in several forms of tumors or cancers. In some instances, BCMA is a tumor associated antigen for a hematological cancer. In some instances, BCMA is a myeloma tumor associated antigen. In some instances, BCMA is a multiple myeloma tumor associated antigen. In some embodiments, the antibody -based BCMA binding moiety of the multispecific binder molecule binds to a tumor associated antigen.

[0039] In some aspects, the antibody-based multispecific binder molecule comprises an FcRH5 binding moiety. FcRH5 is a tumor associated antigen in several forms of tumors or cancers. In some instances, FcRH5 is a tumor associated antigen for a hematological cancer. In some instances, FcRH5 is a myeloma tumor associated antigen. In some instances, FcRH5 is a multiple myeloma tumor associated antigen. In some instances, FcRH5 is a CLL tumor associated antigen. In some instances, FcRH5 is an MCL tumor associated antigen. In some embodiments, the antibody-based FcRH5 binding moiety of the multispecific binder molecule binds to a tumor associated antigen.

[0040] In some aspects, the antibody -based multispecific binder molecule comprises a CD38 binding moiety. CD38 is a tumor associated antigen in several forms of tumors or cancers. In some instances, CD38 is a tumor associated antigen for a hematological cancer. In some instances, CD38 is a myeloma tumor associated antigen. In some instances, CD38 is a multiple myeloma tumor associated antigen. In some instances, the antibody -based CD38 binding moiety of the multispecific binder molecule binds to a tumor associated antigen. In some instances, CD38 is a marker expressed in T cells, NK cells, or NKT cells, or any combination thereof.

[0041] In some aspects, the antibody-based multispecific binder molecule comprises a SLAMF7 binding moiety. SLAMF7 is a tumor associated antigen in several forms of tumors or cancers. In some instances, SLAMF7 is a tumor associated antigen for a hematological cancer. In some instances, SLAMF7 is a myeloma tumor associated antigen. In some instances, SLAMF7 is a multiple myeloma tumor associated antigen. In some instances, the antibody -based SLAMF7 binding moiety of the multispecific binder molecule binds to a tumor associated antigen. In some instances, SLAMF7 is a marker expressed in T cells, NK cells, or NKT cells, or any combination thereof.

[0042] In some aspects, the antibody-based multispecific binder molecule comprises a CD3 binding moiety. In some embodiments, the CD3 binding moiety binds to one or more components of the CD3 co-receptor complex. CD3 is an antigen expressed by several types of immune cells. In some instances, CD3 expression marks immune effector cells. In some instances, CD3 is a marker expressed in T cells, or NKT cells, or T cells and NKT cells. In some instances, CD3 is a marker expressed in effector T cells. In some instances, CD3 is a marker expressed in cytotoxic T cells. In some embodiments, the CD3 binding moiety is an antibodybased CD3 binding moiety. In some embodiments, the antibody-based CD3 binding moiety functions as an immune cell engager.

[0043] In some aspects, the multispecific binder molecule comprises four antibody-based binding moieties. In some instances, the multispecific binder molecule comprises an antibodybased GPRC5D binding moiety, an antibody-based BCMA binding moiety, an antibody-based CD38 binding moiety, and an antibody -based immune cell engager. In some instances, the multispecific binder molecule comprises an antibody-based GPRC5D binding moiety, an antibody-based BCMA binding moiety, an antibody-based SLAMF7 binding moiety, and an antibody-based immune cell engager. In some instances, the multispecific binder molecule comprises an antibody-based GPRC5D binding moiety, an antibody-based SLAMF7 binding moiety, an antibody -based CD38 binding moiety, and an antibody -based immune cell engager. In some instances, the multispecific binder molecule comprises an antibody -based CD38 binding moiety, an antibody-based SLAMF7 binding moiety, an antibody-based BCMA bindingmoiety, and an antibody -based immune cell engager. In some instances, the multi specific binder molecule comprises an antibody-based GPRC5D binding moiety, an antibody-based BCMA binding moiety, an antibody -based FcRH5 binding moiety, and an antibody -based immune cell engager. In some instances, the multispecific binder molecule comprises an antibody-based GPRC5D binding moiety, an antibody -based CD38 binding moiety, an antibody -based FcRH5 binding moiety, and an antibody-based immune cell engager. In some instances, the multispecific binder molecule comprises an antibody-based GPRC5D binding moiety, an antibody -based SLAMF7 binding moiety, an antibody -based FcRH5 binding moiety, and an antibody-based immune cell engager. In some instances, the multispecific binder molecule comprises an antibody -based BCMA binding moiety, an antibody -based CD38 binding moiety, an antibody-based FcRH5 binding moiety, and an antibody-based immune cell engager. In some instances, the multispecific binder molecule comprises an antibody-based BCMA binding moiety, an antibody-based SLAMF7 binding moiety, an antibody-based FcRH5 binding moiety, and an antibody-based immune cell engager. In some instances, the multispecific binder molecule comprises an antibody -based CD38 binding moiety, an antibody -based SLAMF7 binding moiety, an antibody -based FcRH5 binding moiety, and an antibody -based immune cell engager. In some embodiments, one or more non-antibody based binding moieties replace one or more antibody-based binding moieties in a configuration of a multispecific binder molecule.

[0044] In some embodiments, one or more of the antibody -based binding moieties enhances binding of the multispecific binder molecule to plasma B cells. In some embodiments, one or more of the antibody-based binding moieties enhances binding of the multispecific binder molecule to pre-malignant plasma B cells. In some embodiments, one or more of the antibodybased binding moieties enhances binding of the multispecific binder molecule to malignant plasma B cells. In some embodiments, one or more of the antibody-based binding moieties enhances binding of the multispecific binder molecule to plasma B cells from a patient diagnosed with MGUS. In some embodiments, one or more of the antibody -based binding moieties enhances binding of the multispecific binder molecule to plasma B cells from a patient diagnosed with MM. In some embodiments, one or more of the antibody -based binding moieties enhances binding of the multispecific binder molecule to plasma B cells derived from a patient diagnosed with MM. In some embodiments, one or more of the antibody -based binding moieties enhances binding of the multispecific binder molecule to plasma B cells from a patient diagnosed with smoldering MM. In some embodiments, one or more of the antibody -based binding moieties enhances binding of the multispecific binder molecule to plasma B cells from a patient diagnosed with acute MM. In some embodiments, one or more of the antibody -based binding moieties enhances binding of the multispecific binder molecule to plasma B cells from apatient diagnosed with RRMM. In some embodiments, one or more of the antibody -based binding moieties enhances binding of the multispecific binder molecule to plasma B cells derived from a patient diagnosed with RRMM. In some embodiments, one or more of the antibody-based binding moieties enhances binding of the multispecific binder molecule to plasma B cells that have undergone deletion of one or more tumor associated antigens. In some embodiments, one or more of the antibody -based binding moieties enhances binding of the multispecific binder molecule to plasma B cells that have undergone downregulation of one or more tumor associated antigens. In some embodiments, SLAMF7 has undergone deletion or downregulation in plasma B cells or MM plasma B cells. In some embodiments, CD38 has undergone deletion or downregulation in plasma B cells or MM plasma B cells. In some embodiments, BCMA has undergone deletion or downregulation in plasma B cells or MM plasma B cells. In some embodiments, GPRC5D has undergone deletion or downregulation in plasma B cells or MM plasma B cells. In some embodiments, FcRH5 has undergone deletion or downregulation in plasma B cells or MM plasma B cells. In some embodiments, the multispecific binder molecule maintains therapeutic efficacy in a subject in which any one of CD38, BCMA, GPRC5D, FcRH5, or SLAMF7 have undergone deletion or downregulation in plasma B cells or MM plasma B cells by targeting a retained tumor antigen. In some embodiments, the multispecific binder molecule maintains therapeutic efficacy in a subject in which any two of CD38, BCMA, GPRC5D, FcRH5, or SLAMF7 have undergone deletion or downregulation in plasma B cells or MM plasma B cells by targeting a retained tumor antigen. In some embodiments, the multispecific binder molecule maintains therapeutic efficacy in a subject in which BCMA and GPRC5D have undergone deletion or downregulation in plasma B cells or MM plasma B cells by targeting a retained tumor antigen. In some embodiments, the multispecific binder molecule maintains therapeutic efficacy in a subject in which BCMA and FcRH5 have undergone deletion or downregulation in plasma B cells or MM plasma B cells by targeting a retained tumor antigen. In some embodiments, the multispecific binder molecule maintains therapeutic efficacy in a subject in which BCMA and CD38 have undergone deletion or downregulation in plasma B cells or MM plasma B cells by targeting a retained tumor antigen. In some embodiments, the multispecific binder molecule maintains therapeutic efficacy in a subject in which BCMA and SLAMF7 have undergone deletion or downregulation in plasma B cells or MM plasma B cells by targeting a retained tumor antigen. In some embodiments, the multispecific binder molecule maintains therapeutic efficacy in a subject in which GPRC5D and FcRH5 have undergone deletion or downregulation in plasma B cells or MM plasma B cells by targeting a retained tumor antigen. In some embodiments, the multispecific binder molecule maintains therapeutic efficacy in a subject in which GPRC5D andCD38 have undergone deletion or downregulation in plasma B cells or MM plasma B cells by targeting a retained tumor antigen. In some embodiments, the multispecific binder molecule maintains therapeutic efficacy in a subject in which GPRC5D and SLAMF7 have undergone deletion or downregulation in plasma B cells or MM plasma B cells by targeting a retained tumor antigen. In some embodiments, the multispecific binder molecule maintains therapeutic efficacy in a subject in which CD38 and FcRH5 have undergone deletion or downregulation in plasma B cells or MM plasma B cells by targeting a retained tumor antigen. In some embodiments, the multispecific binder molecule maintains therapeutic efficacy in a subject in which SLAMF7 and FcRH5 have undergone deletion or downregulation in plasma B cells or MM plasma B cells by targeting a retained tumor antigen. In some embodiments, the multispecific binder molecule maintains therapeutic efficacy in a subject in which CD38 and SLAMF7 have undergone deletion or downregulation in plasma B cells or MM plasma B cells by targeting a retained tumor antigen.

[0045] In some embodiments, one or more of the antibody -based binding moieties enhances binding of the multispecific binder molecule to plasma B cells in a subject that was determined to have a very good partial response (VGPR) to a previous MM treatment. In some embodiments, one or more of the antibody -based binding moieties enhances binding of the multispecific binder molecule to plasma B cells in a subject that was determined to have a partial response (PR) to a previous MM treatment. In some embodiments, one or more of the antibody-based binding moieties enhances binding of the multispecific binder molecule to plasma B cells in a subject that was determined to be non-responsive to a previous MM treatment. In some embodiments, one or more of the antibody -based binding moieties enhances binding of the multispecific binder molecule to plasma B cells that possess significant upregulation of expression of one or more tumor associated antigens. In some embodiments, the antibody-based GPRC5D binding moiety enhances binding to plasma B cells. In some embodiments, the antibody-based BCMA binding moiety enhances binding to plasma B cells. In some embodiments, the antibody -based FcRH5 binding moiety enhances binding to plasma B cells. In some embodiments, the antibody -based CD38 binding moiety enhances binding to plasma B cells. In some embodiments, the antibody-based SLAMF7 binding moiety enhances binding to plasma B cells. In some embodiments, the antibody-based CD3 binding moiety enhances binding to immune effector cells.

[0046] In some aspects, an antibody-based binder of the multispecific binding molecule comprises an antibody or antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment thereof is a human antibody or antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment thereof is a humanized antibodyor antigen binding fragment thereof. In some embodiments, the antibody or antigen binding fragment thereof comprises a chimeric antibody, a monoclonal antibody, a monovalent Fab’, a divalent Fab2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), a camelid antibody, or antigen binding fragment thereof. In some embodiments, a GPRC5D-binding moiety, a BCMA-binding moiety, an FcRH5 -binding moiety, a CD38-binding moiety, a SLAMF7-binding moiety, a CD3-binding moiety, or any combination thereof comprise an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises Fab’, scFv, IgG-scFv, nanobody, miniantibody, minibody, scFv-CH3 KiH, or scFv-KiH. In some embodiments, an antibody-based binder that binds to GPRC5D is derived from a monoclonal antibody. In some embodiments, an antibody-based binder that binds to BCMA is derived from a monoclonal antibody. In some embodiments, an antibody-based binder that binds to FcRH5 is derived from a monoclonal antibody. In some embodiments, an antibody -based binder that binds to CD38 is derived from a monoclonal antibody. In some embodiments, an antibody-based binder that binds to SLAMF7 is derived from a monoclonal antibody. In some embodiments, an antibody-based binder that binds to CD3 is derived from a monoclonal antibody.

[0047] In certain aspects, the multispecific binder molecule comprises a first immunoglobulin chain constant region and a second immunoglobulin chain constant region. In some embodiments, at least three of the antibody-based binding moieties of the multispecific binder molecule: i) the CD3 binding moiety, ii) the GPRC5D binding moiety, iii) the TNFRSF17 (BCMA) binding moiety, iv) the CD38 binding moiety, v) the SLAMF7 (CD319) binding moiety, and vi) the FcRH5 binding moiety, are linked to either the first immunoglobulin chain constant region or the second immunoglobulin chain constant region. In some embodiments, the TNFRSF17 (BCMA) binding moiety and the GPRC5D binding moiety are linked to the first immunoglobulin chain constant region and the CD3 binding moiety and optionally one of the CD38 binding moiety or the SLAMF7 (CD319) binding moiety are linked to the second immunoglobulin chain constant region. In some embodiments, the TNFRSF17 (BCMA) binding moiety and the CD3 binding moiety are linked to the first immunoglobulin chain constant region and the GPRC5D binding moiety and optionally one of the CD38 binding moiety or the SLAMF7 (CD319) binding moiety are linked to the second immunoglobulin chain constant region. In some embodiments, the CD3 binding moiety and the GPRC5D binding moiety are linked to the first immunoglobulin chain constant region and the TNFRSF17 (BCMA) binding moiety and optionally one of the CD38 binding moiety or the SLAMF7 (CD319) binding moiety are linked to the second immunoglobulin chain constant region. In some embodiments, the CD3 binding moiety and the GPRC5D binding moiety are linked to the first immunoglobulin chainconstant region and the TNFRSF17 (BCMA) binding moiety and the FcRH5 binding moiety are linked to the second immunoglobulin chain constant region. In some embodiments, the CD3 binding moiety and the TNFRSF17 (BCMA) binding moiety are linked to the first immunoglobulin chain constant region and the GPRC5D binding moiety and the FcRH5 binding moiety are linked to the second immunoglobulin chain constant region. In some embodiments, the CD3 binding moiety and the FcRH5binding moiety are linked to the first immunoglobulin chain constant region and the GPRC5D binding moiety and the TNFRSF17 (BCMA) binding moiety are linked to the second immunoglobulin chain constant region. In some embodiments, the linked binding moieties are covalently coupled to a single polypeptide chain. In some embodiments, the linked binding moieties are conjugated to a single polypeptide chain. In some embodiments, the i) CD3 binding moiety, ii) GPRC5D binding moiety, iii) TNFRSF17 (BCMA) binding moiety, iv) CD38 binding moiety, v) SLAMF7 (CD319) binding moiety, and vi) FcRH5 binding moiety comprises an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises Fab’, scFv, IgG-scFv, nanobody, mini-antibody, minibody, scFv-CH3 KiH, or scFv-KiH. In some embodiments, the first or second immunoglobulin chain constant region comprises a heavy chain constant region of IgGl, IgG2, and IgG4, or a variant thereof. In some embodiments, the first or second immunoglobulin chain constant region form an IgG heavy chain, or variant thereof.

[0048] In some aspects, the multispecific binder molecule comprises one or more antibody heavy chains. In some embodiments, the multispecific binder molecule comprises a first heavy chain and a second heavy chain. In some embodiments, i) the first heavy chain; ii) the second heavy chain; or iii) the first and second heavy chains, are modified heavy chains. In some embodiments, i) the first heavy chain or first modified heavy chain; ii) the second heavy chain or second modified heavy chain; iii) the first heavy chain and second heavy chain; iv) the first modified heavy chain and second heavy chain; v) the first heavy chain and second modified heavy chain; or vi) the first modified heavy chain and second modified heavy chain, are variant heavy chains. In some embodiments, a variant heavy chain comprises one or more amino acid substitutions, insertions, deletions, or any combination thereof in a CHI domain, a CH2 domain, a CH3 domain, or any combination of CHI, CH2, and CH3 domains. In some embodiments, a variant heavy chain comprises a CHI domain. In some embodiments, a variant heavy chain comprises a CHI domain and a CH2 domain. In some embodiments, a heavy chain or a variant heavy chain comprises a CHI domain, a CH2 domain, and a CH3 domain. In some embodiments, a heavy chain or a variant heavy chain comprises a CHI domain, a CH2 domain, or a CH3 domain, or any combination thereof. In some embodiments, a modified heavy chain comprises a modification to the N-terminus of the heavy chain. In some embodiments, amodified heavy chain comprises a CHI domain, a CH2 domain, and a CH3 domain with a modification of the N-terminus of the heavy chain. In some embodiments, a modified heavy chain comprises a modification to the C-terminus of the heavy chain. In some embodiments, a modified heavy chain comprises a CHI domain, a CH2 domain, and a CH3 domain with a modification of the C-terminus of the heavy chain. In some embodiments, a modified heavy chain comprises a CHI domain, a CH2 domain, and a CH3 domain with a modification of the N-terminus and the C-terminus of the heavy chain. In some embodiment, a heavy chain or a modified heavy chain comprises a VH domain at the N-terminus. In some embodiments, a heavy chain is modified by coupling one or more protein domains to the N-terminus, C-terminus, or N- terminus and C-terminus of the heavy chain to form a modified heavy chain. In some embodiments, the modification to the N-terminus or C-terminus of the modified heavy chain comprises a binding moiety coupled to the modified heavy chain. In some embodiments, the binding moiety coupled to the modified heavy chain comprises an antibody -based binding moiety. In some embodiments, the antibody-based binding moiety comprises a VH domain, a nanobody, a biparatopic nanobody, a camelid heavy-chain variable domain (VHH), an scFv, a dimeric scFv, a bispecific-scFv, a diabody, a triabody, a tetrabody, an scAb, a V-NAR domain, a minibody, an sdAb, a disulfide stabilized Fv protein ("dsFv"), or antigen binding fragment thereof. In some embodiments, the binding moiety comprises a non-antibody-based binding moiety.

[0049] In some embodiments, the first heavy chain or first modified heavy chain comprises a first immunoglobulin chain constant region and the second heavy chain or second modified heavy chain comprises a second immunoglobulin chain constant region. In some embodiments, the first heavy chain or first modified heavy chain comprises a CD3 binding moiety at the N- terminus of the first heavy chain linked to the first immunoglobulin chain constant region. In some embodiments, the first heavy chain or first modified heavy chain comprises a GPRC5D binding moiety at the N-terminus of the first heavy chain linked to the first immunoglobulin chain constant region. In some embodiments, the first heavy chain or first modified heavy chain comprises a BCMA binding moiety at the N-terminus of the first heavy chain linked to the first immunoglobulin chain constant region. In some embodiments, the first heavy chain or first modified heavy chain comprises a CD38 binding moiety at the N-terminus of the first heavy chain linked to the first immunoglobulin chain constant region. In some embodiments, the first heavy chain or first modified heavy chain comprises a SLAMF7 binding moiety at the N- terminus of the first heavy chain linked to the first immunoglobulin chain constant region. In some embodiments, the first modified heavy chain comprises a CD3 binding moiety at the C- terminus of the first heavy chain. In some embodiments, the first modified heavy chaincomprises a GPRC5D binding moiety at the C-terminus of the first heavy chain. In some embodiments, the first modified heavy chain comprises a BCMA binding moiety at the C- terminus of the first heavy chain. In some embodiments, the first modified heavy chain comprises an FcRH5 binding moiety at the N-terminus of the first heavy chain. In some embodiments, the first modified heavy chain comprises an FcRH5 binding moiety at the C- terminus of the first heavy chain. In some embodiments, the second modified heavy chain comprises an FcRH5 binding moiety at the N-terminus of the second heavy chain. In some embodiments, the second modified heavy chain comprises an FcRH5 binding moiety at the C- terminus of the second heavy chain. In some embodiments, the first modified heavy chain comprises a CD38 binding moiety at the C-terminus of the first heavy chain. In some embodiments, the first modified heavy chain comprises a SLAMF7 binding moiety at the C- terminus of the first heavy chain. In some embodiments, the second heavy chain or second modified heavy chain comprises a CD3 binding moiety at the N-terminus of the second heavy chain linked to the second a immunoglobulin chain constant region. In some embodiments, the second heavy chain or second modified heavy chain comprises a GPRC5D binding moiety at the N-terminus of the second heavy chain linked to the second immunoglobulin chain constant region. In some embodiments, the second heavy chain or second modified heavy chain comprises a BCMA binding moiety at the N-terminus of the second heavy chain linked to the second immunoglobulin chain constant region. In some embodiments, the second heavy chain or second modified heavy chain comprises a CD38 binding moiety at the N-terminus of the second heavy chain linked to the second immunoglobulin chain constant region. In some embodiments, the second heavy chain or second modified heavy chain comprises a SLAMF7 binding moiety at the N-terminus of the second heavy chain linked to the second immunoglobulin chain constant region. In some embodiments, the second modified heavy chain comprises a CD3 binding moiety at the C-terminus of the second heavy chain. In some embodiments, the second modified heavy chain comprises a GPRC5D binding moiety at the C-terminus of the second heavy chain. In some embodiments, the second modified heavy chain comprises a BCMA binding moiety at the C-terminus of the second heavy chain. In some embodiments, the second modified heavy chain comprises a CD38 binding moiety at the C-terminus of the second heavy chain. In some embodiments, the second modified heavy chain comprises a SLAMF7 binding moiety at the C- terminus of the second heavy chain. In some embodiments, the TNFRSF17 (BCMA) binding moiety is coupled to the C-terminus of a modified IgGl heavy chain or a variant thereof. In some embodiments, the CD38 binding moiety is coupled to the C-terminus of a modified IgGl heavy chain or a variant thereof. In some embodiments, the GPRC5D binding moiety is coupled to the C-terminus of a modified IgGl heavy chain or a variant thereof. In some embodiments, the CD3binding moiety is coupled to the C-terminus of a modified IgGl heavy chain or a variant thereof. In some embodiments, the SLAMF7 binding moiety is coupled to the C-terminus of a modified IgGl heavy chain or a variant thereof.

[0050] In some embodiments, a first modified heavy chain, a second modified heavy chain, or a first and a second modified heavy chain comprise a binding moiety at the N-terminus and the C- terminus of a heavy chain. In some embodiments, the first or second modified heavy chain comprises a GPRC5D binding moiety at the N-terminus and a CD3 binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a GPRC5D binding moiety at the N-terminus and a BCMA binding moiety coupled to the C- terminus. In some embodiments, the first or second modified heavy chain comprises a GPRC5D binding moiety at the N-terminus and a CD38 binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a GPRC5D binding moiety at the N-terminus and a SLAMF7 binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a BCMA binding moiety at the N-terminus and a CD3 binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a BCMA binding moiety at the N-terminus and a GPRC5D binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a BCMA binding moiety at the N-terminus and a CD38 binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a BCMA binding moiety at the N-terminus and a SLAMF7 binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a CD38 binding moiety at the N-terminus and a CD3 binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a CD38 binding moiety at the N-terminus and a GPRC5D binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a CD38 binding moiety at the N-terminus and a BCMA binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a CD38 binding moiety at the N-terminus and a SLAMF7 binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a SLAMF7 binding moiety at the N-terminus and a CD3 binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a SLAMF7 binding moiety at the N-terminus and a GPRC5D binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a SLAMF7 binding moiety at the N-terminus and a BCMA binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a SLAMF7 binding moiety at the N-terminus and a CD38 binding moietycoupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a CD3 binding moiety at the N-terminus and a SLAMF7 binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a CD3 binding moiety at the N-terminus and a GPRC5D binding moiety coupled to the C- terminus. In some embodiments, the first or second modified heavy chain comprises a CD3 binding moiety at the N-terminus and a BCMA binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises a CD3 binding moiety at the N-terminus and a CD38 binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises an FcRH5 binding moiety at the N-terminus and a CD3 binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises an FcRH5 binding moiety at the N-terminus and a BCMA binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises an FcRH5 binding moiety at the N-terminus and a GPRC5D binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises an FcRH5 binding moiety at the N-terminus and a CD38 binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises an FcRH5 binding moiety at the N-terminus and a SLAMF7 binding moiety coupled to the C-terminus. In some embodiments, the first or second modified heavy chain comprises an FcRH5 binding moiety at the C-terminus and a CD3 binding moiety coupled to the N-terminus. In some embodiments, the first or second modified heavy chain comprises an FcRH5 binding moiety at the C-terminus and a BCMA binding moiety coupled to the N-terminus. In some embodiments, the first or second modified heavy chain comprises an FcRH5 binding moiety at the C-terminus and a GPRC5D binding moiety coupled to the N-terminus. In some embodiments, the first or second modified heavy chain comprises an FcRH5 binding moiety at the C-terminus and a CD38 binding moiety coupled to the N-terminus. In some embodiments, the first or second modified heavy chain comprises an FcRH5 binding moiety at the C-terminus and a SLAMF7 binding moiety coupled to the N-terminus.

[0051] In some embodiments, a first heavy chain comprising at least two binding moieties is paired with a second heavy chain comprising at least two binding moieties to form a tetraspecific binding molecule comprising a CD3 binding moiety, a GPRC5D binding moiety, a BCMA binding moiety, and a CD38 binding moiety. In some embodiments, a first heavy chain comprising at least two binding moieties is paired with a second heavy chain comprising at least two binding moieties to form a tetraspecific binding molecule comprising a CD3 binding moiety, a GPRC5D binding moiety, a BCMA binding moiety, and a SLAMF7 binding moiety. In some embodiments, a first heavy chain comprising at least two binding moieties is pairedwith a second heavy chain comprising at least two binding moieties to form a tetraspecific binding molecule comprising a CD3 binding moiety, a GPRC5D binding moiety, a CD38 binding moiety, and a SLAMF7 binding moiety. In some embodiments, a first heavy chain comprising at least two binding moieties is paired with a second heavy chain comprising at least two binding moieties to form a tetraspecific binding molecule comprising a CD3 binding moiety, a CD38 binding moiety, a BCMA binding moiety, and a SLAMF7 binding moiety. In some embodiments, a first heavy chain comprising at least two binding moieties is paired with a second heavy chain comprising at least two binding moieties to form a tetraspecific binding molecule comprising a CD3 binding moiety, a GPRC5D binding moiety, a BCMA binding moiety, and an FcRH5 binding moiety. In some embodiments, a first heavy chain comprising at least two binding moieties is paired with a second heavy chain comprising at least two binding moieties to form a tetraspecific binding molecule comprising a CD3 binding moiety, a CD38 binding moiety, a BCMA binding moiety, and an FcRH5 binding moiety. In some embodiments, a first heavy chain comprising at least two binding moieties is paired with a second heavy chain comprising at least two binding moieties to form a tetraspecific binding molecule comprising a CD3 binding moiety, a SLAMF7 binding moiety, a BCMA binding moiety, and an FcRH5 binding moiety. In some embodiments, a first heavy chain comprising at least two binding moieties is paired with a second heavy chain comprising at least two binding moieties to form a tetraspecific binding molecule comprising a CD3 binding moiety, a GPRC5D binding moiety, a CD38 binding moiety, and an FcRH5 binding moiety. In some embodiments, a first heavy chain comprising at least two binding moieties is paired with a second heavy chain comprising at least two binding moieties to form a tetraspecific binding molecule comprising a CD3 binding moiety, a GPRC5D binding moiety, a SLAMF7 binding moiety, and an FcRH5 binding moiety. In some embodiments, a first heavy chain comprising at least two binding moieties is paired with a second heavy chain comprising at least two binding moieties to form a tetraspecific binding molecule comprising a CD3 binding moiety, a CD38 binding moiety, a SLAMF7 binding moiety, and an FcRH5 binding moiety. In some embodiments, a VH domain residing within a heavy chain is paired with a VL domain residing within an antibody light chain to form a binding moiety. In some embodiments, a VH domain and VL domain that form a binding moiety are present in a single antibody chain.

[0052] In some embodiments, the multispecific binder molecule comprises one or more heavy chains paired with one or more antibody light chains. In some embodiments, the one or more light chains are variant or modified light chains. In some embodiments, the one or more light chains comprise one or more binding moieties. In some embodiments, the one or more light chains comprises one or more VL domains. In some embodiments, a VL domain pairs with aVH domain in a heavy chain to form a binding moiety. In some embodiments, the light chain or modified light chain comprises a CD3 binding moiety at the N-terminus or C-terminus. In some embodiments, the light chain or modified light chain comprises a GPRC5D binding moiety at the N-terminus or C-terminus. In some embodiments, the light chain or modified light chain comprises a BCMA binding moiety at the N-terminus or C-terminus. In some embodiments, the light chain or modified light chain comprises an FcRH5 binding moiety at the N-terminus or C- terminus. In some embodiments, the light chain or modified light chain comprises a CD38 binding moiety at the N-terminus or C-terminus. In some embodiments, the light chain or modified light chain comprises a SLAMF7 binding moiety at the N-terminus or C-terminus. In some embodiments, the multispecific binder molecule comprises two modified heavy chains and at least one, at least two, at least three, or at least four light chains. In some embodiments, the multispecific binder molecule comprises two modified heavy chains and four light chains. In some embodiments, the multispecific binder molecule comprises two modified heavy chains, wherein the modified heavy chains comprise different amino acid sequences. In some embodiments, the multispecific binder molecule comprises four light chains, wherein the four light chains each comprise at least one portion of non-identical amino acid sequence when compared to each other. In some embodiments, the multispecific binder molecule comprises four light chains, wherein two of the four light chains comprise an identical amino acid protein sequence. In some embodiments, wherein two of the four light chains comprise an identical amino acid protein sequence, the identical light chains are CD3 light chains, each CD3 light chain comprising a CD3 VL domain. In some embodiments, the multispecific binder molecule comprises four light chains, wherein two of the four light chains consist of identical amino acid protein sequences. In some embodiments, the multispecific binder molecule comprises four light chains, wherein three of the four light chains comprise an identical amino acid protein sequence. In some embodiments, wherein three of the four light chains comprise an identical amino acid protein sequence, the identical light chains are CD3 light chains, each CD3 light chain comprising a CD3 VL domain. In some embodiments, the multispecific binder molecule comprises four light chains, wherein three of the four light chains consist of identical amino acid protein sequences. In some embodiments wherein the multispecific binder molecules comprises two identical CD3 light chain, a first CD3 light chain is paired with a region comprising a CD3 VH domain and a CHI domain, and a second CD3 light chain is paired with a region comprising: i) a BCMA VH domain and a CHI domain, ii) a CD38 VH domain and a CHI domain, or iii) a SLAMF7 VH domain and a CHI domain. In some embodiments wherein the multispecific binder molecules comprises three identical CD3 light chains, a first CD3 light chain is paired with a region comprising a CD3 VH domain and a CHI domain, and a secondCD3 light chain and a third CD3 light chain are paired respectively with regions selected from: i) a BCM A VH domain and a CHI domain, ii) a CD38 VH domain and a CHI domain, and iii) a SLAMF7 VH domain and a CHI domain. In some embodiments wherein the multispecific binder molecules comprises two identical CD3 light chain, a first CD3 light chain is paired with a region comprising a CD3 VH domain and a CHI domain, and a second CD3 light chain is paired with a region comprising: i) a BCMA VH domain and a CHI domain, or ii) an FcRH5 VH domain and a CHI domain.

[0053] In some embodiments, the multispecific binder molecule comprises four light chains, wherein two of the four light chains comprise an identical amino acid amino acid sequences. In some embodiments, a disulfide bond formed between a CHI on a heavy chain or modified heavy chain and a CL region on a light chain aids in the stabilization of the structure of the multispecific binder molecules.

[0054] In some embodiments, the antibody-based binders bind to mammalian antigens. In some embodiments, the anti-GPRC5D antibody-based binder specifically binds to mammalian GPRC5D. In some embodiments, the anti-GPRC5D antibody-based binder specifically binds to mouse GPRC5D. In some embodiments, the anti-GPRC5D antibody-based binder specifically binds to cynomolgus monkey GPRC5D. In some embodiments, the anti-GPRC5D antibodybased binder specifically binds to human GPRC5D. In some embodiments, the anti-GPRC5D antibody-based binder specifically binds to one or more extracellular portions of GPRC5D. In some embodiments, the anti-GPRC5D antibody -based binder specifically binds to one or more extracellular portions of human GPRC5D. In some embodiments, the anti-BCMA antibodybased binder specifically binds to mammalian BCMA. In some embodiments, the anti-BCMA antibody -based binder specifically binds to mouse BCMA. In some embodiments, the anti- BCMA antibody-based binder specifically binds to cynomolgus monkey BCMA. In some embodiments, the anti-BCMA antibody -based binder specifically binds to human BCMA. In some embodiments, the anti-BCMA antibody-based binder specifically binds to one or more extracellular portions of BCMA. In some embodiments, the anti-BCMA antibody -based binder specifically binds to one or more extracellular portions of human BCMA. In some embodiments, the anti-FcRH5 antibody-based binder specifically binds to mammalian FcRH5. In some embodiments, the anti- FcRH5 antibody-based binder specifically binds to mouse FcRH5. In some embodiments, the anti-FcRH5 antibody -based binder specifically binds to cynomolgus monkey FcRH5. In some embodiments, the anti- FcRH5 antibody-based binder specifically binds to human FcRH5. In some embodiments, the anti- FcRH5 antibody -based binder specifically binds to one or more extracellular portions of FcRH5. In some embodiments, the anti-FcRH5 antibody -based binder specifically binds to one or more extracellular portions ofhuman FcRH5. In some embodiments, the anti-FcRH5 antibody-based binder specifically binds to soluble human FcRH5. In some embodiments, the anti-CD38 antibody -based binder specifically binds to mammalian CD38. In some embodiments, the anti-CD38 antibody -based binder specifically binds to mouse CD38. In some embodiments, the anti-CD38 antibody -based binder specifically binds to cynomolgus monkey CD38. In some embodiments, the anti-CD38 antibody -based binder specifically binds to human CD38. In some embodiments, the anti-CD38 antibody -based binder specifically binds to one or more extracellular portions of CD38. In some embodiments, the anti-CD38 antibody -based binder specifically binds to one or more extracellular portions of human CD38. In some embodiments, the anti-SLAMF7 antibody-based binder specifically binds to mammalian SLAMF7. In some embodiments, the anti-SLAMF7 antibody-based binder specifically binds to mouse SLAMF7. In some embodiments, the anti- SLAMF7 antibody-based binder specifically binds to cynomolgus monkey SLAMF7. In some embodiments, the anti-SLAMF7 antibody-based binder specifically binds to human SLAMF7. In some embodiments, the anti-SLAMF7 antibody-based binder specifically binds to one or more extracellular portions of SLAMF7. In some embodiments, the anti-SLAMF7 antibodybased binder specifically binds to one or more extracellular portions of human SLAMF7. In some embodiments, the anti-CD3 antibody -based binder specifically binds to mammalian CD3. In some embodiments, the anti-CD3 antibody -based binder specifically binds to mouse CD3. In some embodiments, the anti-CD3 antibody-based binder specifically binds to cynomolgus monkey CD3. In some embodiments, the anti-CD3 antibody -based binder specifically binds to human CD3. In some embodiments, the anti-CD3 antibody -based binder specifically binds to one or more extracellular portions of CD3. In some embodiments, the anti-CD3 antibody -based binder specifically binds to one or more extracellular portions of human CD3. In some embodiments, the anti-CD3 antibody -based binder specifically binds to one or more epitopes of CD3. In some embodiments, the anti-CD3 antibody -based binder specifically binds to a CD3 gamma chain. In some embodiments, the anti-CD3 antibody-based binder specifically binds to a CD3 delta chain. In some embodiments, the anti-CD3 antibody -based binder specifically binds to a CD3 epsilon chain. In some embodiments, the anti-CD3 antibody -based binder specifically binds to a CD3 zeta chain. In some embodiments, the anti-CD3 antibody-based binder specifically binds to any combination of a CD3 gamma chain, a CD3 delta chain, a CD3 epsilon chain, a CD3 zeta chain, and a T-cell receptor.

[0055] In some embodiments, the antibody-based binders of the multispecific binder molecule comprise an antibody or antigen binding fragment thereof. In some embodiments, the anti- GPRC5D antibody-based binder is derived from a human antibody, a rat antibody, a mouse antibody, a rabbit antibody, a camelid antibody, a humanized antibody, or a chimeric antibody.In some embodiments, the anti-BCMA antibody-based binder is derived from a human antibody, a rat antibody, a mouse antibody, a rabbit antibody, a camelid antibody, a humanized antibody, or a chimeric antibody. In some embodiments, the anti-FcRH5 antibody-based binder is derived from a human antibody, a rat antibody, a mouse antibody, a rabbit antibody, a camelid antibody, a humanized antibody, or a chimeric antibody. In some embodiments, the anti-CD38 antibodybased binder is derived from a human antibody, a rat antibody, a mouse antibody, a rabbit antibody, a camelid antibody, a humanized antibody, or a chimeric antibody. In some embodiments, the anti-SLAMF7 antibody-based binder is derived from a human antibody, a rat antibody, a mouse antibody, a rabbit antibody, a camelid antibody, a humanized antibody, or a chimeric antibody. In some embodiments, the anti-CD3 antibody-based binder is derived from a human antibody, a rat antibody, a mouse antibody, a rabbit antibody, a camelid antibody, a humanized antibody, or a chimeric antibody.

[0056] In some embodiments, the antibody-based binders of the multispecific binder molecule are derived from chimeric amino acid sequences. In some embodiments, one or more of the antibody -based binders are made of chimeric amino acid sequences some of which are murine- derived and some of which are human-derived. In some embodiments, one or more of the antibody -based binders are made with complementarity-determining regions (CDRs) that have been incorporated into an antibody scaffold. In some embodiments, one or more of the antibodybased binders are made with complementarity-determining regions (CDRs) incorporated into a human antibody variable region framework. In some instances, the human antibody variable region framework has been sequence-optimized to retain GPRC5D affinity with the engrafted mouse CDR sequences. In some instances, the human antibody variable region framework has been sequence-optimized to retain BCMA affinity with the engrafted mouse CDR sequences. In some instances, the human antibody variable region framework has been sequence-optimized to retain FcRH5 affinity with the engrafted mouse CDR sequences. In some instances, the human antibody variable region framework has been sequence-optimized to retain CD38 affinity with the engrafted mouse CDR sequences. In some instances, the human antibody variable region framework has been sequence-optimized to retain SLAMF7 affinity with the engrafted mouse CDR sequences. In some instances, the human antibody variable region framework has been sequence-optimized to retain CD3 affinity with the engrafted mouse CDR sequences.

[0057] In some embodiments, amino acids sequences corresponding to CDR sequences of an antibody variable domain described herein are used in a binding moiety within the multispecific binder molecule. In some embodiments, a set of HCDR sequences listed Table 1 are used in a VH domain that forms a CD3 binding moiety, a GPRC5D binding moiety, a BCMA binding moiety, an FcRH5 binding moiety, a CD38 binding moiety, or a SLAMF7 binding moiety. Insome embodiments, a set of LCDR sequences listed Table 2 are used in a VL domain that forms a CD3 binding moiety, a GPRC5D binding moiety, a BCMA binding moiety, an FcRH5 binding moiety, a CD38 binding moiety, or a SLAMF7 binding moiety. In some embodiments, a VH domain comprising a set of CDR sequences listed in Table 1 is paired with a VL domain comprising a set of CDR sequences listed in Table 2, wherein the paired VH and VL domain form a CD3 binding moiety, a GPRC5D binding moiety, a BCMA binding moiety, an FcRH5 binding moiety, a CD38 binding moiety, or a SLAMF7 binding moiety.

[0058] In some embodiments, the VH and VL domains are formatted in a configuration to form a binding moiety. In some embodiments, the GPRC5D-binding moiety comprises a VH and a VL in the format of a single-chain variable fragment (scFv) domain. In some embodiments, the BCMA-binding moiety comprises a VH and a VL in the format of a single-chain variable fragment (scFv) domain. In some embodiments, the FcRH5-binding moiety comprises a VH and a VL in the format of a single-chain variable fragment (scFv) domain. In some embodiments, the CD38-binding moiety comprises a VH and a VL in the format of a single-chain variable fragment (scFv) domain. In some embodiments, the SLAMF7-binding moiety comprises a VH and a VL in the format of a single-chain variable fragment (scFv) domain. In some embodiments, the CD3-binding moiety comprises a VH and a VL in the format of a single-chain variable fragment (scFv) domain. In some embodiments, the GPRC5D-binding scFv domain is paired with a second scFv domain to form a tandem scFv. In some embodiments, the BCMA- binding scFv domain is paired with a second scFv domain to form a tandem scFv. In some embodiments, the FcRH5-binding scFv domain is paired with a second scFv domain to form a tandem scFv. In some embodiments, the CD38-binding scFv domain is paired with a second scFv domain to form a tandem scFv. In some embodiments, the SLAMF7-binding scFv domain is paired with a second scFv domain to form a tandem scFv. In some embodiments, the CD3- binding scFv domain is paired with a second scFv domain to form a tandem scFv. In some embodiments, the tandem scFv comprises a bivalent GPRC5D-binding moiety. In some embodiments, the tandem scFv comprises a bivalent BCMA-binding moiety. In some embodiments, the tandem scFv comprises a bivalent FcRH5-binding moiety. In some embodiments, the tandem scFv comprises a bivalent CD38-binding moiety. In some embodiments, the tandem scFv comprises a bivalent SLAMF7-binding moiety. In some embodiments, the tandem scFv comprises a bivalent CD3-binding moiety. In some embodiments, the tandem scFv comprises a bi-specific binding moiety comprising a GPRC5D- binding moiety and a second binding moiety. In some embodiments, the tandem scFv comprises a bi-specific binding moiety comprising a BCMA-binding moiety and a second binding moiety. In some embodiments, the tandem scFv comprises a bi-specific binding moiety comprising anFcRH5 binding moiety and a second binding moiety. In some embodiments, the tandem scFv comprises a bi-specific binding moiety comprising a CD38-binding moiety and a second binding moiety. In some embodiments, the tandem scFv comprises a bi-specific binding moiety comprising a SLAMF7-binding moiety and a second binding moiety. In some embodiments, the tandem scFv comprises a bi-specific binding moiety comprising a CD3-binding moiety and a second binding moiety. In some embodiments, a noncovalent dimer of scFv fragments comprised of a heavy chain variable and a light chain variable regions connected by a small peptide linker form a diabody that functions as a GPRC5D-binding moiety. In some embodiments, a noncovalent dimer of scFv fragments comprised of a heavy chain variable and a light chain variable regions connected by a small peptide linker form a diabody that functions as a BCMA-binding moiety. In some embodiments, a noncovalent dimer of scFv fragments comprised of a heavy chain variable and a light chain variable regions connected by a small peptide linker form a diabody that functions as an FcRH5 -binding moiety. In some embodiments, a noncovalent dimer of scFv fragments comprised of a heavy chain variable and a light chain variable regions connected by a small peptide linker form a diabody that functions as a CD38-binding moiety. In some embodiments, a noncovalent dimer of scFv fragments comprised of a heavy chain variable and a light chain variable regions connected by a small peptide linker form a diabody that functions as a SLAMF7-binding moiety. In some embodiments, a noncovalent dimer of scFv fragments comprised of a heavy chain variable and a light chain variable regions connected by a small peptide linker form a diabody that functions as a CD3-binding moiety. In some embodiments, the diabody is a bivalent GPRC5D-binding moiety, a bivalent BCMA-binding moiety, a bivalent FcRH5-binding moiety, a bivalent CD38- binding moiety, a bivalent SLAMF7-binding moiety, or a bivalent CD3-binding moiety. In some embodiments, the diabody is a bi-specific binding moiety comprising a GPRC5D-binding moiety and a second binding moiety. In some embodiments, the diabody is a bi-specific binding moiety comprising a BCMA-binding moiety and a second binding moiety. In some embodiments, the diabody is a bi-specific binding moiety comprising an FcRH5-binding moiety and a second binding moiety. In some embodiments, the diabody is a bi-specific binding moiety comprising a CD38-binding moiety and a second binding moiety. In some embodiments, the diabody is a bi-specific binding moiety comprising a SLAMF7-binding moiety and a second binding moiety. In some embodiments, the diabody is a bi-specific binding moiety comprising a CD3-binding moiety and a second binding moiety. In some embodiments, three scFv fragments are linked together to form a triabody that functions as a GPRC5D-binding moiety, a BCMA- binding moiety, a CD38-binding moiety, an FcRH5-binding moiety, a SLAMF7-binding moiety, or a CD3-binding moiety. In some embodiments, three scFv fragments are linked together toform a triabody that functions as a GPRC5D-binding moiety and a binding moiety for a second binding moiety. In some embodiments, three scFv fragments are linked together to form a triabody that functions as a BCMA-binding moiety and a binding moiety for a second binding moiety. In some embodiments, three scFv fragments are linked together to form a triabody that functions as an FcRH5-binding moiety and a binding moiety for a second binding moiety. In some embodiments, three scFv fragments are linked together to form a triabody that functions as a CD38-binding moiety and a binding moiety for a second binding moiety. In some embodiments, three scFv fragments are linked together to form a triabody that functions as a SLAMF7-binding moiety and a binding moiety for a second binding moiety. In some embodiments, three scFv fragments are linked together to form a triabody that functions as a CD3-binding moiety and a binding moiety for a second binding moiety. In some embodiments, three scFv fragments are linked together to form a triabody that functions as a GPRC5D-binding moiety and a binding moiety for a second binding moiety and a third binding moiety. In some embodiments, three scFv fragments are linked together to form a triabody that functions as a BCMA-binding moiety and a binding moiety for a second binding moiety and a third binding moiety. In some embodiments, three scFv fragments are linked together to form a triabody that functions as an FcRH5-binding moiety and a binding moiety for a second binding moiety and a third binding moiety. In some embodiments, three scFv fragments are linked together to form a triabody that functions as a CD38-binding moiety and a binding moiety for a second binding moiety and a third binding moiety. In some embodiments, three scFv fragments are linked together to form a triabody that functions as a SLAMF7-binding moiety and a binding moiety for a second binding moiety and a third binding moiety. In some embodiments, three scFv fragments are linked together to form a triabody that functions as a CD3 -binding moiety and a binding moiety for a second binding moiety and a third binding moiety. In some embodiments, two scFv fragments are covalently linked to each other to from a single-chain (Fv)2 that functions as a GPRC5D-binding moiety, a BCMA-binding moiety, an FcRH5-binding moiety, a CD38-binding moiety, a SLAMF7-binding moiety, or a CD3-binding moiety. In some embodiments, the scFv is a disulfide-bond stabilized scFv. In some embodiments, the GPRC5D- binding moiety is in the format of a tandem diabody (bispecific tetravalent antibody). In some embodiments, the BCMA-binding moiety is in the format of a tandem diabody (bispecific tetravalent antibody). In some embodiments, the FcRH5-binding moiety is in the format of a tandem diabody (bispecific tetraval ent antibody). In some embodiments, the CD38-binding moiety is in the format of a tandem diabody (bispecific tetravalent antibody). In some embodiments, the SLAMF7-binding moiety is in the format of a tandem diabody (bispecific tetravalent antibody). In some embodiments, the CD3-binding moiety is in the format of atandem diabody (bispecific tetravalent antibody). In some embodiments, the tandem diabody comprises two VH / VL pairs from two distinct Fv regions. In some embodiments, the GPRC5D- binding moiety is in the format of a dual affinity retargeting (DART) format comprising two Fv fragments, wherein Fvl comprises a VH domain from an anti-GPRC5D antibody and a VL from a second antibody, and Fv2 comprises a VH domain from a second antibody and a VL domain from an anti-GPRC5D antibody. In some embodiments, the BCMA-binding moiety is in the format of a dual affinity retargeting (DART) format comprising two Fv fragments, wherein Fvl comprises a VH domain from an anti-BCMA antibody and a VL from a second antibody, and Fv2 comprises a VH domain from a second antibody and a VL domain from an anti-BCMA antibody. In some embodiments, the FcRH5-binding moiety is in the format of a dual affinity retargeting (DART) format comprising two Fv fragments, wherein Fvl comprises a VH domain from an anti- FcRH5 antibody and a VL from a second antibody, and Fv2 comprises a VH domain from a second antibody and a VL domain from an anti- FcRH5 antibody. In some embodiments, the CD38-binding moiety is in the format of a dual affinity retargeting (DART) format comprising two Fv fragments, wherein Fvl comprises a VH domain from an anti-CD38 antibody and a VL from a second antibody, and Fv2 comprises a VH domain from a second antibody and a VL domain from an anti-CD38 antibody. In some embodiments, the SLAMF7- binding moiety is in the format of a dual affinity retargeting (DART) format comprising two Fv fragments, wherein Fvl comprises a VH domain from an anti-SLAMF7 antibody and a VL from a second antibody, and Fv2 comprises a VH domain from a second antibody and a VL domain from an anti-SLAMF7 antibody. In some embodiments, the CD3-binding moiety is in the format of a dual affinity retargeting (DART) format comprising two Fv fragments, wherein Fvl comprises a VH domain from an anti-CD3 antibody and a VL from a second antibody, and Fv2 comprises a VH domain from a second antibody and a VL domain from an anti-CD3 antibody. In some embodiments, the GPRC5D-binding moiety is in the format of a bi-specific T-cell engager (BiTE) wherein an scFv domain comprising a VH domain and VL domain from an anti- GPRC5D antibody is linked in a single polypeptide chain to a second scFv domain comprising a VH domain and VL domain derived from a T-cell binding antibody. In some embodiments, the BCMA-binding moiety is in the format of a bi-specific T-cell engager (BiTE) wherein an scFv domain comprising a VH domain and VL domain from an anti-BCMA antibody is linked in a single polypeptide chain to a second scFv domain comprising a VH domain and VL domain derived from a T-cell binding antibody. In some embodiments, the FcRH5-binding moiety is in the format of a bi-specific T-cell engager (BiTE) wherein an scFv domain comprising a VH domain and VL domain from an anti-FcRH5 antibody is linked in a single polypeptide chain to a second scFv domain comprising a VH domain and VL domain derived from a T-cell bindingantibody. In some embodiments, the CD38-binding moiety is in the format of a bi-specific T- cell engager (BiTE) wherein an scFv domain comprising a VH domain and VL domain from an anti-CD38 antibody is linked in a single polypeptide chain to a second scFv domain comprising a VH domain and VL domain derived from a T-cell binding antibody. In some embodiments, the SLAMF7-binding moiety is in the format of a bi-specific T-cell engager (BiTE) wherein an scFv domain comprising a VH domain and VL domain from an anti-SLAMF7 antibody is linked in a single polypeptide chain to a second scFv domain comprising a VH domain and VL domain derived from a T-cell binding antibody. In some embodiments, the CD3-binding moiety is in the format of a bi-specific T-cell engager (BiTE) wherein an scFv domain comprising a VH domain and VL domain from an anti-CD3 antibody is linked in a single polypeptide chain to a second scFv domain comprising a VH domain and VL domain derived from a T-cell binding antibody.

[0059] In some embodiments, VH and VL domains are located on separate polypeptides and form a binding moiety in the multispecific binder molecule. In some embodiments, the GPRC5D VH and GPRC5D VL are near the N-terminus of polypeptides which are paired together to form a GPRC5D-binding moiety. In some embodiments, the BCMA VH and BCMA VL are near the N-terminus of polypeptides which are paired together to form a BCMA-binding moiety. In some embodiments, the FcRH5 VH and RcRH5 VL are near the N-terminus of polypeptides which are paired together to form an FcRH5-binding moiety. In some embodiments, the CD38 VH and CD38 VL are near the N-terminus of polypeptides which are paired together to form a CD38- binding moiety. In some embodiments, the SLAMF7 VH and SLAMF7 VL are near the N- terminus of polypeptides which are paired together to form a SLAMF7-binding moiety. In some embodiments, the CD3 VH and CD3 VL are near the N-terminus of polypeptides which are paired together to form a CD3-binding moiety. In some embodiments, the GPRC5D VH and GPRC5D VL are near the C-terminus of polypeptides which are paired together to form a GPRC5D-binding moiety. In some embodiments, the BCMA VH and BCMA VL are near the C-terminus of polypeptides which are paired together to form a BCMA-binding moiety. In some embodiments, the FcRH5 VH and FcRH5 VL are near the C-terminus of polypeptides which are paired together to form an FcRH5-binding moiety. In some embodiments, the CD38 VH and CD38 VL are near the C-terminus of polypeptides which are paired together to form a CD38- binding moiety. In some embodiments, the SLAMF7 VH and SLAMF7 VL are near the C- terminus of polypeptides which are paired together to form a SLAMF7-binding moiety. In some embodiments, the CD3 VH and CD3 VL are near the C-terminus of polypeptides which are paired together to form a CD3-binding moiety. In some embodiments, an scFv comprising a GPRC5D VH and a GPRC5D VL that forms a GPRC5D-binding moiety is located at the N- terminus of a modified heavy chain. In some embodiments, an scFv comprising a BCMA VHand a BCMA VL that forms a BCMA-binding moiety is located at the N-terminus of a modified heavy chain. In some embodiments, an scFv comprising an FcRH5 VH and an FcRH5 VL that forms an FcRH5-binding moiety is located at the N-terminus of a modified heavy chain. In some embodiments, an scFv comprising a CD38 VH and a CD38 VL that forms a CD38-binding moiety is located at the N-terminus of a modified heavy chain. In some embodiments, an scFv comprising a SLAMF7 VH and a SLAMF7 VL that forms a SLAMF7-binding moiety is located at the N-terminus of a modified heavy chain. In some embodiments, an scFv comprising a CD3 VH and a CD3 VL that forms a CD3-binding moiety is located at the N-terminus of a modified heavy chain. In some embodiments, an scFv comprising a GPRC5D VH and a GPRC5D VL that forms a GPRC5D-binding moiety is located at the C-terminus of a modified heavy chain. In some embodiments, an scFv comprising a BCMA VH and a BCMA VL that forms a BCMA- binding moiety is located at the C-terminus of a modified heavy chain. In some embodiments, an scFv comprising an FcRH5 VH and an FcRH5 VL that forms an FcRH5-binding moiety is located at the C-terminus of a modified heavy chain. In some embodiments, an scFv comprising a CD38 VH and a CD38 VL that forms a CD38-binding moiety is located at the C-terminus of a modified heavy chain. In some embodiments, an scFv comprising a SLAMF7 VH and a SLAMF7 VL that forms a SLAMF7-binding moiety is located at the C-terminus of a modified heavy chain. In some embodiments, an scFv comprising a CD3 VH and a CD3 VL that forms a CD3-binding moiety is located at the C-terminus of a modified heavy chain. In some embodiments, an scFv comprising a GPRC5D VH and a GPRC5D VL that forms a GPRC5D- binding moiety is located at the N-terminus of a modified light chain. In some embodiments, an scFv comprising a BCMA VH and a BCMA VL that forms a BCMA-binding moiety is located at the N-terminus of a modified light chain. In some embodiments, an scFv comprising an FcRH5 VH and an FcRH5 VL that forms an FcRH5-binding moiety is located at the N-terminus of a modified light chain. In some embodiments, an scFv comprising a CD38 VH and a CD38 VL that forms a CD38-binding moiety is located at the N-terminus of a modified light chain. In some embodiments, an scFv comprising a SLAMF7 VH and a SLAMF7 VL that forms a SLAMF7-binding moiety is located at the N-terminus of a modified light chain. In some embodiments, an scFv comprising a CD3 VH and a CD3 VL that forms a CD3-binding moiety is located at the N-terminus of a modified light chain. In some embodiments, an scFv comprising a GPRC5D VH and a GPRC5D VL that forms a GPRC5D-binding moiety is coupled to the C-terminus of a modified light chain. In some embodiments, an scFv comprising a BCMA VH and a BCMA VL that forms a BCMA-binding moiety is coupled to the C-terminus of a modified light chain. In some embodiments, an scFv comprising an FcRH5 VH and an FcRH5 VL that forms an FcRH5-binding moiety is coupled to the C-terminus of a modifiedlight chain. In some embodiments, an scFv comprising a CD38 VH and a CD38 VL that forms a CD38-binding moiety is coupled to the C-terminus of a modified light chain. In some embodiments, an scFv comprising a SLAMF7 VH and a SLAMF7 VL that forms a SLAMF7- binding moiety is coupled to the C-terminus of a modified light chain. In some embodiments, an scFv comprising a CD3 VH and a CD3 VL that forms a CD3-binding moiety is coupled to the C-terminus of a modified light chain. In some embodiments, coupled binding moieties are covalently coupled to a polypeptide chain. In some embodiments, coupled binding moieties are conjugated to a polypeptide chain.

[0060] In some aspects, VH and VL domains are located on separate polypeptides and form a binding moiety in the multispecific binder molecule. In some embodiments, the VH and VL domains located on separate polypeptides are paired together and form a binding moiety. In some embodiments, the VH domain comprises HCDR sequences which confer antigen binding specificity for either GPRC5D, BCMA, FcRH5, CD38, SLAMF7, or CD3. In some embodiments, the GPRC5D VH domain comprising HCDR sequences which confers antigen binding specificity for GPRC5D is paired with a GPRC5D VL domain comprising GPRC5D LCDR sequences which when paired together with the GPRC5D VH, confers high affinity antigen binding specificity for GPRC5D. In some embodiments, the BCMA VH domain comprising HCDR sequences which confers antigen binding specificity for BMCA is paired with a BCMA VL domain comprising BCMA LCDR sequences which when paired together with the BCMA VH, confers high affinity antigen binding specificity for BCMA. In some embodiments, the BCMA VH domain comprising HCDR sequences which confers antigen binding specificity for BMCA is paired with a CD3 VL domain comprising CD3 LCDR sequences which when paired together with the BCMA VH, confers high affinity antigen binding specificity for BCMA. In some embodiments, the FcRH5 VH domain comprising HCDR sequences which confers antigen binding specificity for FcRH5 is paired with an FcRH5 VL domain comprising FcRH5 LCDR sequences which when paired together with the FcRH5 VH, confers high affinity antigen binding specificity for FcRH5. In some embodiments, the FcRH5 VH domain comprising HCDR sequences which confers antigen binding specificity for FcRH5 is paired with a CD3 VL domain comprising CD3 LCDR sequences which when paired together with the FcRH5 VH, confers high affinity antigen binding specificity for FcRH5. In some embodiments, the CD38 VH domain comprising HCDR sequences which confers antigen binding specificity for CD38 is paired with a CD38 VL domain comprising CD38 LCDR sequences which when paired together with the CD38 VH, confers high affinity antigen binding specificity for CD38. In some embodiments, the CD38 VH domain comprising HCDR sequences which confers antigen binding specificity for CD38 is paired with a CD3 VL domaincomprising CD3 LCDR sequences which when paired together with the CD38 VH, confers high affinity antigen binding specificity for CD38. In some embodiments, the SLAMF7 VH domain comprising HCDR sequences which confers antigen binding specificity for SLAMF7 is paired with a SLAMF7 VL domain comprising SLAMF7 LCDR sequences which when paired together with the SLAMF7 VH, confers high affinity antigen binding specificity for CD38. In some embodiments, the SLAMF7 VH domain comprising HCDR sequences which confers antigen binding specificity for SLAMF7 is paired with a CD3 VL domain comprising CD3 LCDR sequences which when paired together with the CD38 VH, confers high affinity antigen binding specificity for CD38. In some embodiments, the CD3 VH domain comprising HCDR sequences which confers antigen binding specificity for CD3 is paired with a CD3 VL domain comprising CD3 LCDR sequences which when paired together with the CD3 VH, confers high affinity antigen binding specificity for CD3.

[0061] In some embodiments, the multispecific binder molecule comprises a first immunoglobulin chain constant region on a first heavy chain and a second immunoglobulin chain constant region on a second heavy chain. In some embodiments, the first and second heavy chains are paired together in the multispecific binder molecule. In some embodiments, the first heavy chain comprises a modified heavy chain comprising two VH domains. In some embodiments, the configuration of the modified heavy chain comprises a GPRC5D VH located at the N-terminus, followed by CHI, CH2, CH3, CD3 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a GPRC5D VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and CD3 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a GPRC5D VH located at the N-terminus, followed by CHI, CH2, CH3, BCMA VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a GPRC5D VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and BCMA VH domains. In some embodiments, the configuration of the modified heavy chain comprises a GPRC5D VH located at the N-terminus, followed by CHI, CH2, CH3, CD38 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a GPRC5D VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and CD38 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a GPRC5D VH located at the N-terminus, followed by CHI, CH2, CH3, SLAMF7 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a GPRC5D VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and SLAMF7 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a GPRC5D VH located at the N-terminus, followed by CHI, CH2, CH3, FcRH5 VH, and CHI domains. In someembodiments, the configuration of the modified heavy chain comprises a GPRC5D VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and FcRH5 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a BCMA VH located at the N-terminus, followed by CHI, CH2, CH3, CD3 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a BCMA VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and CD3 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a BCMA VH located at the N-terminus, followed by CHI, CH2, CH3, GPRC5D VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a BCMA VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and GPRC5D VH domains. In some embodiments, the configuration of the modified heavy chain comprises a BCMA VH located at the N-terminus, followed by CHI, CH2, CH3, CD38 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a BCMA VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and CD38 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a BCMA VH located at the N-terminus, followed by CHI, CH2, CH3, SLAMF7 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a BCMA VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and SLAMF7 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a BCMA VH located at the N-terminus, followed by CHI, CH2, CH3, FcRH5 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a BCMA VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and FcRH5 VH domains. In some embodiments, the configuration of the modified heavy chain comprises an FcRH5 VH located at the N-terminus, followed by CHI, CH2, CH3, GPRC5D VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises an FcRH5 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and GPRC5D VH domains. In some embodiments, the configuration of the modified heavy chain comprises an FcRH5 VH located at the N-terminus, followed by CHI, CH2, CH3, BCMA VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises an FcRH5 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and BCMA VH domains. In some embodiments, the configuration of the modified heavy chain comprises a FcRH5 VH located at the N-terminus, followed by CHI, CH2, CH3, CD3 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises an FcRH5 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and CD3 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a FcRH5 VH located atthe N-terminus, followed by CHI, CH2, CH3, CD38 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises an FcRH5 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and CD38 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a FcRH5 VH located at the N-terminus, followed by CHI, CH2, CH3, SLAMF7 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises an FcRH5 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and SLAMF7 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a CD38 VH located at the N-terminus, followed by CHI, CH2, CH3, CD3 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a CD38 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and CD3 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a CD38 VH located at the N-terminus, followed by CHI, CH2, CH3, GPRC5D VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a CD38 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and GPRC5D VH domains. In some embodiments, the configuration of the modified heavy chain comprises a CD38 VH located at the N-terminus, followed by CHI, CH2, CH3, BCMA VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a CD38 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and BCMA VH domains. In some embodiments, the configuration of the modified heavy chain comprises a CD38 VH located at the N-terminus, followed by CHI, CH2, CH3, SLAMF7 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a CD38 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and SLAMF7 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a CD38 VH located at the N-terminus, followed by CHI, CH2, CH3, FcRH5 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a CD38 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and FcRH5 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a SLAMF7 VH located at the N-terminus, followed by CHI, CH2, CH3, CD3 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a SLAMF7 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and CD3 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a SLAMF7 VH located at the N-terminus, followed by CHI, CH2, CH3, GPRC5D VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a SLAMF7 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and GPRC5D VH domains. In someembodiments, the configuration of the modified heavy chain comprises a SLAMF7 VH located at the N-terminus, followed by CHI, CH2, CH3, BCMA VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a SLAMF7 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and BCMA VH domains. In some embodiments, the configuration of the modified heavy chain comprises a SLAMF7 VH located at the N-terminus, followed by CHI, CH2, CH3, CD38 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a SLAMF7 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and CD38 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a SLAMF7 VH located at the N-terminus, followed by CHI, CH2, CH3, FcRH5 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a SLAMF7 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and FcRH5 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a CD3 VH located at the N-terminus, followed by CHI, CH2, CH3, SLAMF7 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a CD3 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and SLAMF7 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a CD3 VH located at the N-terminus, followed by CHI, CH2, CH3, GPRC5D VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a CD3 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and GPRC5D VH domains. In some embodiments, the configuration of the modified heavy chain comprises a CD3 VH located at the N-terminus, followed by CHI, CH2, CH3, BCMA VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a CD3 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and BCMA VH domains. In some embodiments, the configuration of the modified heavy chain comprises a CD3 VH located at the N-terminus, followed by CHI, CH2, CH3, CD38 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a CD3 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and CD38 VH domains. In some embodiments, the configuration of the modified heavy chain comprises a CD3 VH located at the N-terminus, followed by CHI, CH2, CH3, FcRH5 VH, and CHI domains. In some embodiments, the configuration of the modified heavy chain comprises a CD3 VH located at the N-terminus, followed by CHI, CH2, CH3, CHI, and FcRH5 VH domains.

[0062] In some embodiments, the multispecific binder molecule comprises a first immunoglobulin chain constant region on a first modified heavy chain and a second immunoglobulin chain constant region on a second modified heavy chain. In someembodiments, the first and second modified heavy chains are paired together in the multispecific binder molecule. In some embodiments, the first immunoglobulin chain constant region and the second immunoglobulin chain constant region each comprise a CHI domain. In some embodiments, a BCMA VH domain is positioned N-terminal to the CHI domain of the first immunoglobulin chain constant region and a CD3 VH domain is positioned N-terminal to the CHI domain of the second immunoglobulin chain constant region. In some embodiments, the first modified heavy chain comprises a CH2 domain or a mutated CH2 domain C-terminal to the CHI domain. In some embodiments, the second modified heavy chain comprises a CH2 domain or a mutated CH2 domain C-terminal to the CHI domain. In some embodiments, the first modified heavy chain comprises a CH3 domain or a mutated CH3 domain C-terminal to the CH2 domain. In some embodiments, the second modified heavy chain comprises a CH3 domain or a mutated CH3 domain C-terminal to the CH2 domain. In some embodiments, the first modified heavy chain comprises an FcRH5 VH domain C-terminal to the CH3 domain or mutated CH3 domain. In some embodiments, the second modified heavy chain comprises a GPRC5D VH domain C-terminal to the CH3 domain or mutated CH3 domain. In some embodiments, the mutated CH3 domain or domains comprises one or more KiH substitutions. In some embodiments, the first modified heavy chain comprises two VH domains. In some embodiments, the configuration of the first modified heavy chain comprises a BCMA VH located at the N-terminus, followed by CHI, CH2, CH3, FcRH5 VH, and CHI domains. In some embodiments, the second modified heavy chain comprises two VH domains. In some embodiments, the configuration of the second modified heavy chain comprises a CD3 VH located at the N-terminus, followed by CHI, CH2, CH3, GPRC5D VH, and CHI domains. In some embodiments, the CH3 of the first modified heavy chain comprises one or more KiH knob substitutions. In some embodiments, the one or more KiH knob substitutions comprise either S354C, T366W, or S354C and T366W. In some embodiments, the one or more KiH knob substitutions comprise S354C and T366W. In some embodiments, the CH3 of the first modified heavy chain comprises one or more KiH hole substitutions. In some embodiments, the one or more KiH hole substitutions comprise Y349C, T366S, L368A, Y407V, or any combination thereof. In some embodiments, the one or more KiH hole substitutions comprise Y349C, T366S, L368A, and Y407V. In some embodiments, the CH3 of the second modified heavy chain comprises one or more KiH knob substitutions. In some embodiments, the one or more KiH knob substitutions comprise either S354C, T366W, or S354C and T366W. In some embodiments, the one or more KiH knob substitutions comprise S354C and T366W. In some embodiments, the CH3 of the second modified heavy chain comprises one or more KiH hole substitutions. In some embodiments, the one or more KiH hole substitutions comprise Y349C,T366S, L368A, Y407V, or any combination thereof. In some embodiments, the one or more KiH hole substitutions comprise Y349C, T366S, L368A, and Y407V. In some embodiments, the multispecific binder molecule comprises two modified heavy chains comprising KiH knob substitutions and KiH hole substitutions respectively which aid in heterodimeric pairing of the two distinct modified heavy chains. In some embodiments, the first modified heavy chain comprising KiH knob mutations is paired with the second modified heavy chain comprising KiH hole mutations to aid in heterodimerization of the separate modified heavy chains. In some embodiments, the multispecific binder molecule comprises four light chains. In some embodiments, each of the four light chains is paired with a distinct VH domain to form a binding moiety. In some embodiments, the multispecific binder molecule comprises three light chains each comprising a CD3 binding moiety and a fourth light chain comprising a GPRC5D binding moiety. In some embodiments, the multispecific binder molecule comprises four distinct light chains, wherein the first light chain comprises a CD3 binding moiety, the second light chain comprises a BCMA binding moiety, the third light chain comprises an FcRH5 binding moiety, and the fourth light chain comprises a GPRC5D binding moiety. In some embodiments, a first light chain comprising a CD3 VL domain is paired with a CD3 VH domain on a modified heavy chain to form a CD3 binding moiety. In some embodiments, a second light chain comprising a CD3 VL domain is paired with a BCMA VH domain on a modified heavy chain to form a BCMA binding moiety. In some embodiments, a second light chain comprising a BCMA VL domain is paired with a BCMA VH domain on a modified heavy chain to form a BCMA binding moiety. In some embodiments, a third light chain comprising a CD3 VL domain is paired with an FcRH5 VH domain on a modified heavy chain to form an FcRH5 binding moiety. In some embodiments, a third light chain comprising a FcRH5 VL domain is paired with an FcRH5 VH domain on a modified heavy chain to form an FcRH5 binding moiety. In some embodiments, a fourth light chain comprising a GPRC5D VL domain is paired with a GPRC5D VH domain on a modified heavy chain to form a GPRC5D binding moiety. In some embodiments, the multispecific binder molecule comprises: i) a first modified heavy chain comprising an N-terminal BCMA binding moiety and a C-terminal FcRH5 binding moiety, ii) a second modified heavy chain comprising an N-terminal CD3 binding moiety and a C-terminal GPRC5D binding moiety, iii) a first light chain comprising a CD3 VL domain, iv) a second light chain comprising a BCMA VL domain or a CD3 VL domain, v) a third light chain comprising a FcRH5 VL domain or a CD3 VL domain, and vi), a fourth light chain comprising a GPRC5D VL domain.

[0063] In some embodiments, the multispecific binder molecule comprises one or more linker sequences. In some embodiments, one or more linker sequences separate peptide domains withina single heavy chain polypeptide. In some embodiments, one or more linker sequences separate peptide domains within a single light chain polypeptide. In some embodiments, the linker sequence is a rigid linker sequence. In some embodiments, the rigid linker sequence comprises a proline-rich sequence. In some embodiments, the linker sequence is a flexible linker sequence. In some embodiments, the flexible linker sequence comprises a glycine-rich sequence. In some embodiments, the flexible linker sequence comprises a glycine-serine linker sequence. In some embodiments, the glycine-serine linker sequence comprises an amino sequence of GS(n) wherein n is 1-10. In some embodiments, the glycine-serine linker sequence comprises an amino sequence of GGGGS(n) wherein n is 1-6. In some embodiments, a linker sequence positioned between a binding moiety and a heavy chain antibody constant region comprises a sequence listed in Table 21. In some embodiments, the linker sequence positioned between a binding moiety and a light chain antibody constant region comprises a sequence listed in Table 21.

[0064] In some embodiments, the multispecific binder molecule comprises at least three binding moieties selected from the group consisting of: a GPRC5D-binding moiety, a BCMA-binding moiety, an FcRH5-binding moiety, a CD38-binding moiety, a SLAMF7-binding moiety, and a CD3-binding moiety. In some embodiments, the multispecific binder molecule comprises at least four binding moieties selected from the group consisting of: a GPRC5D-binding moiety, a BCMA-binding moiety, an FcRH5-binding moiety, a CD38-binding moiety, a SLAMF7-binding moiety, and a CD3-binding moiety. In some embodiments, at least one of the at least three binding moieties is coupled to a heavy chain. In some embodiments, at least one of the at least four binding moieties is coupled to a heavy chain. In some embodiments, the GPRC5D-binding moiety is coupled to the N-terminus of an IgGl heavy chain. In some embodiments, the BCMA- binding moiety is coupled to the N-terminus of an IgGl heavy chain. In some embodiments, the FcRH5-binding moiety is coupled to the N-terminus of an IgGl heavy chain. In some embodiments, the CD38-binding moiety is coupled to the N-terminus of an IgGl heavy chain. In some embodiments, the SLAMF7-binding moiety is coupled to the N-terminus of an IgGl heavy chain. In some embodiments, the CD3-binding moiety is coupled to the N-terminus of an IgGl heavy chain. In some embodiments, the GPRC5D-binding moiety is coupled to the C- terminus of an IgGl heavy chain. In some embodiments, the BCMA-binding moiety is coupled to the C-terminus of an IgGl heavy chain. In some embodiments, the FcRH5-binding moiety is coupled to the C-terminus of an IgGl heavy chain. In some embodiments, the CD38-binding moiety is coupled to the C-terminus of an IgGl heavy chain. In some embodiments, the SLAMF7-binding moiety is coupled to the C-terminus of an IgGl heavy chain. In some embodiments, the CD3-binding moiety is coupled to the C-terminus of an IgGl heavy chain. In some embodiments, the IgGl heavy chain is a modified IgGl heavy chain. In someembodiments, at least one of the at least three binding moieties is coupled to a light chain. In some embodiments, at least one of the at least four binding moieties is coupled to a light chain. In some embodiments, the GPRC5D-binding moiety is coupled to an immunoglobulin kappa light chain domain. In some embodiments, the BCMA-binding moiety is coupled to an immunoglobulin kappa light chain domain. In some embodiments, the FcRH5-binding moiety is coupled to an immunoglobulin kappa light chain domain. In some embodiments, the CD38- binding moiety is coupled to an immunoglobulin kappa light chain domain. In some embodiments, the SLAMF7-binding moiety is coupled to an immunoglobulin kappa light chain domain. In some embodiments, the CD3-binding moiety is coupled to an immunoglobulin kappa light chain domain. In some embodiments, the GPRC5D-binding moiety is coupled to an immunoglobulin lambda light chain domain. In some embodiments, the BCMA-binding moiety is coupled to an immunoglobulin lambda light chain domain. In some embodiments, the FcRH5- binding moiety is coupled to an immunoglobulin lambda light chain domain. In some embodiments, the CD38-binding moiety is coupled to an immunoglobulin lambda light chain domain. In some embodiments, the SLAMF7-binding moiety is coupled to an immunoglobulin lambda light chain domain. In some embodiments, the CD3-binding moiety is coupled to an immunoglobulin lambda light chain domain. In some embodiments, one of the at least three binding moieties is coupled to an immunoglobulin lambda light chain domain and another of the at least three binding moieties is coupled to an immunoglobulin kappa light chain domain. In some embodiments, one of the at least four binding moieties is coupled to an immunoglobulin lambda light chain domain and another of the at least three binding moieties is coupled to an immunoglobulin kappa light chain domain. In some embodiments, the light chain is a modified light chain. In some embodiments, the immunoglobulin kappa light chain domain resides on a modified light chain. In some embodiments, the immunoglobulin lambda light chain domain resides on a modified light chain. In some embodiments, the GPRC5D-binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a SLAMF7-binding moiety, and a BCMA-binding moiety. In some embodiments, the GPRC5D- binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a CD38-binding moiety, and a BCMA-binding moiety. In some embodiments, the GPRC5D-binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a CD38-binding moiety, and a SLAMF7-binding moiety. In some embodiments, the BCMA-binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a SLAMF7-binding moiety, and a GPRC5D-binding moiety. In some embodiments, the BCMA-binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a CD38-binding moiety, and a GPRC5D -bindingmoiety. In some embodiments, the BCMA-binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a CD38-binding moiety, and a SLAMF7- binding moiety. In some embodiments, the FcRH5-binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a BCMA-binding moiety, and a GPRC5D-binding moiety. In some embodiments, the FcRH5 -binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a CD38-binding moiety, and a GPRC5D -binding moiety. In some embodiments, the FcRH5-binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a CD38- binding moiety, and a SLAMF7-binding moiety. In some embodiments, the FcRH5-binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a CD38-binding moiety, and a BCMA-binding moiety. In some embodiments, the FcRH5- binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a BCMA-binding moiety, and a SLAMF7-binding moiety. In some embodiments, the CD38-binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3- binding moiety, a SLAMF7-binding moiety, and a GPRC5D-binding moiety. In some embodiments, the CD38-binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a SLAMF7-binding moiety, and a BCMA-binding moiety. In some embodiments, the CD38-binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a GPRC5D-binding moiety, and a BCMA-binding moiety. In some embodiments, the SLAMF7-binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a BCMA-binding moiety, and a GPRC5D- binding moiety. In some embodiments, the SLAMF7-binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a CD38-binding moiety, and a BCMA-binding moiety. In some embodiments, the SLAMF7-binding moiety is a feature of a tetraspecific binder molecule that also comprises a CD3-binding moiety, a GPRC5D-binding moiety, and a CD38-binding moiety. In some embodiments, the multispecific binder molecule at least two immune cell binders. In some embodiments, the multispecific binder molecule at least three immune cell binders. In some embodiments, the multispecific binder molecule four immune cell binders.Antibody-Based Immune Cell Engagers

[0065] Provided herein are antibody -based binders that bind to CD3. In some embodiments, the antibody-based binder comprises an immune cell engager. In some instances, the immune cell engager is a T cell binding moiety. In some instances, the immune cell engager binds to a cell surface marker of the T cell. In some instances, the immune cell engager comprises a CD3binding moiety. In some embodiments, the immune cell engager comprises an NK cell binding moiety. In some instances, the NK cell binding moiety is selected from a moiety that binds to CD56, CD161, CD94, CD16, NKG2A, NKG2C, NKG2D, MFI, NKp30, NKp44, NKp46, TBR1, +CD158a or CD158b. In some embodiments, the immune cell engager comprises an NKT cell binding moiety. In some instances, the NKT cell binding moiety is selected from a moiety that binds to CD 161, CD 16, CD 158a, CD 158b, NKG2A, NKG2C, NKp30, NKp44, or NKp46. In some embodiments, the multispecific binder molecule comprises the immune cell engager, a GPRC5D binding moiety, a BCMA binding moiety, and a CD38 binding moiety. In some embodiments, the multispecific binder molecule comprises the immune cell engager, a GPRC5D binding moiety, a BCMA binding moiety, and a SLAMF7 binding moiety. In some embodiments, the multispecific binder molecule comprises the immune cell engager, a GPRC5D binding moiety, a SLAMF7 binding moiety, and a CD38 binding moiety. In some embodiments, the multispecific binder molecule comprises the immune cell engager, a SLAMF7 binding moiety, a BCMA binding moiety, and a CD38 binding moiety. In some embodiments, the multispecific binder molecule comprises the immune cell engager, a GPRC5D binding moiety, a BCMA binding moiety, and an FcRH5 binding moiety. In some embodiments, the multispecific binder molecule comprises the immune cell engager, a GPRC5D binding moiety, a CD38 binding moiety, and an FcRH5 binding moiety. In some embodiments, the multispecific binder molecule comprises the immune cell engager, a GPRC5D binding moiety, a SLAMF7 binding moiety, and an FcRH5 binding moiety. In some embodiments, the multispecific binder molecule comprises the immune cell engager, a CD38 binding moiety, a SLAMF7 binding moiety, and an FcRH5 binding moiety.

[0066] In some embodiments, the CD3 binding moiety enhances binding of the multispecific binder molecule to T cells. In some embodiments, the CD3 binding moiety enhances binding of the multispecific binder molecule to NKT cells. In some embodiments, the CD3 binding moiety enhances binding of the multispecific binder molecule to T cells and NKT cells. In some embodiments, the CD3 binding moiety engages one or more classes of immune cells. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to bind one or more T cells simultaneously as binding one or more plasma cells. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to bind one or more T cells simultaneously as binding one or more malignant plasma cells. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to bind one or more NKT cells simultaneously as binding one or more malignant plasma cells. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing any one of BCMA, CD38, SLAMF7, or GPRC5D. Insome embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing any two of BCMA, CD38, SLAMF7, or GPRC5D. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing BCMA, CD38, and SLAMF7.

[0067] In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing any one of BCMA, CD38, SLAMF7, GPRC5D, or FcRH5. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing any two of BCMA, CD38, SLAMF7, GPRC5D, or FcRH5. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing BCMA, GPRC5D, and FcRH5. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing BCMA, CD38, and FcRH5. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing BCMA, SLAMF7, and FcRH5. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing CD38, GPRC5D, and FcRH5. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing SLAMF7, GPRC5D, and FcRH5. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing CD38, SLAMF7, and FcRH5. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing BCMA, CD38, and GPRC5D. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing BCMA, SLAMF7, and GPRC5D. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing CD38, SLAMF7, and GPRC5D. In some embodiments, the tumor cells are from a hematological cancer. In some embodiments, the tumor cells are from myeloma. In some embodiments, the tumor cells are from multiple myeloma. In some embodiments, the multispecific binder molecule brings T cells closer in proximity to tumor cells. In some embodiments, the binding of the multispecific binder molecule potentiates unstimulated T cells or unstimulated NKT cellsand induces direct cytotoxicity against tumor cells expressing BCMA, CD38, FcRH5, SLAMF7, or GPRC5D, or any combination thereof.

[0068] In some embodiments, the multispecific binder molecules comprises at least two immune cell engagers. In some embodiments, the multispecific binder molecules comprises at least two T cell engagers. In some embodiments, the at least two T cell engagers comprise a CD3-binding moiety and a second binding moiety selected from the group consisting of a CD2-binding moiety, a CD5-binding moiety, a CD8-binding moiety, a CD25-binding moiety, a CD27-binding moiety, and a CD28-binding moiety.Targeted Therapeutics

[0069] Various targeted therapeutics have been developed to create immunotherapies that can be applied to the treatment of hematological cancers including MM. Bispecific targeted therapeutics eliciting binding to both BCMA and CD3 include AMG 701, Alnuctamab, Elranatamab, Linvoseltamab, Teclistamab, ABBV-383, and HPN217. Bispecific targeted therapeutics eliciting binding to both CD38 and CD3 include XmAb969 and ISB1347.Bispecific targeted therapeutics eliciting binding to both GPRC5D and CD3 include Talquetamab and RG6234. Bispecific targeted therapeutics eliciting binding to both FcRH5 and CD3 include Cevostamab. A trispecific targeted therapeutic eliciting binding to CD38, CD28, and CD3 is SAR442257. A trispecific targeted therapeutic eliciting binding to BCMA, CD38, and CD3 is ISB 2001. Binding moieties from previously developed targeted therapeutics can be derived from them and adapted for use in targeting the multispecific binder molecule. In some embodiments, the multispecific binder molecule comprises a GPRC5D binding moiety derived from Talquetamab or RG6234. In some embodiments, the multispecific binder molecule comprises a TNFRSF17 (BCMA) binding moiety derived from AMG 701 (pavurutamab), Alnuctamab (EM 801), Elranatamab, Linvoseltamab (REGN5458), Teclistamab (Tecvayli™), ABBV-383 (TNB383B), HPN217, ISB 2001, GSK287916, MEDI2228, or AMG 420. In some embodiments, the multispecific binder molecule comprises a SLAMF7 (CD319) binding moiety derived from ABBV-838, Luc63, or Elotuzumab. In some embodiments, the multispecific binder molecule comprises an FcRH5 binding moiety derived from Cevostamab. In some embodiments, the multispecific binder molecule comprises an FcRH5 binding moiety derived from DFRF4539A. In some embodiments, the multispecific binder molecule comprises a CD38 binding moiety derived from Daratumumab, Isatuximab, ISB 2001, or MOR202. In some embodiments, the multispecific binder molecule comprises an immune cell engager. In some embodiments, an immune cell engager from previously developed targeted therapeutics can be derived from one of them and adapted for use in engaging immune cells with the targeted tumorcells. In some embodiments, the immune cell engager binds to one or more CD3 chains. In some embodiments, the immune cell engager binds to CD3 gamma chain. In some embodiments, the immune cell engager binds to CD3 delta chain. In some embodiments, the immune cell engager binds to CD3 epsilon chain. In some embodiments, the immune cell engager binds to CD3 zeta chain. In some embodiments, multispecific binder molecule comprises an immune cell engager comprising a CD3 binding moiety derived from AMG 701, Alnuctamab, Elranatamab, Linvoseltamab, Teclistamab, ABBV-383, HPN217, XmAb969, ISB1347, Talquetamab, RG6234, Cevostamab, SAR442257, Cevostamab, or ISB 2001. In some embodiments, the multispecific binder molecule comprises a tetraspecific binder molecule.

[0070] In some embodiments, the tetraspecific binder molecule comprises a CD38-binding moiety derived from Daratumumab, a SLAMF7-binding moiety derived from Elotuzumab, a BCMA-binding moiety derived from Teclistamab, and a CD3-binding moiety. In some embodiments, the tetraspecific binder molecule comprises a CD38-binding moiety derived from Daratumumab, a SLAMF7-binding moiety derived from Elotuzumab, a GPRC5D-binding moiety derived from Talquetamab, and a CD3-binding moiety. In some embodiments, the tetraspecific binder molecule comprises a CD38-binding moiety derived from Daratumumab, a BCMA-binding moiety derived from Teclistamab, a GPRC5D-binding moiety derived from Talquetamab, and a CD3-binding moiety. In some embodiments, the tetraspecific binder molecule comprises a SLAMF7-binding moiety derived from Elotuzumab, a BCMA-binding moiety derived from Teclistamab, a GPRC5D-binding moiety derived from Talquetamab, and a CD3-binding moiety. In some embodiments, a binding moiety derived from a targeted therapeutic listed herein comprises amino acids of a CDR series described herein. In some embodiments, the CDR series is located in a VH domain and described in Table 1. In some embodiments, the CDR series is located in a VL domain and described in Table 2. In some embodiments, a binding moiety derived from a targeted therapeutic listed herein comprises amino acids of a VH domain described herein. In some embodiments, the VH domain sequence is listed in Table 3. In some embodiments, a binding moiety derived from a targeted therapeutic listed herein comprises amino acids of a VL domain described herein. In some embodiments, the VL domain sequence is listed in Table 4.

[0071] Heavy chain CDR sequences listed according to different antibody numbering schemes derived from targeted therapeutics are listed in Table 1. Heavy chain CDR sequences listed in Table 1 are adapted for use in generating a GPRC5D binding moiety in the multispecific binder molecule. Heavy chain CDR sequences listed in Table 1 are adapted for use in generating a TNFRSF17 (BCMA) binding moiety in the multispecific binder molecule. Heavy chain CDR sequences listed in Table 1 are adapted for use in generating an FcRH5 binding moiety in themultispecific binder molecule. Heavy chain CDR sequences listed in Table 1 are adapted for use in generating a CD38 binding moiety in the multispecific binder molecule. Heavy chain CDR sequences listed in Table 1 are adapted for use in generating a SLAMF7 (CD319) binding moiety in the multispecific binder molecule. Heavy chain CDR sequences listed in Table 1 are adapted for use in generating a T cell binding moiety that binds to CD3 in the multispecific binder molecule. Heavy chain CDR sequences listed in Table 1 are adapted for use in generating a NK cell binding moiety that binds to CD3 in the multispecific binder molecule. Heavy chain CDR sequences listed in Table 1 are adapted for use in generating a NKT cell binding moiety that binds to CD3 in the multispecific binder molecule. Light chain CDR sequences listed according to different antibody numbering schemes derived from targeted therapeutics are listed in Table 2. Light chain CDR sequences listed in Table 2 are adapted for use in generating a GPRC5D binding moiety in the multispecific binder molecule. Light chain CDR sequences listed in Table 2 are adapted for use in generating a TNFRSF17 (BCMA) binding moiety in the multispecific binder molecule. Light chain CDR sequences listed in Table 2 are adapted for use in generating an FcRH5 binding moiety in the multispecific binder molecule. Light chain CDR sequences listed in Table 2 are adapted for use in generating a CD38 binding moiety in the multispecific binder molecule. Light chain CDR sequences listed in Table 2 are adapted for use in generating a SLAMF7 (CD319) binding moiety in the multispecific binder molecule. Light chain CDR sequences listed in Table 2 are adapted for use in generating a T cell binding moiety that binds to CD3 in the multispecific binder molecule. Light chain CDR sequences listed in Table 2 are adapted for use in generating a NK cell binding moiety that binds to CD3 in the multispecific binder molecule. Light chain CDR sequences listed in Table 2 are adapted for use in generating a NKT cell binding moiety that binds to CD3 in the multispecific binder molecule.Table 1: HCDR Sequences Derived from Targeted Therapeutics

[0072] In some embodiments, the VH region of the GPRC5D binding moiety comprises HCDR1, HCDR2, and HCDR3 sequences selected from the sequences listed in Table 1. In some embodiments, the VH region of the TNFRSF17 (BCMA) binding moiety comprises HCDR1, HCDR2, and HCDR3 sequences selected from the sequences listed in Table 1. In some embodiments, the VH region of the FcRH5 binding moiety comprises HCDR1, HCDR2, and HCDR3 sequences selected from the sequences listed in Table 1. In some embodiments, the VH region of the CD38 binding moiety comprises HCDR1, HCDR2, and HCDR3 sequences selected from the sequences listed in Table 1. In some embodiments, the VH region of the SLAMF7 (CD319) binding moiety HCDR1, HCDR2, and HCDR3 sequences selected from the sequences listed in Table 1. In some embodiments, the VH region of the immune cell engager CD3 binding moiety comprises HCDR1, HCDR2, and HCDR3 sequences selected from the sequences listed in Table 1.

[0073] In some embodiments, the VL region of the GPRC5D binding moiety comprises LCDR1, LCDR2, and LCDR3 sequences selected from the sequences listed in Table 2. In some embodiments, the VL region of the TNFRSF17 (BCMA) binding moiety comprises LCDR1, LCDR2, and LCDR3 sequences selected from the sequences listed in Table 2. In some embodiments, the VL region of the FcRH5 binding moiety comprises LCDR1, LCDR2, and LCDR3 sequences selected from the sequences listed in Table 2. In some embodiments, the VL region of the CD38 binding moiety comprises LCDR1, LCDR2, and LCDR3 sequences selected from the sequences listed in Table 2. In some embodiments, the VL region of the SLAMF7 (CD319) binding moiety comprises LCDR1, LCDR2, and LCDR3 sequences selected from the sequences listed in Table 2. In some embodiments, the VL region of the immune cell engager CD3 binding moiety comprises LCDR1, LCDR2, and LCDR3 sequences selected from the sequences listed in Table 2.Table 2: LCDR Sequences Derived from Targeted Therapeutics

[0074] In some aspects, the multispecific binding molecule comprises a VH domain disclosed herein. In some embodiments, the VH domain comprises a CDR sequence listed in Table 1. In some embodiments, the VH domain comprises a first binding moiety to a first tumor associated antigen. In some embodiments, the VH domain comprises a second binding moiety to a second tumor associated antigen. In some embodiments, the VH domain comprises a third binding moiety to a third tumor associated antigen. In some embodiments, the VH domain comprises an immune cell engager. In some embodiments, the immune cell engager is a T cell binding moiety, an NK cell binding moiety, an NKT cell binding moiety, or a combination thereof. In some embodiments, the first, second, and third binding moieties comprise a GPRC5D binding moiety, a TNFRSF17 (BCMA) binding moiety, and a CD38 binding moiety. In some embodiments, the first, second, and third binding moieties comprise a GPRC5D binding moiety, a TNFRSF17 (BCMA) binding moiety, and a SLAMF7 (CD319) binding moiety. In some embodiments, the first, second, and third binding moieties comprise a GPRC5D binding moiety, a CD38 binding moiety, and a SLAMF7 (CD319) binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a GPRC5D binding moiety, aTNFRSF17 (BCMA) binding moiety, and a CD38 binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a GPRC5D binding moiety, a TNFRSF17 (BCMA) binding moiety, and a SLAMF7 (CD319) binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a GPRC5D binding moiety, a CD38 binding moiety, and a SLAMF7 (CD319) binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a BCMA binding moiety, a CD38 binding moiety, and a SLAMF7 (CD319) binding moiety.

[0075] In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a GPRC5D binding moiety, a BCMA binding moiety, and an FcRH5 binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a GPRC5D binding moiety, a CD38 binding moiety, and an FcRH5 binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a GPRC5D binding moiety, a SLAMF7 binding moiety, and an FcRH5 binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a CD38 binding moiety, a BCMA binding moiety, and an FcRH5 binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a SLAMF7 binding moiety, a BCMA binding moiety, and an FcRH5 binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a CD38 binding moiety, a SLAMF7 binding moiety, and an FcRH5 binding moiety.

[0076] In some embodiments, the multispecific binding molecule comprises one or more VH domains listed in Table 3. In some embodiments, the multispecific binding molecule comprises one or more VH domains derived from one or more sequences listed in Table 5. In some embodiments, the multispecific binding molecule comprises one or more VH domains derived from one or more sequences listed in Table 5 or Table 3. Exemplary VH domains for use in the multispecific binding molecule are listed in Table 3. Exemplary heavy chains for use in the multispecific binding molecule are listed in Table 5. In some embodiments, the multispecificbinding molecule comprises one or more VH domains derived from one or more sequences listed in Table 7.

[0077] In some aspects, the multispecific binding molecule comprises a VL domain disclosed herein. In some embodiments, the VL domain comprises a CDR sequence listed in Table 2. In some embodiments, the VL domain comprises a first binding moiety to a first tumor associated antigen. In some embodiments, the VL domain comprises a second binding moiety to a second tumor associated antigen. In some embodiments, the VL domain comprises a third binding moiety to a third tumor associated antigen. In some embodiments, the VL domain comprises an immune cell engager. In some embodiments, the immune cell engager is a T cell binding moiety, an NK cell binding moiety, an NKT cell binding moiety, or a combination thereof. In some embodiments, the first, second, and third binding moieties comprise a GPRC5D binding moiety, a TNFRSF17 (BCMA) binding moiety, and a CD38 binding moiety. In some embodiments, the first, second, and third binding moieties comprise a GPRC5D binding moiety, a TNFRSF17 (BCMA) binding moiety, and a SLAMF7 (CD319) binding moiety. In some embodiments, the first, second, and third binding moieties comprise a GPRC5D binding moiety, a TNFRSF17 (BCMA) binding moiety, and a TNFRSF17 (BCMA) binding moiety. In some embodiments, the first, second, and third binding moieties comprise a GPRC5D binding moiety, a TNFRSF17 (BCMA) binding moiety, and an FcRH5 binding moiety. In some embodiments, the first, second, and third binding moieties comprise a GPRC5D binding moiety, a CD38 binding moiety, and an FcRH5 binding moiety. In some embodiments, the first, second, and third binding moieties comprise a GPRC5D binding moiety, a SLAMF7 binding moiety, and an FcRH5 binding moiety. In some embodiments, the first, second, and third binding moieties comprise a CD38 binding moiety, a TNFRSF17 (BCMA) binding moiety, and an FcRH5 binding moiety. In some embodiments, the first, second, and third binding moieties comprise a SLAMF7 binding moiety, a TNFRSF17 (BCMA) binding moiety, and an FcRH5 binding moiety. In some embodiments, the first, second, and third binding moieties comprise a CD38 binding moiety, a SLAMF7 binding moiety, and an FcRH5 binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a GPRC5D binding moiety, a TNFRSF17 (BCMA) binding moiety, and a CD38 binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a GPRC5D binding moiety, a TNFRSF17 (BCMA) binding moiety, and a SLAMF7 (CD319) binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moietiescomprising a GPRC5D binding moiety, a CD38 binding moiety, and a SLAMF7 (CD319) binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moi eties comprising a BCMA binding moiety, a CD38 binding moiety, and a SLAMF7 (CD319) binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moi eties comprising a GPRC5D binding moiety, a TNFRSF17 (BCMA) binding moiety, and an FcRH5 binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a GPRC5D binding moiety, a CD38 binding moiety, and an FcRH5 binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a GPRC5D binding moiety, a SLAMF7, and an FcRH5 binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a CD38 binding moiety, a TNFRSF17 (BCMA) binding moiety, and an FcRH5 binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a SLAMF7 binding moiety, a TNFRSF17 (BCMA) binding moiety, and an FcRH5 binding moiety. In some embodiments, the multispecific binding molecule comprises an immune cell engager comprising a CD3 binding moiety, and a first, second, and third binding moieties comprising a CD38 binding moiety, a SLAMF7 binding moiety, and an FcRH5 binding moiety.

[0078] In some embodiments, the multispecific binding molecule comprises one or more VL domains listed in Table 4. In some embodiments, the multispecific binding molecule comprises one or more VL domains derived from one or more sequences listed in Table 6. In some embodiments, the multispecific binding molecule comprises one or more VL domains derived from one or more sequences listed in Table 4 or Table 6. In some embodiments, the multispecific binding molecule comprises one or more VL domains derived from one or more sequences listed in Table 7. In some embodiments, a VH domain comprising a GPRC5D binding moiety is paired with a VL domain comprising a GPRC5D binding moiety in the multispecific binding molecule. In some embodiments, a VH domain comprising a BCMA binding moiety is paired with a VL domain comprising a BCMA binding moiety in the multispecific binding molecule. In some embodiments, a VH domain comprising an FcRH5 binding moiety is paired with a VL domain comprising an FcRH5 binding moiety in the multispecific binding molecule. In some embodiments, a VH domain comprising a SLAMF7binding moiety is paired with a VL domain comprising a SLAMF7 binding moiety in the multispecific binding molecule. In some embodiments, a VH domain comprising a CD38 binding moiety is paired with a VL domain comprising a CD38 binding moiety in the multispecific binding molecule. In some embodiments, a VH domain comprising a CD3 binding moiety is paired with a VL domain comprising a CD3 binding moiety in the multispecific binding molecule. In some embodiments, a VH domain comprising a BCMA binding moiety is paired with a VL domain comprising a CD3 binding moiety in the multispecific binding molecule. In some embodiments, a VH domain comprising an FcRH5 binding moiety is paired with a VL domain comprising a CD3 binding moiety in the multispecific binding molecule. In some embodiments, a VH domain comprising a CD38 binding moiety is paired with a VL domain comprising a CD3 binding moiety in the multispecific binding molecule. In some embodiments, a VH domain comprising a SLAMF7 binding moiety is paired with a VL domain comprising a CD3 binding moiety in the multispecific binding molecule. Exemplary VL domains for use in the multispecific binding molecule are listed in Table 4. Exemplary light chains for use in the multispecific binding molecule are listed in Table 6.Table 3: Heavy chain variable domain (VH) SequencesTable 4: Light chain variable domain (VL) Sequences

[0079] In some embodiments, an antibody-based multispecific binder molecule described herein comprises a full-length antibody. In other aspects, the antibody-based multispecific binder molecule comprises an antigen-binding fragment thereof. In some embodiments, the antibodybased multispecific binder molecule comprises an intact IgGl. In some embodiments, the antibody-based multispecific binder molecule comprises an intact IgG2. In some embodiments, the antibody -based multispecific binder molecule comprises an intact IgG3. In some embodiments, the antibody-based multispecific binder molecule comprises an intact IgG4. In some embodiments, the antibody-based multispecific binder molecule comprises an intact IgA. In some embodiments, the antibody-based multispecific binder molecule comprises an intact IgM. In some embodiments, the antibody-based multispecific binder molecule comprises anintact IgE. In some embodiments, the antibody-based multispecific binder molecule comprises an intact IgD. In some cases, the antibody-based multispecific binder molecule comprises a humanized antibody or an antigen-binding fragment thereof, a chimeric antibody or an antigenbinding fragment thereof, a monoclonal antibody or an antigen-binding fragment thereof. In some cases, the antibody-based multispecific binder molecule comprises a monovalent Fab’, F(ab)'3 fragments, single-chain variable fragment (scFv), (scFv)2, minibody, nanobody, disulfide stabilized Fv protein ("dsFv"), single-domain antibody (sdAb), Ig NAR, camelid antibody or an antigen-binding fragment thereof, or a chemically-modified derivative thereof. In some embodiments, the antibody-based multispecific binder molecule comprises an arrangement of binding moi eties in an IgG-scFv format. In some embodiments, the antibody -based multispecific binder molecule comprises an arrangement of binding moieties in an scFv-Fc-scFv format. In some embodiments, the antibody-based multispecific binder molecule comprises an arrangement of binding moieties in a IgG-dAb format. In some embodiments, the antibodybased multispecific binder molecule comprises an arrangement of binding moieties in a bispecific antibody format. In some embodiments, the antibody-based multispecific binder molecule comprises an arrangement of binding moieties in a bispecific killer engager (BiKE) format. In some embodiments, the antibody-based multispecific binder molecule comprises an arrangement of binding moieties in a trispecific killer engager (TriKE) format. In some embodiments, the antibody-based multispecific binder molecule comprises an arrangement of binding moieties in a tetraspecific killer engager (TetraKE) format.

[0080] In some cases, the antibody-based multispecific binder molecule comprises one or more mutations in a framework region, e.g., in the CHI domain, CH2 domain, CH3 domain, hinge region, or a combination thereof. In some instances, the one or more mutations are to stabilize the antibody-based multispecific binder molecule. In some instances, the one or more mutations are to increase half-life. In some instances, the one or more mutations are to modulate Fc receptor interactions. In some instances, the one or more mutations are to reduce or eliminate Fc effector functions such as FcyR, antibody-dependent cell-mediated cytotoxicity (ADCC), or complement-dependent cytotoxicity (CDC). In additional instances, the one or more mutations are to modulate glycosylation.

[0081] The term Fc region is used herein to specify a C-terminal region of an immunoglobulin heavy chain. The Fc region of the antibodies described herein may be a wild-type sequence. In some embodiments, the Fc region is human Fc region. In some embodiments, the Fc region is a mouse Fc region. Although the boundaries of the Fc region of an immunoglobulin heavy chain might vary, the human IgG heavy chain Fc region is typically defined to stretch from an amino acid residue at position Cys226, or from Pro230, to the carboxyl -terminus thereof. The Fc regionof an immunoglobulin generally comprises two constant domains, CH2 and CHS. An Fc region can be present in a monomeric form or a dimeric form. The Fc region can bind to various cell receptors, such as Fc receptors, and other immune molecules, including complement proteins. In some embodiments, the one or more mutations are located in the Fc region.

[0082] In some embodiments, the human IgG constant region is modified to alter antibodydependent cellular cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC), e.g., with an amino acid modification described in Natsume et al., 2008 Cancer Res, 68(10): 3863-72; Idusogie et al., 2001 J Immunol, 166(4): 2571-5; Moore et al., 2010 mAbs, 2(2): 181- 189;Lazar et al., 2006 PNAS, 103(11): 4005-4010, Shields et al., 2001 JBC, 276( 9): 6591- 6604; Stavenhagen et al., 2007 Cancer Res, 67(18): 8882-8890; Stavenhagen et al., 2008 Advan. Enzyme Regul., 48: 152-164; Alegre et al, 1992 J Immunol, 148: 3461-3468; Urban et al., 2021 Front Immunol. Nov 25;12:724361; Zhou et al., 2020 MAbs. Jan-Dec;12(l): 1814583; Reviewed in Kaneko and Niwa, 2011 Biodrugs, 25(1): 1-11.

[0083] In some embodiments, an antibody-based multispecific binder molecule described herein comprises a full-length antibody, comprising a heavy chain (HC) and a light chain (LC). In some embodiments, the HC comprises about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to a sequence listed in Table 5. In some embodiments, the LC comprises about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to a sequence listed in Table 6. In some cases, the heavy chain (HC) comprises a sequence selected from the sequences listed in Table 5. In some cases, the light chain (LC) comprises a sequence selected from the sequences listed in Table 6.Table 5: Antibody heavy chain sequences(X)n=i4-4o is a leader sequenceTable 6: Antibody light chain sequences(X)n=i4-4o is a leader sequenceTable 7: Sequences of antibody-based targeted therapeutics in non-conventional antibody formats

[0084] In some embodiments, the antibody-based multispecific binding molecules have a leader sequence near an amino-terminal region of each polypeptide. In some embodiments, the leader sequence is N-terminal to an antibody heavy chain sequence or modified heavy chain sequence. In some embodiments, the leader sequence is N-terminal to an antibody heavy chain sequence provided in Table 5. In some embodiments, the leader sequence is N-terminal to an antibody light chain sequence or modified light chain sequence. In some embodiments, the leader sequence is N-terminal to an antibody light chain sequence provided in Table 6. In some embodiments, (X)n=i4-4o is used to represent amino acids of a leader sequence at the aminoterminal end of an antibody heavy chain sequence. In some embodiments, (X)n=i4-4o is used to represent amino acids of a leader sequence at the amino-terminal end of an antibody light chain sequence. In some embodiments, the leader sequence is a length of between 14-40 amino acids. In some embodiments, the leader sequence is a length of between 15-35 amino acids. In some embodiments, the leader sequence of an antibody heavy chain and an antibody light chain paired to form multispecific binding molecule are not identical to each other. In some embodiments, the leader sequence comprises an amino acid sequence listed in Table 20.

[0085] In some embodiments, the antibody-based multispecific binder molecule comprises a full-length antibody. In other aspects, the antibody-based multispecific binder molecule comprises an antigen-binding fragment thereof. In some cases, the antibody-based multispecific binder molecule comprises a humanized antibody or an antigen-binding fragment thereof, a chimeric antibody or an antigen-binding fragment thereof, a monoclonal antibody or an antigenbinding fragment thereof. In some cases, the antibody-based multispecific binder molecule comprises a monovalent Fab’, F(ab)'3 fragments, single-chain variable fragment (scFv), (scFv)2, minibody, nanobody, disulfide stabilized Fv protein ("dsFv"), single-domain antibody (sdAb), IgNAR, camelid antibody or an antigen-binding fragment thereof, or a chemically-modified derivative thereof.

[0086] In some embodiments, the multispecific binder molecule comprises one or more immunoglobulin chain constant regions. In some embodiments, the one or more immunoglobulin chain constant regions are derived from IgGl, IgG2, and / or IgG4 antibodies. In some embodiments, the one or more immunoglobulin chain constant regions are derived from human IgGl, IgG2, and / or IgG4 antibodies. In some embodiments, the one or more immunoglobulin chain constant regions is a CHI, CH2, or CH3 domain. In some embodiments, the one or more immunoglobulin chain constant regions is a CL domain. In some embodiments, the one or more immunoglobulin heavy chain constant regions in the multispecific binding molecule is derived from one or more sequences listed in Table 8. In some embodiments, the one or more immunoglobulin heavy chain constant regions in the multispecific binding molecule is selected from one or more sequences listed in Table 8. In some embodiments, the one or more immunoglobulin light chain constant regions in the multispecific binding molecule is derived from a sequence listed in Table 9. In some embodiments, the one or more immunoglobulin light chain constant regions in the multispecific binding molecule is selected from one or more sequences listed in Table 9. In some embodiments, a CHI domain listed in a portion of sequence in Table 8 is positioned C-terminal to a GPRC5D binding moiety in the multispecific binder molecule. In some embodiments, a CHI domain listed in a portion of sequence in Table 8 is positioned C-terminal to a BCMA binding moiety in the multispecific binder molecule. In some embodiments, a CHI domain listed in a portion of sequence in Table 8 is positioned C- terminal to an FcRH5 binding moiety in the multispecific binder molecule. In some embodiments, a CHI domain listed in a portion of sequence in Table 8 is positioned C-terminal to a CD38 binding moiety in the multispecific binder molecule. In some embodiments, a CHI domain listed in a portion of sequence in Table 8 is positioned C-terminal to a SLAMF7 binding moiety in the multispecific binder molecule. In some embodiments, a CHI domain listed in a portion of sequence in Table 8 is positioned C-terminal to a CD3 binding moiety in the multispecific binder molecule. In some embodiments, a CH2 and CH3 domain listed in a portion of sequence in Table 8 is positioned C-terminal to a GPRC5D binding moiety in the multispecific binder molecule. In some embodiments, a CH2 and CH3 domain listed in a portion of sequence in Table 8 is positioned C-terminal to a BCMA binding moiety in the multispecific binder molecule. In some embodiments, a CH2 and CH3 domain listed in a portion of sequence in Table 8 is positioned C-terminal to an FcRH5 binding moiety in the multispecific binder molecule. In some embodiments, a CH2 and CH3 domain listed in a portion of sequence in Table 8 is positioned C-terminal to a CD38 binding moiety in the multispecific binder molecule.In some embodiments, a CH2 and CH3 domain listed in a portion of sequence in Table 8 is positioned C-terminal to a SLAMF7 binding moiety in the multispecific binder molecule. In some embodiments, a CH2 and CH3 domain listed in a portion of sequence in Table 8 is positioned C-terminal to a CD3 binding moiety in the multispecific binder molecule. In some embodiments, a CH2 and CH3 domain listed in a portion of sequence in Table 8 is positioned C-terminal to a CHI domain. In some embodiments, the multispecific binder molecule comprises a sequence at least 80%, 85%, 90%, 92%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence listed in Table 8. In some embodiments, the multispecific binder molecule comprises a sequence selected from a sequence listed in Table 8. In some embodiments, the multispecific binder molecule comprises a sequence at least 80%, 85%, 90%, 92%, 94%, 95%, 96%, 97%, 98%, or 99% identical to a sequence listed in Table 9. In some embodiments, the multispecific binder molecule comprises a sequence selected from a sequence listed in Table 9. In some embodiments, the multispecific binder molecule comprises two modified heavy chains with different sequences which are paired together to form a multispecific binding format. In some embodiments, the multispecific binder molecule comprises two modified heavy chains comprising KiH knob substitutions and KiH hole substitutions respectively which aid in heterodimeric pairing of the two distinct modified heavy chains. In some embodiments, the multispecific binder molecule comprises four light chains. In some embodiments, the multispecific binder molecule comprises three light chains each comprising a CD3 binding moiety and a fourth light chain comprising a GPRC5D binding moiety. In some embodiments, the multispecific binder molecule comprises three light chains each comprising a CD3 binding moiety and a fourth light chain comprising an FcRH5 binding moiety. In some embodiments, the multispecific binder molecule comprises two modified heavy chains and four light chains. In some embodiments, the multispecific binder molecule is produced in single cells. In some embodiments, the multispecific binder molecule is assembled in vitro.

[0087] In some aspects, the multispecific binder molecule comprises one or more antibody heavy chains. In some embodiments, the one or more antibody heavy chains are modified antibody heavy chains. In some embodiments, the multispecific binder molecule is organized as a tetraspecific binding molecule capable of high specificity and high affinity binding to four distinct antigens. In some embodiments, the tetraspecific binding molecule is configured with four binding arms (A-D) linked in two modified heavy chains as illustrated in FIG. 1. In some embodiments, each of binding arms A-D is configured to elicit high specificity and high affinity binding to a distinct antigen. In some embodiments, the format of the multispecific binder molecule comprising a tetraspecific binder molecule is listed in FIG. 2. In some embodiments,the format of the multispecific binder molecule comprising a tetraspecific binder molecule is listed in FIG. 3. In some embodiments, the format of the multispecific binder molecule comprising a tetraspecific binder molecule is listed in FIG. 4. In some embodiments, the format of the multispecific binder molecule comprising a tetraspecific binder molecule is listed in FIG. 5. In some embodiments, the format of the multispecific binder molecule comprising a tetraspecific binder molecule is listed in FIG. 6. In some embodiments, the formats of the multispecific binder molecule in FIG. 1-FIG. 12 are formed with six polypeptides. In some embodiments, the six polypeptides comprises two modified heavy chains and four light chains. In some embodiments, the multispecific binder molecule comprises six polypeptides comprising two modified heavy chains and four light chains. In some embodiments, the tetraspecific binder molecule comprises six polypeptides comprising two modified heavy chains and four light chains. In some embodiments, the multispecific binder molecule consists of six polypeptides comprising two modified heavy chains and four light chains. In some embodiments, the tetraspecific binder molecule consists of six polypeptides comprising two modified heavy chains and four light chains.

[0088] In some embodiments, the binding arms in the tetraspecific binder molecule are configured to create four distinct binding moi eties according to FIG. 1, labeled as binding arm 1, binding arm 2, binding arm 3, and binding arm 4. In some embodiments, the tetraspecific binder molecule is configured according to one of the twenty-four possible configurations for an anti-CD3 / BCMA / GPRC5D / FCRH5 tetraspecific binder molecule indicated as Configurations A1-A24 in Table 10.

[0089] Exemplary configurations of tetraspecific binder molecules selected from Table 10 are listed below.

[0090] Configuration A6 of tetraspecific binder molecule: In some embodiments, the tetraspecific binding molecule is configured according to the configuration for an anti- CD3 / BCMA / GPRC5D / FCRH5 tetraspecific binder molecule indicated in FIG. 2. FIG. 2 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG- Fab configuration. A first modified heavy chain is configured from N-terminal to C-terminal as: i) Binding arm A - BCMA heavy chain variable region (VH), ii) a first constant Ig domain of a heavy chain (CHI), iii) a second constant Ig domain of a heavy chain (CH2), iv) a mutated third Ig domain of a heavy chain (CH3) comprising KiH knob substitutions, v) Binding arm C - FcRH5 VH, and vi) CHI. A second modified heavy chain is configured from N-terminal to C- terminal as: i) Binding arm B - GPRC5D VH, ii) CHI, iii) CH2 iv) a mutated CH3 comprising KiH hole substitutions, v) Binding arm D - CD3 VH, and vi) CHI. A first light chain is configured from N-terminal to C-terminal as: i) Binding arm A - BMCA light chain variableregion (VL). and ii) a constant Ig domain of a light chain (CL - K set 1 or CL - K set 2). Paired Binding arm A VH and Binding arm A VL form a BCMA binding moiety. A second light chain is configured from N-terminal to C-terminal as: i) Binding arm B - GPRC5D VL and ii) CL - K set 1 or CL - K set 2. Paired Binding arm B VH and Binding arm B VL form a GPRC5D binding moiety. A third light chain is configured from N-terminal to C-terminal as: i) Binding arm C - FcRH5 VL and ii) CL - K set 1 or CL - K set 2. Paired Binding arm C VH and Binding arm C VL form an FcRH5 binding moiety. A fourth light chain is configured from N-terminal to C- terminal as: i) Binding arm D - CD3 VL, and ii) CL - K set 1 or CL - K set 2. Paired Binding arm D VH and Binding arm D VL form a CD3 binding moiety. In some embodiments, the tetraspecific binder molecule comprises four light chains wherein each light chain comprises a CL - K set 1. In some embodiments, the tetraspecific binder molecule comprises four light chains wherein each light chain comprises a CL - K set 2. In some embodiments, the tetraspecific binder molecule comprises four light chains wherein one light chain comprises a CL - K set 1 and three light chains comprise a CL - K set 2. In some embodiments, the tetraspecific binder molecule comprises four light chains wherein two light chains comprise a CL - K set 1 and two light chains comprise a CL - K set 2. In some embodiments, the tetraspecific binder molecule comprises four light chains wherein three light chains comprise a CL - K set 1 and one light chain comprises a CL - K set 2.

[0091] Configuration A2 of tetraspecific binder molecule: In some embodiments, the tetraspecific binding molecule is configured according to the configuration for an anti- CD3 / BCMA / GPRC5D / FCRH5 tetraspecific binder molecule indicated in FIG. 7. FIG. 7 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG- Fab configuration. A first modified heavy chain is configured from N-terminal to C-terminal as: i) BCMA VH, ii) CHI, iii) CH2, iv) a mutated CH3 comprising KiH knob substitutions, v) FcRH5 VH, and vi) CHI. A second modified heavy chain is configured from N-terminal to C- terminal with: i) CD3 VH, ii) CHI, iii) CH2 iv) a mutated CH3 comprising KiH hole substitutions, v) GPRC5D VH, and vi) CHI. A first light chain in binding arm A is configured from N-terminal to C-terminal as either : i-a) BCMA VL or i-b) CD3 VL, and ii) CL - K set 1. A second light chain in binding arm B is configured from N-terminal to C-terminal as: i) CD3 VL and ii) CL - K set 1. A third light chain in binding arm C is configured from N-terminal to C- terminal as either: i-a) FcRH5 VL or i-b) CD3 VL, and ii) CL - K set 1. A fourth light chain in binding arm D is configured from N-terminal to C-terminal as: i) GPRC5D and ii) CL - K set 2. Two light chains are paired with each modified heavy chain with the respective VH and VL regions arranged to form a BCMA binding moiety in binding arm A, a CD3 binding moiety inbinding arm B, a FcRH5 binding moiety in binding arm C, and a GPRC5D binding moiety in binding arm D.

[0092] Configuration Al of tetraspecific binder molecule: In some embodiments, the tetraspecific binding molecule is configured according to the configuration for an anti- CD3 / BCMA / GPRC5D / FCRH5 tetraspecific binder molecule indicated in FIG. 8. FIG. 8 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG- Fab configuration. A first modified heavy chain is configured from N-terminal to C-terminal as: i) BCMA VH, ii) CHI, iii) CH2, iv) a mutated CH3 comprising KiH knob substitutions, v) GPRC5D VH, and vi) CHI. A second modified heavy chain is configured from N-terminal to C- terminal with: i) CD3 VH, ii) CHI, iii) CH2 iv) a mutated CH3 comprising KiH hole substitutions, v) FcRH5 VH, and vi) CHI. A first light chain in binding arm A is configured from N-terminal to C-terminal as either : i-a) BCMA VL or i-b) CD3 VL, and ii) CL - K set 1. A second light chain in binding arm B is configured from N-terminal to C-terminal as: i) CD3 VL and ii) CL - K set 1. A third light chain in binding arm C is configured from N-terminal to C- terminal as: i) GPRC5D VL, and ii) CL - K set 2. A fourth light chain in binding arm D is configured from N-terminal to C-terminal as either: i-a) FcRH5 VL or i-b) CD3 VL and ii) CL- K set 1. Two light chains are paired with each modified heavy chain with the respective VH and VL regions arranged to form a BCMA binding moiety in binding arm A, a CD3 binding moiety in binding arm B, a GPRC5D binding moiety in binding arm C, and a FcRH5 binding moiety in binding arm D.

[0093] Configuration Al 6 of tetraspecific binder molecule: In some embodiments, the tetraspecific binding molecule is configured according to the configuration for an anti- CD3 / BCMA / GPRC5D / FCRH5 tetraspecific binder molecule indicated in FIG. 9. FIG. 9 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG- Fab configuration. A first modified heavy chain is configured from N-terminal to C-terminal as: i) FcRH5 VH, ii) CHI, iii) CH2, iv) a mutated CH3 comprising KiH knob substitutions, v) GPRC5D VH, and vi) CHI. A second modified heavy chain is configured from N-terminal to C- terminal with: i) CD3 VH, ii) CHI, iii) CH2 iv) a mutated CH3 comprising KiH hole substitutions, v) BCMA VH, and vi) CHI. A first light chain in binding arm A is configured from N-terminal to C-terminal as either : i-a) FcRH5 VL or i-b) CD3 VL, and ii) CL - K set 1. A second light chain in binding arm B is configured from N-terminal to C-terminal as: i) CD3 VL and ii) CL - K set 1. A third light chain in binding arm C is configured from N-terminal to C- terminal as: i) GPRC5D VL, and ii) CL - K set 2. A fourth light chain in binding arm D is configured from N-terminal to C-terminal as either: i-a) BCMA VL or i-b) CD3 VL and ii) CL- K set 1. Two light chains are paired with each modified heavy chain with the respective VHand VL regions arranged to form a FcRH5 binding moiety in binding arm A, a CD3 binding moiety in binding arm B, a GPRC5D binding moiety in binding arm C, and a BCMA binding moiety in binding arm D.

[0094] Configuration Al 5 of tetraspecific binder molecule: In some embodiments, the tetraspecific binding molecule is configured according to the configuration for an anti- CD3 / BCMA / GPRC5D / FCRH5 tetraspecific binder molecule indicated in FIG. 10. FIG. 10 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. A first modified heavy chain is configured from N-terminal to C- terminal as: i) FcRH5 VH, ii) CHI, iii) CH2, iv) a mutated CH3 comprising KiH knob substitutions, v) BCMA VH, and vi) CHI. A second modified heavy chain is configured from N-terminal to C-terminal with: i) CD3 VH, ii) CHI, iii) CH2 iv) a mutated CH3 comprising KiH hole substitutions, v) GPRC5D VH, and vi) CHI. A first light chain in binding arm A is configured from N-terminal to C-terminal as either : i-a) FcRH5 VL or i-b) CD3 VL, and ii) CL - K set 1. A second light chain in binding arm B is configured from N-terminal to C-terminal as: i) CD3 VL and ii) CL - K set 1. A third light chain in binding arm C is configured from N- terminal to C-terminal as either: i-a) BCMA VL or i-b) CD3 VL and ii) CL - K set 1. A fourth light chain in binding arm D is configured from N-terminal to C-terminal as: i) GPRC5D VL and ii) CL - K set 2. Two light chains are paired with each modified heavy chain with the respective VH and VL regions arranged to form a FcRH5 binding moiety in binding arm A, a CD3 binding moiety in binding arm B, a BCMA binding moiety in binding arm C, and a GPRC5D binding moiety in binding arm D.

[0095] Configuration A22 of tetraspecific binder molecule: In some embodiments, the tetraspecific binding molecule is configured according to the configuration for an anti- CD3 / BCMA / GPRC5D / FCRH5 tetraspecific binder molecule indicated in FIG. 11. FIG. 11 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. A first modified heavy chain is configured from N-terminal to C- terminal as: i) GPRC5D VH, ii) CHI, iii) CH2, iv) a mutated CH3 comprising KiH knob substitutions, v) FcRH5 VH, and vi) CHI. A second modified heavy chain is configured from N-terminal to C-terminal with: i) CD3 VH, ii) CHI, iii) CH2 iv) a mutated CH3 comprising KiH hole substitutions, v) BCMA VH, and vi) CHI. A first light chain in binding arm A is configured from N-terminal to C-terminal as: i) GPRC5D VL and ii) CL - K set 2. A second light chain in binding arm B is configured from N-terminal to C-terminal as: i) CD3 VL and ii) CL - K set 1. A third light chain in binding arm C is configured from N-terminal to C-terminal as either: i-a) FcRH5 VL or i-b) CD3 VL, and ii) CL - K set 1. A fourth light chain in binding arm D is configured from N-terminal to C-terminal as either: i-a) BCMA VL or i-b) CD3 VL,and ii) CL - K set 1. Two light chains are paired with each modified heavy chain with the respective VH and VL regions arranged to form a GPRC5D binding moiety in binding arm A, a CD3 binding moiety in binding arm B, a FcRH5 binding moiety in binding arm C, and a BCMA binding moiety in binding arm D.

[0096] Configuration A21 of tetraspecific binder molecule: In some embodiments, the tetraspecific binding molecule is configured according to the configuration for an anti- CD3 / BCMA / GPRC5D / FCRH5 tetraspecific binder molecule indicated in FIG. 12. FIG. 12 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. A first modified heavy chain is configured from N-terminal to C- terminal as: i) GPRC5D VH, ii) CHI, iii) CH2, iv) a mutated CH3 comprising KiH knob substitutions, v) BCMA VH, and vi) CHI. A second modified heavy chain is configured from N-terminal to C-terminal with: i) CD3 VH, ii) CHI, iii) CH2 iv) a mutated CH3 comprising KiH hole substitutions, v) FcRH5 VH, and vi) CHI. A first light chain in binding arm A is configured from N-terminal to C-terminal as: i) GPRC5D VL and ii) CL - K set 2. A second light chain in binding arm B is configured from N-terminal to C-terminal as: i) CD3 VL and ii) CL - K set 1. A third light chain in binding arm C is configured from N-terminal to C-terminal as either: i-a) BCMA VL or i-b) CD3 VL, and ii) CL - K set 1. A fourth light chain in binding arm D is configured from N-terminal to C-terminal as either: i-a) FcRH5 VL or i-b) CD3 VL, and ii) CL - K set 1. Two light chains are paired with each modified heavy chain with the respective VH and VL regions arranged to form a GPRC5D binding moiety in binding arm A, a CD3 binding moiety in binding arm B, a BCMA binding moiety in binding arm C, and a FcRH5 binding moiety in binding arm D.

[0097] In some embodiments, the tetraspecific binding molecule is configured according to one of the twenty-four possible configurations for an anti-CD3 / BCMA / GPRC5D / CD38 tetraspecific indicated as Configurations B1-B24 in Table 11. In some embodiments, the tetraspecific binding molecule is configured according to the configuration for an anti- CD3 / BCMA / GPRC5D / CD38 tetraspecific binder molecule indicated in FIG. 3. Configuration Bl : FIG. 3 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. A first modified heavy chain is configured from N- terminal to C-terminal as: i) BCMA heavy chain variable region (VH), ii) a first constant Ig domain of a heavy chain (CHI), iii) a second constant Ig domain of a heavy chain (CH2), iv) a mutated third Ig domain of a heavy chain (CH3) comprising KiH knob substitutions, v) GPRC5D VH, and vi) CHI. A second modified heavy chain is configured from N-terminal to C- terminal as: i) CD3 VH, ii) CHI, iii) CH2 iv) a mutated CH3 comprising KiH hole substitutions, v) CD38 VH, and vi) CHI. A first light chain is configured from N-terminal to C-terminal as-n-either: i-a) BCMA light chain variable region (VL) or i-b) CD3 VL, and ii) a constant Ig domain of a light chain (CL - K set 1). A second light chain is configured from N-terminal to C-terminal as: i) GPRC5D VL and ii) CL - K set 2. A third light chain is configured from N-terminal to C- terminal as: i) CD3 VL and ii) CL - K set 1. A fourth light chain is configured from N-terminal to C-terminal as either: i-a) CD38 VL or i-b) CD3 VL, and ii) CL - K set 1. Two light chains are paired with each modified heavy chain with the respective VH and VL regions arranged to form a BCMA binding moiety, a GPRC5D binding moiety, a CD3 binding moiety, and a CD38 binding moiety. In some embodiments, the tetraspecific binding molecule is configured according to one of the twenty-four possible configurations for an anti- CD3 / BCMA / GPRC5D / SLAMF7 tetraspecific indicated as Configurations C1-C24 in Table 12. In some embodiments, the tetraspecific binding molecule is configured according to the configuration for an anti-CD3 / BCMA / GPRC5D / SLAMF7 tetraspecific indicated in FIG. 4. Configuration Cl : FIG. 4 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. A first modified heavy chain is configured from N-terminal to C-terminal as: i) BCMA VH, ii) CHI, iii) CH2, iv) a mutated CH3 comprising KiH knob substitutions, v) GPRC5D VH, and vi) CHI. A second modified heavy chain is configured from N-terminal to C-terminal as: i) CD3 VH, ii) CHI, iii) CH2 iv) a mutated CH3 comprising KiH hole substitutions, v) SLAMF7 VH, and vi) CHI. A first light chain is configured from N-terminal to C-terminal as either: i-a) BCMA VL or i-b) CD3 VL, and ii) CL - K set 1. A second light chain is configured from N-terminal to C-terminal as: i) GPRC5D VL and ii) CL - K set 2. A third light chain is configured from N-terminal to C- terminal as: i) CD3 VL and ii) CL - K set 1. A fourth light chain is configured from N-terminal to C-terminal as either: i-a) SLAMF7 VL or i-b) CD3 VL, and ii) CL - K set 1. Two light chains are paired with each modified heavy chain with the respective VH and VL regions arranged to form a BCMA binding moiety, a GPRC5D binding moiety, a CD3 binding moiety, and a SLAMF7 binding moiety. In some embodiments, the tetraspecific binding molecule is configured according to one of the twenty-four possible configurations for an anti- CD3 / BCMA / CD38 / SLAMF7 tetraspecific indicated as Configurations D1-D24 in Table 13. In some embodiments, the tetraspecific binding molecule is configured according to the configuration for an anti-CD3 / BCMA / CD38 / SLAMF7 tetraspecific indicated in FIG. 6. Configuration D2: FIG. 6 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. A first modified heavy chain is configured from N-terminal to C-terminal as: i) BCMA VH, ii) CHI, iii) CH2, iv) a mutated CH3 comprising KiH knob substitutions, v) SLAMF7 VH, and vi) CHI. A second modified heavy chain is configured from N-terminal to C-terminal with: i) CD3 VH, ii) CHI, iii) CH2 iv) amutated CH3 comprising KiH hole substitutions, v) CD38 VH, and vi) CHI. A first light chain is configured from N-terminal to C-terminal as either : i-a) BCMA VL or i-b) CD3 VL, and ii) CL - K set 1. A second light chain is configured from N-terminal to C-terminal as either: i-a) SLAMF7 VL or i-b) CD3 VL, and ii) CL - K set 1. A third light chain is configured from N- terminal to C-terminal as: i) CD3 VL and ii) CL - K set 1. A fourth light chain is configured from N-terminal to C-terminal as either: i) CD38 VL or CD3 VL, and ii) CL - K set 1. Two light chains are paired with each modified heavy chain with the respective VH and VL regions arranged to form a BCMA binding moiety, a SLAMF7 binding moiety, a CD3 binding moiety, and a CD38 binding moiety. In some embodiments, the tetraspecific binding molecule is configured according to one of the twenty-four possible configurations for an anti- CD3 / GPRC5D / SLAMF7 / CD38 tetraspecific indicated as Configurations E1-E24 in Table 14. In some embodiments, the tetraspecific binding molecule is configured according to the configuration for an anti-CD3 / GPRC5D / SLAMF7 / CD38 tetraspecific indicated in FIG. 5. Configuration El 5: FIG. 5 shows a diagram of a tetraspecific binder molecule formed from six polypeptide sequences in an IgG-Fab configuration. A first modified heavy chain is configured from N-terminal to C-terminal as: i) SLAMF7 VH, ii) CHI, iii) CH2, iv) a mutated CH3 comprising KiH knob substitutions, v) GPRC5D VH, and vi) CHI. A second modified heavy chain is configured from N-terminal to C-terminal as: i) CD3 VH, ii) CHI, iii) CH2 iv) a mutated CH3 comprising KiH hole substitutions, v) CD38 VH, and vi) CHI. A first light chain is configured from N-terminal to C-terminal as either: i-a) SLAMF7 VL or i-b) CD3 VL, and ii) CL - K set 1. A second light chain is configured from N-terminal to C-terminal as: i) GPRC5D VL and ii) CL - K set 2. A third light chain is configured from N-terminal to C-terminal as: i) CD3 VL and ii) CL - K set 1. A fourth light chain is configured from N-terminal to C-terminal as either: i-a) CD38 VL or i-b) CD3 VL, and ii) CL - K set 1. Two light chains are paired with each modified heavy chain with the respective VH and VL regions arranged to form a SLAMF7 binding moiety, a GPRC5D binding moiety, a CD3 binding moiety, and a CD38 binding moiety. In some embodiments, the tetraspecific binding molecule is configured according to one of the twenty -four possible configurations for an anti-CD3 / BCMA / CD38 / FCRH5 tetraspecific indicated as Configurations F1-F24 in Table 15. In some embodiments, the tetraspecific binding molecule is configured according to the configuration for an anti-CD3 / BCMA / GPRC5D / FCRH5 tetraspecific indicated in FIG. 7. In some embodiments, the tetraspecific binding molecule is configured according to one of the twenty-four possible configurations for an anti- CD3 / BCMA / SLAMF7 / FCRH5 tetraspecific indicated as Configurations G1-G24 in Table 16. In some embodiments, the tetraspecific binding molecule is configured according to one of the twenty -four possible configurations for an anti-CD3 / GPRC5D / CD38 / FCRH5 tetraspecificindicated as Configurations H1-H24 in Table 17. In some embodiments, the tetraspecific binding molecule is configured according to one of the twenty-four possible configurations for an anti-CD3 / GPRC5D / SLAMF7 / FCRH5 tetraspecific indicated as Configurations 11-124 in Table 18. In some embodiments, the tetraspecific binding molecule is configured according to one of the twenty-four possible configurations for an anti-CD3 / CD38 / SLAMF7 / FCRH5 tetraspecific indicated as Configurations J1-J24 in Table 19.

[0098] In some embodiments, the two modified heavy chains are connected in a hinge region by a variable number of disulfide bonds: 2 for IgGl and IgG4, 4 for IgG2 and 11 for IgG3. In some embodiments, a light chain of the IgGl-format multispecific binder molecule is connected to the modified heavy chain by a disulfide bond between the last cysteine residue of the light chain and the fifth cysteine residue of the modified heavy chain. In some embodiments, the light chain comprising a GPRC5D VL domain comprises a CL - K set 2 sequence. In some embodiments, the light chain comprising a BCMA VL domain comprises a CL - K set 1 sequence. In some embodiments, the light chain comprising an FcRH5 VL domain comprises a CL - K set 1 sequence. In some embodiments, the light chain comprising a CD38 VL domain comprises a CL - K set 1 sequence. In some embodiments, the light chain comprising a SLAMF7 VL domain comprises a CL - K set 1 sequence. In some embodiments, the light chain comprising a CD3 VL domain comprises a CL - K set 1 sequence. In some embodiments, the CL - K set 1 sequence of i) the light chain comprising the BCMA VL domain, ii) the light chain comprising the CD38 VL domain, iii) the light chain comprising the SLAMF7 VL domain, and iv) the light chain comprising the CD3 VL domain, comprise identical CL - K set 1 sequences. In some embodiments, the CL - K set 1 sequence of i) the light chain comprising the BCMA VL domain, ii) the light chain comprising the FcRH5 VL domain, and iii) the light chain comprising the CD3 VL domain, comprise identical CL - K set 1 sequences.

[0099] In some embodiments, a high affinity GPRC5D binding moiety is formed by pairing the GPRC5D VH domain with a GPRC5D VL domain. In some embodiments, a high affinity BCMA binding moiety is formed by pairing the BCMA VH domain with a BCMA VL domain. In some embodiments, a high affinity BCMA binding moiety is formed by pairing the BCMA VH domain with a CD3 VL domain. In some embodiments, a high affinity FcRH5 binding moiety is formed by pairing the FcRH5 VH domain with an FcRH5VL domain. In some embodiments, a high affinity FcRH5 binding moiety is formed by pairing the FcRH5 VH domain with a CD3 VL domain. In some embodiments, a high affinity CD38 binding moiety is formed by pairing the CD38 VH domain with a CD38 VL domain. In some embodiments, a high affinity CD38 binding moiety is formed by pairing the CD38 VH domain with a CD3 VL domain. In some embodiments, a high affinity SLAMF7 binding moiety is formed by pairing theSLAMF7 VH domain with a SLAMF7 VL domain. In some embodiments, a high affinity SLAMF7 binding moiety is formed by pairing the SLAMF7 VH domain with a CD3 VL domain. In some embodiments, a high affinity CD3 binding moiety is formed by pairing the CD3 VH domain with a CD3 VL domain. In some embodiments, as illustrated as non-limiting examples in FIG. 1-FIG. 12, multispecific binder molecules comprise six polypeptide chains, each polypeptide chain comprising one or more regions of amino acids sequence which are not identical to any of the other five polypeptide chain sequences. In some embodiments, the six polypeptide chains comprise one CD3 light chain. In some embodiments, the six polypeptide chains comprise two CD3 light chains. In some embodiments, the two CD3 light chains comprises identical amino acid sequences. In some embodiments, the six polypeptide chains comprise three CD3 light chains. In some embodiments, the three CD3 light chains comprises identical amino acid sequences. In some embodiments, two CD3 light chains, or the three CD3 light chains are identical. In some embodiments, the multispecific binder molecule comprises a CD3 light chain that pairs a CD3 VL domain together with a CD3 VH domain residing on a modified heavy chain to form a CD3 binding moiety. In some embodiments, the multispecific binder molecule comprises a first CD3 light chain that pairs a CD3 VL domain together with a CD3 VH domain residing on a first modified heavy chain to form a CD3 binding moiety, and a second CD3 light chain that pairs a CD3 VL domain together with a BCMA VH domain residing on a second modified heavy chain to form a BCMA binding moiety. In some embodiments, the multispecific binder molecule comprises a first CD3 light chain that pairs a CD3 VL domain together with a CD3 VH domain residing on a modified heavy chain to form a CD3 binding moiety, and a second CD3 light chain that pairs a CD3 VL domain together with a CD38 VH domain residing on a modified heavy chain to form a CD38 binding moiety. In some embodiments, the multispecific binder molecule comprises a first CD3 light chain that pairs a CD3 VL domain together with a CD3 VH domain residing on a modified heavy chain to form a CD3 binding moiety, and a second CD3 light chain that pairs a CD3 VL domain together with a SLAMF7 VH domain residing on a modified heavy chain to form a SLAMF7 binding moiety. In some embodiments, the multispecific binder molecule comprises two modified heavy chains, two identical CD3 light chains, and two light chains not identical to CD3 light chains. In some embodiments, the multispecific binder molecule comprises two modified heavy chains, three identical CD3 light chains, and one light chain not identical to CD3 light chains. In some embodiments, the CD3 light chains comprising a CD3 VL domain may be paired with any of: i) a CD3 VH domain, ii) a BCMA VH domain, iii) a CD38 VH domain, iv) a SLAMF7 VH domain, or v) an FcRH5 VH domain.

[0100] In some cases, an antibody-based multispecific binder molecule comprises one or more mutations in a framework region, e.g., in the CHI domain, CH2 domain, CH3 domain, hinge region, or a combination thereof. In some instances, the one or more mutations are to stabilize the antibody. In some instances, the one or more mutations are to increase half-life. In some instances, the one or more mutations are to modulate Fc receptor interactions. In some instances, the one or more mutations are to reduce or eliminate Fc effector functions such as FcyR, antibody-dependent cell-mediated cytotoxicity (ADCC), or complement-dependent cytotoxicity (CDC). In additional instances, the one or more mutations are to modulate glycosylation.

[0101] In some embodiments, the one or more mutations are located in the Fc region. In some embodiments, the one or more mutations are located in the CHI region. In some embodiments, the one or more mutations are located in the CH2 region. In some embodiments, the one or more mutations are located in the CH3 region.

[0102] In some embodiments, the human IgG constant region is modified to alter antibodydependent cellular cytotoxicity (ADCC) and / or complement-dependent cytotoxicity (CDC), e.g., with an amino acid modification described in Natsume et al., 2008 Cancer Res, 68(10): 3863-72; Idusogie et al., 2001 J Immunol, 166(4): 2571-5; Moore et al., 2010 mAbs, 2(2): 181- 189; Lazar et al., 2006 PNAS, 103(11): 4005-4010, Shields et al., 2001 JBC, 276( 9): 6591- 6604; Stavenhagen et al., 2007 Cancer Res, 67(18): 8882-8890; Stavenhagen et al., 2008 Advan. Enzyme Regul., 48: 152-164; Alegre et al, 1992 J Immunol, 148: 3461-3468; Urban et al., 2021 Front Immunol. Nov 25;12:724361; Zhou et al., 2020 MAbs. Jan-Dec;12(l): 1814583; Reviewed in Kaneko and Niwa, 2011 Biodrugs, 25(1): 1-11.

[0103] In some embodiments, the heavy chain constant regions of a multispecific binding molecule antibody heavy chain described herein is categorized as IgGl, IgG2, or IgG4. In some embodiments, the IgGl, IgG2, or IgG4 is human IgGl, human IgG2, or human IgG4. In some embodiments, the IgGl, IgG2, or IgG4 is mouse IgGl, mouse IgG2, or mouse IgG4. In some embodiments, the IgGl, IgG2, or IgG4 is rat IgGl, rat IgG2, or rat IgG4. In some embodiments, the constant regions of the multispecific binding molecule antibody heavy chain are human IgG4 wild-type. In some embodiments, the constant regions of the multispecific binding molecule antibody heavy chain are human IgGl wild-type. In some embodiments, the constant regions of the multispecific binding molecule antibody heavy chain are human IgGl wild-type having a REEM allotype sequence. In some embodiments, the constant regions of the multispecific binding molecule antibody heavy chain are human IgG2 wild-type. In some embodiments, the constant regions of the multispecific binding molecule antibody heavy chain are human IgGl- 3M wild-type. In some embodiments, the constant regions of the multispecific binding molecule antibody heavy chain are human IgGl-3M wild-type having a REEM allotype sequence.

[0104] In some embodiments, constant regions of the multispecific binding molecule antibody heavy chain have one or more mutations. In some embodiments, the one or more mutations comprise one or more amino acid substitutions, insertions, or deletions. In some embodiments, a variant or modified heavy chain comprises a mutation that reduced FcyR binding. In some embodiments, a variant or modified IgGl heavy chain comprises a mutation that reduced FcyR binding. In some embodiments, the constant regions of the multispecific binding molecule antibody heavy chain are human IgG4 having a S228P substitution. In some embodiments, the constant regions of the multispecific binding molecule antibody heavy chain are human IgGl having a L234A substitution. In some embodiments, the constant regions of the multispecific binding molecule antibody heavy chain are human IgGl having a L235A substitution. In some embodiments, the constant regions of the multispecific binding molecule antibody heavy chain are human IgGl having L234A and L235A substitutions. In some embodiments, the constant regions of the multispecific binding molecule antibody heavy chain are human IgGl having L234A, L235A, and P329G substitutions. In some embodiments, the constant regions of the multispecific binding molecule antibody heavy chain are human IgGl having L234A, L235A, and P329S substitutions. In some embodiments, the constant regions of the multispecific binding molecule antibody heavy chain are human IgGl having L234A, L235A, and P329G substitutions. In some embodiments, the constant regions of the multispecific human IgGl wildtype having a REEM allotype sequence and L234A, L235A, and P329G substitutions. In some embodiments, the CH2 domain of the multispecific binder molecule comprises L234A, L235A, and P329G substitutions. In some embodiments, the L234A, L235A, and P329G substitutions decrease binding of the multispecific binder molecule to Fc gamma receptors and to complement components preventing Fc gamma receptor-mediated activation of innate immune effector cells including NK cells, monocytes, macrophages, and neutrophils. In some embodiments, the CH2 domain of the multispecific binder molecule comprises L234A, L235A, and P329S substitutions. In some embodiments, the CH2 domain of the multispecific binder molecule comprises an N297A substitution. In some embodiments, a substitution in a heavy chain constant region in the multispecific binder molecule is referred to as a mutation. In some embodiments, the multispecific binder molecule comprises a first heavy chain and a second heavy chain. In some embodiments, the first heavy chain, the second heavy chain, or the first and second heavy chains are modified heavy chains or variant heavy chains. In some embodiments, one or more amino acid substitutions in the first, second, or first and second heavy chains aid in heterodimer formation of the multispecific binder molecule comprising at least two heavy chains. In some embodiments, the CH3 domain of the multispecific binder molecule comprises substitutions which contribute to forming a knob structure for knob-in-hole(KiH) technology for use in aiding in heterodimerization of modified heavy chains. In some embodiments, the knob substitutions comprise either S354C, T366W, or S354C and T366W. In some embodiments, the CH3 domain of the multispecific binder molecule comprises substitutions which contribute to forming a hole structure for KiH technology for use in aiding in heterodimerization of modified heavy chains. In some embodiments, the knob substitutions comprise Y349C, T366S, L368A, Y407V, or any combination thereof. In some embodiments, a first heavy chain comprising KiH knob mutations is paired with a second heavy chain comprising KiH hole mutations to aid in heterodimerization of the separate modified heavy chains. Representative heavy chain constant region sequences used in antibody heavy chains described herein are listed in Table 8. In some embodiments, the heavy chain constant region sequences of the multispecific binder molecule heavy chain comprise an amino acid sequence selected from a sequence of SEQ ID NOs: 49-68. In some embodiments, a CHI region present in Table 8 is positioned C-terminal to a VH domain described here in the multispecific binder molecule. In some embodiments, a CH2 region present in Table 8 is positioned C-terminal to a CHI domain in the multispecific binder molecule. In some embodiments, a CH3 region present in Table 8 is positioned C-terminal to a CH2 domain in the multispecific binder molecule. A representative light chain constant region sequence used in antibody light chains described herein are listed in Table 9.

[0105] In some embodiments, the binding moieties of the multispecific binding molecule are linked to other elements of the molecule by linker sequences. In some embodiments, a linker sequence is positioned between a first binding moiety and a second binding moiety. In some embodiments, a linker sequence is positioned between a first binding moiety and a second unit of the first binding moiety. In some embodiments, a linker sequence is positioned between a first binding moiety and an antibody constant region. In some embodiments, a linker sequence is positioned between a second binding moiety and an antibody constant region. In some embodiments, a linker sequence is positioned between a third binding moiety and an antibody constant region. In some embodiments, a linker sequence is positioned between an immune cell engager and an antibody constant region. In some embodiments, a linker sequence is positioned between a first binding moiety and a CHI region. In some embodiments, a linker sequence is positioned between a first binding moiety and a CH2 region. In some embodiments, a linker sequence is positioned between a second binding moiety and a CHI region. In some embodiments, a linker sequence is positioned between a second binding moiety and a CH2 region. In some embodiments, a linker sequence is positioned between a third binding moiety and a CHI region. In some embodiments, a linker sequence is positioned between a third binding moiety and a CH2 region. In some embodiments, a linker sequence is positionedbetween a first binding moiety and a CHI region. In some embodiments, a linker sequence is positioned C-terminal to a CH3 domain. In some embodiments, a VH and CHI domain are linked to a linker C-terminal to a CH3 domain comprising a single modified heavy chain. In some embodiments, the linker sequence positioned between a binding moiety and an antibody constant region comprises one or more sequences listed in Table 21.Table 8: Heavy chain constant region sequencesTable 9: Light chain constant region sequencesTable 10: Anti-CD3 / BCMA / GPRC5D / FCRH5 tetraspecific configurationsTable 11: Anti-CD3 / BCMA / GPRC5D / CD38 tetraspecific configurationsTable 12: Anti-CD3 / BCMA / GPRC5D / SLAMF7 tetraspecific configurationsTable 13: Anti-CD3 / BCMA / CD38 / SLAMF7 tetraspecific configurationsTable 14: Anti-CD3 / GPRC5D / SLAMF7 / CD38 tetraspecific configurationsTable 15: Anti-CD3 / BCMA / CD38 / FCRH5 tetraspecific configurationsTable 16: Anti-CD3 / BCMA / SLAMF7 / FCRH5 tetraspecific configurationsTable 17: Anti-CD3 / GPRC5D / CD38 / FCRH5 tetraspecific configurationsTable 18: Anti-CD3 / GPRC5D / SLAMF7 / FCRH5 tetraspecific configurationsTable 19: Anti-CD3 / CD38 / SLAMF7 / FCRH5 tetraspecific configurationsTable 20: Leader Sequences for use with heavy chains and light chainsTable 21: Linker Sequences for use in modified heavy chains and / or modified light chains

[0106] In some embodiments, the antibody-based multispecific binder molecule comprises one, two, three, or four light chains. In some embodiments, the antibody-based multispecific binder molecule comprises four light chains. In some embodiments, the one or more light chains comprise one or more light chain constant regions. In some embodiments, the light chain constant region is a kappa light chain constant region. In some embodiments, the light chain constant region is a lambda light chain constant region. In some embodiments, the light chain constant region is a human kappa light chain constant region. In some embodiments, the light chain constant region is a human lambda light chain constant region. In some embodiments, the light chain constant region is a mouse kappa light chain constant region. In some embodiments, the light chain constant region is a mouse lambda light chain constant region. In some embodiments, the light chain constant region is a rat kappa light chain constant region. In some embodiments, the light chain constant region is a rat lambda light chain constant region. In some embodiments, amino acid sequences of the human kappa light chain constant region is listed in Table 9. In some embodiments, the human kappa light chain constant region comprises an amino acid sequence of SEQ ID NO: 69.

[0107] In some embodiments, an antibody-based multispecific binder molecule described herein comprises a full-length antibody, comprising a heavy chain (HC) and a light chain (LC). In some embodiments, the HC comprises about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 21-34. In some embodiments, the HC comprises at least 80%, at least 85%, at least 90%, or at least 95% sequence identity sequence identity to a sequence selected from SEQ ID NOs: 28-34. In some embodiments, the LC comprises about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 35-46. In some embodiments, the LC comprises at least 80%, at least 85%, at least 90%, or at least 95% sequence identity sequence identity to a sequence selected from SEQ ID NOs: 35-46. In some cases, the heavy chain (HC) comprises an amino acid sequence selected from a sequence listed in Table 5. In some cases, the light chain (LC) comprises an amino acid sequence selected from a sequence listed in Table 6. In some cases, two modified heavy chains comprising a sequence listed inTable 5 and at least one LC comprising a sequence listed in Table 6 are paired together to form the antibody-based multispecific binder molecule.

[0108] In some embodiments, an antibody-based multispecific binder molecule described herein comprises at least four VH domains and at least four VL domains. In some embodiments, at least one of the four VH domains comprises about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 1-11. In some embodiments, at least two of the four VH domains each comprises about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 1- 11. In some embodiments, at least three of the four VH domains each comprises about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 1-11. In some embodiments, at least one of the four VH domains comprises about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to the VH domain region of a sequence selected from SEQ ID NOs: 21-34. In some embodiments, at least two of the four VH domains each comprise about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to a VH domain region of a sequence selected from SEQ ID NOs: 21- 34. In some embodiments, at least three of the four VH domains each comprise about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to a VH domain region of a sequence selected from SEQ ID NOs: 21-34. In some embodiments, at least one of the four VL domains comprises about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 12-20. In some embodiments, at least two of the four VL domains each comprise about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 12-20. In some embodiments, at least three of the four VL domains each comprise about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to a sequence selected from SEQ ID NOs: 12- 20. In some embodiments, at least one of the four VL domains comprises about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to a VL domain region of a sequence selected from SEQ ID NOs: 35-46. In some embodiments, at least two of the four VL domains each comprise about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to a VL domain region of a sequence selected from SEQ ID NOs: 35-46. In some embodiments, at least three of the four VL domains each comprise about 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% sequence identity to a VL domain region of a sequence selected from SEQ ID NOs: 35-46. In some embodiments, an antigen binding regions of the multispecific binding molecule comprises a sequence of great than 80 amino acids that is 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% identical to a portion of a SEQ ID NO: 47. In some embodiments, an antigen binding regions of the multispecific binding molecule comprises a sequence of greatthan 80 amino acids that is 80%, 85%, 90%, 95%, 96% 97%, 98%, 99%, or 100% identical to a portion of a SEQ ID NO: 48.Production and Manufacture of Antibodies or Antigen-Binding Fragments Thereof

[0109] In some embodiments, polypeptides described herein (e.g., antibodies or antigen-binding fragments thereof) are produced using any method known in the art to be useful for the synthesis of polypeptides (e.g., antibodies), in particular, by chemical synthesis or by recombinant expression, and are preferably produced by use of a recombinant expression technique.

[0110] In some instances, an antibody or antigen-binding fragment thereof is expressed recombinantly, and the nucleic acid encoding the antibody or its antigen-binding fragment is assembled from chemically synthesized oligonucleotides (e.g., as described in Kutmeier et al., 1994, BioTechniques 17:242), which involves the synthesis of overlapping oligonucleotides containing portions of the sequence encoding the antibody, annealing and ligation of those oligonucleotides, and then amplification of the ligated oligonucleotides by PCR.

[0111] Alternatively, a nucleic acid molecule encoding an antibody is optionally generated from a suitable source (e.g., an antibody cDNA library, or cDNA library generated from any tissue or cells expressing the immunoglobulin) by PCR amplification using synthetic primers hybridizable to the 5' and 3' ends of the sequence or by cloning using an oligonucleotide specific for the particular nucleic acid sequence.

[0112] In some instances, an antibody or its binding is optionally made by generating monoclonal antibodies, e.g., as described by Kohler and Milstein (1975, Nature 256:495-497) or, as described by Kozbor et al. (1983, Immunology Today 4:72) or Cole et al. (1985 in Monoclonal Antibodies and Cancer Therapy, Alan R. Liss, Inc., pp. 77-96). Alternatively, a clone encoding at least the Fab portion of the antibody is optionally obtained by screening Fab expression libraries (e.g., as described in Huse et al., 1989, Science 246: 1275-1281) for clones of Fab fragments that bind the specific antigen or by screening antibody libraries (See, e.g., Clackson et al., 1991, Nature 352:624; Hane et al., 1997 Proc. Natl. Acad. Sci. USA 94:4937.

[0113] In some embodiments, techniques developed for the production of “chimeric antibodies” (Morrison et al., 1984, Proc. Natl. Acad. Sci. 81 :851-855; Neuberger et al., 1984, Nature 312:604-608; Takeda et al., 1985, Nature 314:452-454) by splicing genes from a mouse antibody molecule of appropriate antigen specificity together with genes from a human antibody molecule of appropriate biological activity are used. A chimeric antibody is a molecule in which different portions are derived from different animal species, such as those having a variable region derived from a murine monoclonal antibody and a human immunoglobulin constant region, e.g., humanized antibodies.

[0114] In some embodiments, techniques described for the production of single chain antibodies (U.S. Pat. No. 4,694,778; Bird, 1988, Science 242:423-42; Huston et al., 1988, Proc. Natl. Acad. Sci. USA 85:5879-5883; and Ward et al., 1989, Nature 334:544-54) are adapted to produce single chain antibodies. Single chain antibodies are formed by linking the heavy and light chain fragments of the Fv region via an amino acid bridge, resulting in a single chain polypeptide. Techniques for the assembly of functional Fv fragments in E. coli are also optionally used (Skerra et al., 1988, Science 242: 1038-1041).

[0115] In some embodiments, a nucleic acid sequence encodes the antibodies disclosed herein. In some embodiments, the polynucleotide sequence encoding the antibodies is operatively coupled to a eukaryotic regulatory sequence. In some embodiments, a cell comprises the nucleic acid sequence. In some embodiments, a cell comprises a nucleic acid encoding the antibodies disclosed herein. In some embodiments, the cell comprises a prokaryotic cell. In some embodiments, the prokaryotic cell is an Escherichia coli cell. In some embodiments, the cell comprises a eukaryotic cell. In some embodiments, the eukaryotic cell is a Chines Hamster Ovary (CHO) cell, a HEK293 cell, a BHK cell, an NSO murine myeloma cell, or a PER.C6® human cell. In some embodiments, an expression vector comprising the nucleotide sequence of an antibody or the nucleotide sequence of an antibody is transferred to a host cell by conventional techniques (e.g., electroporation, liposomal transfection, and calcium phosphate precipitation), and the transfected cells are then cultured by conventional techniques to produce the antibody. In specific aspects, the expression of the antibody is regulated by a constitutive, an inducible or a tissue, specific promoter. Standard cell lines and methods for the production of antibodies from a large-scale cell culture are known in the art. See e.g., Li et al., “Cell culture processes for monoclonal antibody production.” Mabs. 2010 Sep-Oct; 2(5): 466-477.

[0116] In certain aspects, described herein is a method of making antibodies comprising culturing a cell comprising a nucleic acid encoding a antibodies under conditions in vitro sufficient to allow production and secretion of the antibodies. In some embodiments, antibodies are harvested from the cell culture medium. The harvesting can further comprise one or more purification steps to remove live cells, cellular debris, non-antibody proteins or polypeptides, undesired salts, buffers, and medium components. In certain aspects, the additional purification step(s) include centrifugation, ultracentrifugation, protein A, protein G, protein A / G, or protein L purification, and / or ion exchange chromatography.Non-antibody based multi-specific binders

[0117] In some aspects, the multi-specific binder comprises a non-antibody based binder that binds to a tumor associated antigen or binds to a molecule expressed on an immune effector cell.In some embodiments, the tumor associated antigen is GPRC5D, BCMA, FcRH5, CD38, or SLAMF7. In some embodiments, the molecule expressed on an immune effector cell is CD3. In some embodiments, the molecule expressed on an immune effector cell is one of the elements comprising the CD3 receptor complex. In some embodiments, the multi-specific binder comprises one or more non-antibody based binders and one or more antibody based binders. In some embodiments, the multi-specific binder comprises one non-antibody based binder and at least one antibody based binder. In some embodiments, the multi-specific binder comprises two non-antibody based binders. In some embodiments, the multi-specific binder comprises two non-antibody based binders and at least one antibody based binder. In some embodiments, the multi-specific binder comprises three non-antibody based binders. In some embodiments, the multi-specific binder comprises three non-antibody based binders and one antibody based binder. In some embodiments, the multi-specific binder comprises four non-antibody based binders. In some embodiments, the multi-specific binder comprises a non-antibody based binder that binds GPRC5D. In some embodiments, the multi-specific binder comprises a non-antibody based binder that binds BCMA. In some embodiments, the multi-specific binder comprises a non-antibody based binder that binds FcRH5. In some embodiments, the multi-specific binder comprises a non-antibody based binder that binds CD38. In some embodiments, the multispecific binder comprises a non-antibody based binder that binds SLAMF7. In some embodiments, the multi-specific binder comprises a non-antibody based binder that binds CD3. In some embodiments, the multi-specific binder comprises two non-antibody based binders, each non-antibody based binder capable of binding specifically to any one of GPRC5D, BCMA, FcRH5, CD38, SLAMF7, or CD3. In some embodiments, the multi-specific binder comprises three non-antibody based binders, each non-antibody based binder capable of binding specifically to any one of GPRC5D, BCMA, FcRH5, CD38, SLAMF7, or CD3. In some embodiments, the multi-specific binder comprises four non-antibody based binders, each nonantibody based binder capable of binding specifically to any one of GPRC5D, BCMA, FcRH5, CD38, SLAMF7, or CD3. In some embodiments, the multi-specific binder comprises four nonantibody based binders comprising: i) a GPRC5D binding moiety, ii) a BCMA binding moiety, iii) an FcRH5 binding moiety, and iv) a CD3 binding moiety. In some embodiments, the multispecific binder comprises four non-antibody based binders comprising: i) a GPRC5D binding moiety, ii) a BCMA binding moiety, iii) a CD38 binding moiety, and iv) a CD3 binding moiety. In some embodiments, the multi-specific binder comprises four non-antibody based binders comprising: i) a GPRC5D binding moiety, ii) a BCMA binding moiety, iii) a SLAMF7 binding moiety, and iv) a CD3 binding moiety. In some embodiments, the multi-specific binder comprises four non-antibody based binders comprising: i) a GPRC5D binding moiety, ii) aSLAMF7 binding moiety, iii) a CD38 binding moiety, and iv) a CD3 binding moiety. In some embodiments, the multi-specific binder comprises four non-antibody based binders comprising: i) a SLAMF7 binding moiety, ii) a BCMA binding moiety, iii) a CD38 binding moiety, and iv) a CD3 binding moiety. In some embodiments, the GPRC5D binding moiety enhances binding of the multispecific binder molecule to plasma B cells. In some embodiments, the GPRC5D binding moiety enhances binding of the multispecific binder molecule to malignant plasma B cells. In some embodiments, the BCMA binding moiety enhances binding of the multispecific binder molecule to plasma B cells. In some embodiments, the BCMA binding moiety enhances binding of the multispecific binder molecule to malignant plasma B cells. In some embodiments, the FcRH5 binding moiety enhances binding of the multispecific binder molecule to plasma B cells. In some embodiments, the FcRH5 binding moiety enhances binding of the multispecific binder molecule to malignant plasma B cells. In some embodiments, the CD38 binding moiety enhances binding of the multispecific binder molecule to plasma B cells. In some embodiments, the CD38 binding moiety enhances binding of the multispecific binder molecule to malignant plasma B cells. In some embodiments, the SLAMF7 binding moiety enhances binding of the multispecific binder molecule to plasma B cells. In some embodiments, the SLAMF7 binding moiety enhances binding of the multispecific binder molecule to malignant plasma B cells. In some embodiments, the immune cell binder binds to CD3. In some embodiments, the immune cell engager binds to CD3. In some embodiments, the immune cell binder binding to CD3 functions as an immune cell engager. In some embodiments, the BCMA binding moiety, the GPRC5D binding moiety, and the FcRH5 binding moiety enhance binding of the multispecific binder molecule to yield a higher binding affinity to a population of plasma B cells compared to a multispecific binder molecule comprising any two of a BCMA binding moiety, a GPRC5D binding moiety, or an FcRH5 binding moiety. In some embodiments, the BCMA binding moiety, the GPRC5D binding moiety, and the SLAMF7 binding moiety enhance binding of the multispecific binder molecule to yield a higher binding affinity to a population of plasma B cells compared to a multispecific binder molecule comprising any two of a BCMA binding moiety, a GPRC5D binding moiety, or a SLAMF7 binding moiety. In some embodiments, the BCMA binding moiety, the GPRC5D binding moiety, and the CD38 binding moiety enhance binding of the multispecific binder molecule to yield a higher binding affinity to a population of plasma B cells compared to a multispecific binder molecule comprising any two of a BCMA binding moiety, a GPRC5D binding moiety, or a CD38 binding moiety. In some embodiments, the BCMA binding moiety, the CD38 binding moiety, and the SLAMF7 binding moiety enhance binding of the multispecific binder molecule to yield a higher binding affinity to a population of plasma B cells compared to a multispecific binder molecule comprising any two of a BCMAbinding moiety, a CD38 binding moiety, or a SLAMF7 binding moiety. In some embodiments, the CD38 binding moiety, the GPRC5D binding moiety, and the SLAMF7 binding moiety enhance binding of the multispecific binder molecule to yield a higher binding affinity to a population of plasma B cells compared to a multispecific binder molecule comprising any two of a CD38 binding moiety, a GPRC5D binding moiety, or a SLAMF7 binding moiety.

[0118] Provided herein are non-antibody -based binders that bind to CD3. In some embodiments, the CD3 binding moiety enhances binding of the multispecific binder molecule to T cells, NKT cells, or T cells and NKT cells. In some embodiments, the CD3 binding moiety engages one or more classes of immune cells. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind one or more T cells or NKT cells as binding one or more plasma cells. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind one or more T cells or NKT cells as binding one or more malignant plasma cells. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing any one of BCMA, CD38, FcRH5, SLAMF7, or GPRC5D. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing any two of BCMA, CD38, FcRH5, SLAMF7, or GPRC5D. In some embodiments, the CD3 binding moiety allows the multispecific binder molecule to simultaneously bind to a T cell or an NKT cell and a tumor cells expressing at least three of BCMA, CD38, FcRH5, SLAMF7, or GPRC5D. In some embodiments, the tumor cells are from a hematological cancer. In some embodiments, the tumor cells are from myeloma. In some embodiments, the tumor cells are from multiple myeloma. In some embodiments, the multispecific binder molecule brings T cells closer in proximity to tumor cells. In some embodiments, the multispecific binder molecule brings T cells closer in proximity to tumor cells in a BM microenvironment. In some embodiments, the multispecific binder molecule brings NK cells closer in proximity to tumor cells. In some embodiments, the multispecific binder molecule brings NKT cells closer in proximity to tumor cells.

[0119] Nucleic acid aptamers are short, single-stranded oligonucleotides (ssDNA, ssRNA, or ssXNA) able to bind selectively to a specific target such as a protein, a peptide, a carbohydrate, a toxin, or a live cell. In some embodiments, the tumor associated antigen binding moiety (e.g., GPRC5D binding moiety, BCMA binding moiety, FcRH5 binding moiety, SLAMF7 binding moiety, CD38 binding moiety) and / or the immune cell binding moiety (e.g., CD3 binding moiety) is a nucleic acid aptamer. In some embodiments, the nucleic acid aptamer is based on an oligonucleotide structure with specificity and affinity for GPRC5D, BCMA, FcRH5, CD38, SLAMF7, or CD3 similar to that of an anti-GPRC5D antibody, an anti-BCMA antibody, an anti-FcRH5 antibody, an anti-CD38 antibody, an anti-SLAMF7 antibody, an anti-CD3 antibody, respectively.

[0120] Peptide aptamers are small combinatorial proteins, usually between 5-20 amino acid residues in length, that are capable of selective binding to a specific site or sites on a target molecule. In some embodiments, the tumor associated antigen binding moiety (e.g., GPRC5D binding moiety, BCMA binding moiety, FcRH5 binding moiety, SLAMF7 binding moiety, CD38 binding moiety) and / or the immune cell binding moiety (e.g., CD3 binding moiety) is a peptide aptamer. In some embodiments, the peptide aptamer is based on an peptide structure with specificity and affinity for GPRC5D, BCMA, FcRH5, CD38, SLAMF7, or CD3 similar to that of an anti-GPRC5D antibody, an anti -BCMA antibody, an anti-FcRH5 antibody, an anti- CD38 antibody, an anti-SLAMF7 antibody, an anti-CD3 antibody, respectively. In some embodiments, the peptide aptamer is selected from a peptide aptamer library in which a randomized set of peptide sequences which have been engineered into a stable protein scaffold by screening the library using yeast or mammalian cells or by phage display technology. In some embodiments, the GPRC5D binding peptide aptamer is included as a part of a tetraspecific binder molecule that also binds to at least three of either BCMA, CD38, SLAMF7, or CD3. In some embodiments, the BCMA binding peptide aptamer is included as a part of a tetraspecific binder molecule that also binds to at least three of either GPRC5D, CD38, SLAMF7, or CD3. In some embodiments, the FcRH5 binding peptide aptamer is included as a part of a tetraspecific binder molecule that also binds to at least three of either GPRC5D, BCMA, CD38, SLAMF7, or CD3. In some embodiments, the CD38 binding peptide aptamer is included as a part of a tetraspecific binder molecule that also binds to at least three of either GPRC5D, BCMA, SLAMF7, or CD3. In some embodiments, the SLAMF7 binding peptide aptamer is included as a part of a tetraspecific binder molecule that also binds to at least three of either GPRC5D, CD38, BCMA, or CD3. In some embodiments, the CD3 binding peptide aptamer is included as a part of a tetraspecific binder molecule that also binds to at least three of either GPRC5D, FcRH5, CD38, SLAMF7, or BCMA.

[0121] Designed Ankyrin Repeat Proteins (DARPins) are engineered antibody mimetic proteins derived from an ankyrin repeat binding protein. In some embodiments, non-natural amino acids are incorporated into the DARPin. In some embodiments, the GPRC5D binding moiety is a Designed Ankyrin Repeat Protein (DARPin). In some embodiments, the BCMA binding moiety is a DARPin. In some embodiments, the FcRH5 binding moiety is a DARPin. In some embodiments, the SLAMF7 binding moiety is a DARPin. In some embodiments, the CD38 binding moiety is a DARPin. In some embodiments, the CD3 binding moiety is a DARPin. In some embodiments, the DARPin is selected using either phage or ribosome display. In someembodiments, the GPRC5D binding DARPin is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, FcRH5, SLAMF7, or CD38. In some embodiments, the BCMA binding DARPin is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either GPRC5D, FcRH5, SLAMF7, or CD38. In some embodiments, the FcRH5 binding DARPin is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either GPRC5D, BCMA, SLAMF7, or CD38. In some embodiments, the SLAMF7 binding DARPin is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, GPRC5D, or CD38. In some embodiments, the CD38 binding DARPin is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, SLAMF7, or GPRC5D. In some embodiments, the CD3 binding DARPin is included as a part of a tetraspecific binder molecule that binds to at least three of either BCMA, SLAMF7, FcRH5, GPRC5D, or CD38.

[0122] Affimers are small, engineered proteins which bind to target proteins with affinity in the nanomolar range. In some embodiments, phage display technology is used to select for an affimer that binds to an extracellular region of either GPRC5D, BCMA, FcRH5, SLAMF7, CD38, or CD3. In some embodiments, selecting an affimer using yeast display provides affimer binders that possess one or more post-translational modifications. Identified affimers can be generated using recombinant technology. In some embodiments, use of a bacterial host system to produce a recombinant affimer can yield protein titers in the range of 200-400 mg / L. In some embodiments, one or more affimers are conjugated to a multispecific binder molecule. In some embodiments, one or more affimer sequences are included in a peptide that is used to form a multispecific binder molecule. In some embodiments, the GPRC5D binding moiety is an affimer. In some embodiments, the BCMA binding moiety is an affimer. In some embodiments, the FcRH5 binding moiety is an affimer. In some embodiments, the SLAMF7 binding moiety is an affimer. In some embodiments, the CD38 binding moiety is an affimer. In some embodiments, the CD3 binding moiety is an affimer. In some embodiments, the GPRC5D binding affimer is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, FcRH5, SLAMF7, or CD38. In some embodiments, the BCMA binding affimer is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either GPRC5D, FcRH5, SLAMF7, or CD38. In some embodiments, the FcRH5 binding affimer is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either GPRC5D, BCMA, SLAMF7, or CD38. In some embodiments, the SLAMF7 binding affimer is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, GPRC5D, or CD38. In some embodiments, theCD38 binding affimer is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, SLAMF7, or GPRC5D. In some embodiments, the CD3 binding affimer is included as a part of a tetraspecific binder molecule that binds to at least three of either BCMA, SLAMF7, FcRH5, GPRC5D, or CD38.

[0123] An inhibitor cysteine knot (knottin) is a protein structural motif that contains of one of three folds in a cysteine knot motif. In some embodiments, the knottin comprises a loop region of variable length that is engineered to bind to either GPRC5D, BCMA, FcRH5, SLAMF7, CD38, or CD3. In some embodiments, the GPRC5D binding moiety is a knottin. In some embodiments, the BCMA binding moiety is a knottin. In some embodiments, the FcRH5 binding moiety is a knottin. In some embodiments, the SLAMF7 binding moiety is a knottin. In some embodiments, the CD38 binding moiety is a knottin. In some embodiments, the CD3 binding moiety is a knottin. In some embodiments, the GPRC5D binding knottin is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, FcRH5, SLAMF7, or CD38. In some embodiments, the BCMA binding knottin is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either GPRC5D, FcRH5, SLAMF7, or CD38. In some embodiments, the FcRH5 binding knottin is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either GPRC5D, BCMA, SLAMF7, or CD38. In some embodiments, the SLAMF7 binding knottin is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, GPRC5D, or CD38. In some embodiments, the CD38 binding knottin is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, SLAMF7, or GPRC5D. In some embodiments, the CD3 binding knottin is included as a part of a tetraspecific binder molecule that binds to at least three of either BCMA, SLAMF7, FcRH5, GPRC5D, or CD38.

[0124] An avimer (short or avidity multimer) is an engineered protein capable of specifically binding to particular antigens via multiple binding sites. In some embodiments, the avimer is selected by selecting for optimal binders to either GPRC5D, BCMA, FcRH5, SLAMF7, CD38, or CD3 using phage display to screen an avimer library. In some embodiments, the GPRC5D binding moiety is an avimer. In some embodiments, the BCMA binding moiety is an avimer. In some embodiments, the FcRH5 binding moiety is an avimer. In some embodiments, the SLAMF7 binding moiety is an avimer. In some embodiments, the CD38 binding moiety is an avimer. In some embodiments, the CD3 binding moiety is an avimer. In some embodiments, the GPRC5D binding avimer is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, FcRH5, SLAMF7, or CD38. In some embodiments, the BCMA binding avimer is included as a part of a tetraspecific binder molecule that also bindsto CD3, and at least two of either GPRC5D, FcRH5, SLAMF7, or CD38. In some embodiments, the FcRH5 binding avimer is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either GPRC5D, BCMA, SLAMF7, or CD38. In some embodiments, the SLAMF7 binding avimer is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, GPRC5D, or CD38. In some embodiments, the CD38 binding avimer is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, SLAMF7, or GPRC5D. In some embodiments, the CD3 binding avimer is included as a part of a tetraspecific binder molecule that binds to at least three of either BCMA, FcRH5, SLAMF7, GPRC5D, or CD38.

[0125] Monobodies are synthetic, engineered binding proteins constructed using a fibronectin type III domain (FN3) as a scaffold structure. In some embodiments, a library of monobodies is screened for specific binding to either GPRC5D, BCMA, FcRH5, SLAMF7, CD38, or CD3 using either phage display or yeast display technology. In some embodiments, the monobody is expressed in Escherichia coli (E. coli). In some embodiments, the monobody is expressed in a mammalian cell. In some embodiments, the GPRC5D binding moiety is a monobody. In some embodiments, the BCMA binding moiety is a monobody. In some embodiments, the FcRH5 binding moiety is a monobody. In some embodiments, the SLAMF7 binding moiety is a monobody. In some embodiments, the CD38 binding moiety is a monobody. In some embodiments, the CD3 binding moiety is a monobody. In some embodiments, the GPRC5D binding monobody is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, FcRH5, SLAMF7, or CD38. In some embodiments, the BCMA binding monobody is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either GPRC5D, FcRH5, SLAMF7, or CD38. In some embodiments, the FcRH5 binding monobody is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either GPRC5D, BCMA, SLAMF7, or CD38. In some embodiments, the SLAMF7 binding monobody is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, GPRC5D, or CD38. In some embodiments, the CD38 binding monobody is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, SLAMF7, or GPRC5D. In some embodiments, the CD3 binding monobody is included as a part of a tetraspecific binder molecule that binds to at least three of either BCMA, FcRH5, SLAMF7, GPRC5D, or CD38.

[0126] Anticalins are engineered artificial proteins, not structurally related to antibodies, capable of binding to protein antigens or small molecules. In some embodiments, the GPRC5D binding moiety is an anticalin. In some embodiments, the BCMA binding moiety is an anticalin. In some embodiments, the FcRH5 binding moiety is an anticalin. In some embodiments, theCD38 binding moiety is an anticalin. In some embodiments, the SLAMF7 binding moiety is an anticalin. In some embodiments, the CD3 binding moiety is an anticalin. In some embodiments, the GPRC5D binding anticalin is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, FcRH5, SLAMF7, or CD38. In some embodiments, the BCMA binding anticalin is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either GPRC5D, FcRH5, SLAMF7, or CD38. In some embodiments, the FcRH5 binding anticalin is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either GPRC5D, BCMA, SLAMF7, or CD38. In some embodiments, the SLAMF7 binding anticalin is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, GPRC5D, or CD38. In some embodiments, the CD38 binding anticalin is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, SLAMF7, or GPRC5D. In some embodiments, the CD3 binding anticalin is included as a part of a tetraspecific binder molecule that binds to at least three of either BCMA, FcRH5, SLAMF7, GPRC5D, or CD38.

[0127] Fynomers are small binding proteins comprising a human tyrosine kinase Src Homology 3 (SH3) domain derived from human Fyn. In some embodiments, the GPRC5D binding moiety is a fynomer. In some embodiments, the BCMA binding moiety is a fynomer. In some embodiments, the FcRH5 binding moiety is a fynomer. In some embodiments, the SLAMF7 binding moiety is a fynomer. In some embodiments, the CD38 binding moiety is a fynomer. In some embodiments, the CD3 binding moiety is a fynomer. In some embodiments, the GPRC5D binding fynomer is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, FcRH5, SLAMF7, or CD38. In some embodiments, the BCMA binding fynomer is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either GPRC5D, FcRH5, SLAMF7, or CD38. In some embodiments, the FcRH5 binding fynomer is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either GPRC5D, BCMA, SLAMF7, or CD38. In some embodiments, the SLAMF7 binding fynomer is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, GPRC5D, or CD38. In some embodiments, the CD38 binding fynomer is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, SLAMF7, or GPRC5D. In some embodiments, the CD3 binding fynomer is included as a part of a tetraspecific binder molecule that binds to at least three of either BCMA, FcRH5, SLAMF7, GPRC5D, or CD38.

[0128] Affibodies are small proteins engineered to bind to a target protein antigen with high affinity and selectivity. In some embodiments, affibodies are screened and selected for specific,high affinity binding to either GPRC5D, BCMA, FcRH5, SLAMF7, CD38, or CD3. In some embodiments, the GPRC5D binding moiety is an affibody. In some embodiments, the BCMA binding moiety is an affibody. In some embodiments, the FcRH5 binding moiety is an affibody. In some embodiments, the SLAMF7 binding moiety is an affibody. In some embodiments, the CD38 binding moiety is an affibody. In some embodiments, the CD3 binding moiety is an affibody. In some embodiments, the GPRC5D binding affibody is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, FcRH5, SLAMF7, or CD38. In some embodiments, the BCMA binding affibody is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either GPRC5D, FcRH5, SLAMF7, or CD38. In some embodiments, the FcRH5 binding affibody is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either GPRC5D, BCMA, SLAMF7, or CD38. In some embodiments, the SLAMF7 binding affibody is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, GPRC5D, or CD38. In some embodiments, the CD38 binding affibody is included as a part of a tetraspecific binder molecule that also binds to CD3, and at least two of either BCMA, SLAMF7, or GPRC5D. In some embodiments, the CD3 binding affibody is included as a part of a tetraspecific binder molecule that binds to at least three of either BCMA, FcRH5, SLAMF7, GPRC5D, or CD38.

[0129] In some embodiments, non-antibody based binders are selected by phage display. Using phage display technology, highly variable sequence library are presented as polypeptides on filamentous phage surfaces to enable selection of binders with specificity and high affinity toward a target protein (e.g., GPRC5D, BCMA, FcRH5, SLAMF7, CD38, or CD3). Selection of non-antibody-based binders using phage display involves biopanning. Biopanning includes the exposure of a phage library to a target or a selected region of the target followed by multiple steps of washing, elution, and amplification to obtain and then identify the most suitable binders for the target. In some embodiments, a non-antibody -based binder can be combined with antibody -based binders comprising a second binding moiety, a third binding moiety, and an immune cell engager to form the multispecific binder molecule.Methods for multiple myeloma (MM) treatment using a multispecific binder molecule

[0130] Disclosed herein, in certain aspects, are multispecific binder molecules for use in methods for treating MM. Also disclosed herein, in certain aspects, are multispecific binder molecules for use in methods of inducing an immune response against a tumor cell. Current approaches to treat MM most often do not produce a desired clinical response or lead to a durable desired clinical outcome. In many instance, MM patients relapse following a treatmentdue to antigen escape, clonal evolution, development of tumor resistance, or any combination thereof. Antigen loss of a previously targeted tumor antigen can result in relapse and ineffectiveness of a previously effective treatment. Mechanisms that lead to tumor resistance can be categorized as either tumor intrinsic mechanisms or immune dependent mechanisms. Tumor intrinsic mechanisms include antigenic loss (either biallelic or functional loss) through deletions or mutations in one or more target genes, increased soluble levels of BCMA (in BCMA- targeting therapy), high tumor burden (bone marrow plasma cells (BMPC) of > 60%), and extramedullary disease. Immune-mediated mechanisms of resistance are primarily dependent on T cell fitness and tolerant immune environment. In some embodiments, multispecific binder molecules described herein are able to facilitate immunological synapse formation in heterogeneous populations of MM cells. In some embodiments, multispecific binder molecules described herein are able to facilitate immunological synapse formation in populations of MM cells that are no longer treatment with single or dual targeting therapies. In some embodiments, multispecific binder molecules described herein are able to facilitate efficient immunological synapse formation in populations of MM cells by targeting two or more tumor-specific antigens to bring an engaged T cell in proximity to an MM cell.

[0131] In some embodiments, the multispecific binding molecule engages one or more immune effector cells and binds to a tumor cell. In some embodiments, the CD3 binding arm of the multispecific binder molecule binds to and engages T cells. In some embodiments, the CD3 binding arm of the multispecific binder molecule binds to and engages T cells in a chimeric antigen receptor therapy (CAR-T therapy). In some embodiments, the FcRH5 binding arm of the multispecific binder molecule binds to and engages B cells. In some embodiments, the FcRH5 binding arm of the multispecific binder molecule binds to and engages plasma cells. In some embodiments, the FcRH5 binding arm of the multispecific binder molecule binds to and engages malignant plasma cells. In some embodiments, the FcRH5 binding arm of the multispecific binder molecule binds to and engages MM cells. In some embodiments, the BCMA binding arm of the multispecific binder molecule binds to and engages plasma cells. In some embodiments, the BCMA binding arm of the multispecific binder molecule binds to and engages malignant plasma cells. In some embodiments, the BCMA binding arm of the multispecific binder molecule binds to and engages MM cells. In some embodiments, the multispecific binder molecule targets cell-surface BCMA preferentially versus soluble BCMA. In some embodiments, the GPRC5D binding arm of the multispecific binder molecule binds to and engages plasma cells. In some embodiments, the GPRC5D binding arm of the multispecific binder molecule binds to and engages malignant plasma cells. In some embodiments, the GPRC5D binding arm of the multispecific binder molecule binds to and engages MM cells. Insome embodiments, the CD38 binding arm of the multispecific binder molecule binds to and engages plasma cells. In some embodiments, the CD38 binding arm of the multispecific binder molecule binds to and engages malignant plasma cells. In some embodiments, the CD38 binding arm of the multispecific binder molecule binds to and engages MM cells. In some embodiments, the SLAMF7 binding arm of the multispecific binder molecule binds to and engages plasma cells. In some embodiments, the SLAMF7 binding arm of the multispecific binder molecule binds to and engages malignant plasma cells. In some embodiments, the SLAMF7 binding arm of the multispecific binder molecule binds to and engages MM cells. In some embodiments, the binding to and engaging a T cell and a malignant plasma cell by the multispecific binding molecule forms an immunological synapse. In some embodiments, following formation of the immunological synapse, T cells become activated. In some embodiments, T cell activation results in multispecific binding molecule-dependent killing of plasma cells, MM cells, or both plasma cells and MM cells in the subject. In some embodiments, the multispecific binding molecule-dependent killing is the result of T cell mediated cytokine release. In some embodiments, the multispecific binding molecule-dependent killing is the result of T cell mediated cytotoxicity through granzyme and perforin-induced cell lysis. In some embodiments, the administering produces plasma cell depletion in the subject. In some embodiments, the administering produces MM cell depletion in the subject. In some embodiments, the administering produces plasma cell and MM cell depletion in the subject. In some embodiments, the administering produces a complete depletion of B cells and plasma cells in BM of the subject. In some embodiments, the administering produces a complete depletion of MM cells in BM of the subject. In some embodiments, the cytotoxic action of the multispecific binding molecule is due to T cell engagement. In some embodiments, Fc receptor-mediated ADCC does not contribute to multispecific binding molecule activity.

[0132] The efficacy of immunotherapy for MM treatment depends on the fitness of the immune effector cells. MM is characterized by progressive T-cell dysfunction. Marrow-infiltrating lymphocytes (MIL) in MM are heterogeneous T-cell populations that typically undergo exhaustion characterized by terminal differentiation, loss of effector functions, and expression of inhibitory receptors from suboptimal priming and chronic antigen stimulation in the immunosuppressive BM tumor microenvironment. Efficient targeting of MM cells by administering a multispecific binder molecule described herein to a subject in need thereof lessens the effect of progressive T-cell dysfunction and produces a more effective clinical outcome. In some embodiments, the methods of treatment described herein induce pooling of peripheral blood T cells to the BM-MM tumor microenvironment and enable the selective expansion of tumor-reactive clonotypic CD8+ T cells. In some embodiments, the methods oftreatment described herein induce pooling of peripheral blood T cells to the BM-multiple myeloma tumor microenvironment and enable the selective expansion of tumor-reactive clonotypic CD4+ T cells. In some embodiments, the multispecific binding molecule targeting a combination of tumor antigens provides superior tumor selectivity in MM treatment compared to a single or dual targeting strategy. In some embodiments, superior tumor selectivity reduces inhibition of tumor-specific T effector cells activated by the multispecific binding molecule. In some embodiments, superior tumor selectivity reduces the induction of T cell anergy in the subject. In some embodiments, superior tumor selectivity leads to a lowered extent of induction of Tregs. In some embodiments, superior tumor selectivity produces a lowered extent of BM microenvironment immunosuppression. In some embodiments, the method reduces an extent of immunosuppression in the BM microenvironment. In some embodiments, the method induces T cell activation. In some embodiments, the method induces tumor cell lysis. In some embodiments, the method promotes T cell proliferation. In some embodiments, the method promote CD8+ T cell cytotoxicity toward MM cells. In some embodiments, the method promote CD4+ T cell cytotoxicity toward MM cells.

[0133] In some aspect, the methods for inducing an immune response against a tumor cell described herein comprise contacting the tumor cell with the multispecific binding molecule comprising three distinct tumor antigen binding moieties (a-c) comprising: a) a TNFRSF17 (BCMA) binding moiety, b) a GPRC5D binding moiety, and c) a FcRH5 binding moiety; and d) an immune cell engager. In some embodiments, the contacting induces proximity between the tumor cell and one or more immune effector cells. In some embodiments, the contacting comprises simultaneous or sequential binding of the multispecific binding molecule to an immune effector cell and a tumor cell. In some embodiments, the tumor cells is a myeloma cell. In some embodiments, the tumor cell is a multiple myeloma cell. In some embodiments, the contacting supports formation of a cytolytic immunological synapse between the tumor cell and one or more immune effector cells. In some embodiments, the one or more immune effector cells comprise one or more activated T cells. In some embodiments, the one or more activated T cells release primary cytokines that induce the activation of other immune cell types wherein the other immune cell types comprise macrophages, dendritic cells, monocytes, or any combination thereof. In some embodiments, the other immune cell types produce elevated levels of secondary cytokines, wherein the secondary cytokines comprise IL6, IL 10, IL5, or any combination thereof. In some embodiments, the one or more immune effector cells induce apoptosis in a target tumor cell. In some embodiments, the one or more immune effector cells induce pyroptosis in a target tumor cell. In some embodiments, the one or more immune effector cells release one or more cytotoxic proteases of the granzyme family following the contacting. Insome embodiments, the one or more cytotoxic proteases of the granzyme family comprise Granzyme B (GrB). In some embodiments, the one or more immune effector cells release one or more lytic proteins following the contacting. In some embodiments, the one or more lytic proteins comprise perforin. In some embodiments, the contacting engages a T cell receptor (TCR) on one or more T cells. In some embodiments, the one or more T cells comprise naive T cells, helper T cells, cytotoxic T cells, or any combination thereof. In some embodiments, the one or more T cells receive a co-stimulatory signal resulting in T cell proliferation, differentiation, and survival. In some embodiments, the contacting induces co-stimulation independent polyclonal T-cell activation.

[0134] A subject having an exhausted T cell profile in both the peripheral blood and BM compartments, is less amenable to treatment efficacy with immunostimulatory therapies. In some embodiments, targeting three tumor-associated antigens with a T-cell engaging molecule improves treatment efficacy and prevents treatment-induced T cell exhaustion in the subject. In some embodiments, administering the multispecific binder molecule to the subject allows for a more durable therapeutic benefit while attenuating the risk of treatment-emergent adverse events.

[0135] In some embodiments, the methods for treatment comprise contacting a plurality of cells in the subject with a multispecific binder molecule described herein. In some embodiments, the methods for inducing an immune response against a tumor cell comprise contacting the tumor cell with a multispecific binding molecule described herein. In some embodiments, the methods for treatment comprise administering a therapeutically effective amount of the multispecific binder molecule to a subject in need thereof. In some embodiments, the multispecific binder molecule engages effector immune cells. In some embodiments, administering the multispecific binder molecule brings effector immune cells in proximity to tumor cells. In some embodiments, administering the multispecific binder molecule induces an immune response in the subject directed against tumor cells. In some embodiments, the multispecific binder molecule gains access to the BM microenvironment. In some embodiments, the multispecific binder molecule simultaneously binds an immune effector cell and a tumor cell. In some embodiments, the multispecific binder molecule simultaneously binds a T cell and a tumor cell. In some embodiments, the multispecific binder molecule simultaneously binds an NK cell and a tumor cell. In some embodiments, the multispecific binder molecule simultaneously binds an NKT cell and a tumor cell. In some embodiments, the simultaneous binding creates an immunological synapse. In some embodiments, a specific T cell response directed against MM tumor cells is elicited following the administering. In some embodiments, the administering reducesproliferation of MM plasma cells in the subject. In some embodiments, the administering enhances immune cell cytotoxicity directed against MM plasma cells in the subject.

[0136] In some aspects, a method for treating a cancer in a subject in need thereof described herein comprises administering a therapeutically effective amount of the multispecific binding molecule described herein to the subject. In some embodiments, the cancer is a hematological cancer. In some embodiments, the cancer is myeloma. In some embodiments, the cancer is multiple myeloma. In some embodiments, the therapeutically effective amount provides at least a PR, a VGPR, a CR , or a sCR and reduces a risk of an adverse event in the subject. In some embodiments, the adverse event that has a reduced risk is infection, neutropenia, nervous system disorder, alanine amino-transferase increased, anemia, aspartate amino-transferase increased, hyperglycemia, hyponatremia, a musculo-skeletal and connective tissue disorder, acute renal failure, or thrombocytopenia, or any combination thereof. In some embodiments, the method comprises co-administration with a first-line, second-line, or third-line treatment. In some embodiments, the first-line, second-line, or third-line treatment comprises administering a proteasome inhibitor to the subject. In some embodiments, the proteasome inhibitor comprises bortezomib, carfilzomib, or ixazomib. In some embodiments, the first-line, second-line, or third- line treatment comprises administering an immunomodulatory agent (IMiD) to the subject. In some embodiments, the IMiD comprises thalidomide, lenolidomide, or pomalidomide. In some embodiments, the first-line, second-line, or third-line treatment comprises administering an anti- CD38 monoclonal antibody to the subject. In some embodiments, the subject is determined to be a triple-class refractory MM patient refractory to proteasome inhibitors, IMiDs, and anti-CD38 monoclonal antibody therapies. In some embodiments, the method of treatment described herein comprises administering a multispecific binding molecule described herein as a monotherapy to a triple-class refractory MM subject. In some embodiments, the method of treatment described herein comprises administering a multispecific binding molecule described herein in combination with a separate therapeutic agent to a triple-class refractory MM subject. In some embodiments, the method of treatment described herein comprises administering a multispecific binding molecule described herein to a transplant ineligible subject. In some embodiments, the therapeutically effective amount reduces a risk of the subject developing cytokine release syndrome (CRS) following the administering. In some embodiments, the treatment results in a durable response in the subject. In some embodiments, the treatment improves progress-free survival (PFS) in the subject. In some embodiments, the treatment improves the depth of response in the subject. In some embodiments, the depth of response is measured in a CR rate or sCR rate. In some embodiments, the treatment increases minimal residual disease (MRD) negativity rate. In some embodiment, the treatment prolongs progression-free survival (PFS)-I l l-and overall survival (OS) in the subject. In some embodiments, the treatment improves an MRD assessment. In some embodiments, the MRD assessment is performed by assaying a BM aspirate sample from the subject following a treatment. In some embodiments, the BM aspirate is assayed using multiparameter flow cytometry (MFC) to identify phenotypically aberrant clonal plasma cells. In some embodiments, the BM aspirate is assayed using qPCR to identify MM plasma cell-specific IGH gene rearrangements. In some embodiments, the BM aspirate is assayed using next-generation sequencing (NGS) to identify genomic alterations. In some embodiments, using NGS, DNA is amplified using primers designed for IGF-VDJH, IGF-DJH, or IGK and sequenced to determine the presence and quantity of clonal DNA sequence. In some embodiments, the BM aspirate is assayed using cytological analysis to identify chromosomal alterations. In some embodiments, the MRD assessment is performed by assaying a serum sample from the subject following a treatment. In some embodiments, the serum sample is assayed using LC MALDI-TOF or mass-fix mass spectrometry. In some embodiments, M- protein detection is determined by scanning the overall mass distribution of denatured intact immunoglobulin light chains. In some embodiments, the serum sample is assayed using clonotypic mass spectrometry. In some embodiments, the treatment increases overall survival (OS) in the subject. Overall survival (OS) is defined as the time from randomization to death. In some embodiments, the treatment increases progression free survival (PFS) in the subject. Progression free survival (PFS) is defined as the time from randomization until first evidence of disease progression or death. In some embodiments, the treatment reduces time to progression (TTP) in the subject. Time to progression (TTP) is defined as the time from randomization until first evidence of disease progression. In some embodiments, the treatment increases disease free survival (DFS) in the subject. Disease free survival (DFS) is defined as the time from randomization until evidence of disease recurrence. In some embodiments, the treatment increases duration of response (DOR) in the subject. (DOR): the length of time a tumor will respond to treatment without growing or metastasizing. In some embodiments, the treatment increase a length of event-free survival of the subject. Event-free survival (EFS) is defined as the time from randomization to an event which may include disease progression, discontinuation of the treatment for any reason, or death. In some embodiments, the treatment decreases time to next treatment (TTNT) in the subject. Time to next treatment (TTNT) is defined as the time from initiating treatment to initiating the next line of therapy. In some embodiments, the treatment increases duration of clinical benefit (DoCB) in the subject. Duration of clinical benefit (DoCB) is defined as the time from randomization to disease progression or death in patients who achieve complete response, partial response, or stable disease for 24 weeks or longer. In some embodiments, the treatment increases duration of response (DoR) in the subject.Duration of response (DoR) is defined as the time from randomization to disease progression or death in patients who achieve complete or partial response. In some embodiments, the treatment increases object response rate (ORR) in the subject. In some embodiments, the treatment improves disease control rate (DCR) in the subject. Disease control rate (DCR) describes the percentage of patients with advanced cancer whose therapeutic intervention has led to a complete response, partial response, or stable disease. In some embodiments, the treatment improves the clinical benefit rate in the subject. Clinical benefit rate (CBR) is defined as the percentage of advanced cancer patients who achieve complete response, partial response, or at least six months of stable disease as a result of therapy. In some embodiments, the treatment increases health-related quality of life (HRQoL) in the subject. Health-related quality of life (HRQoL) is an evaluation of a patient’s quality of life with respect to health status over time. The goal of including HRQoL as a clinical endpoint is to complete the results quantitative endpoints such as OS. Quality of life is often used as a secondary clinical endpoint to compare treatments that have similar effects with differences in toxicity, but it can also be used as a coprimary endpoint with OS.

[0137] In some embodiments, the multispecific binder molecule is administered to a subject in need thereof to treat a hematological cancer. In some embodiments, the hematological cancer is a myeloma. In some embodiments, the hematological cancer is multiple myeloma (MM). In some embodiments, the MM is asymptomatic or smoldering MM. In some embodiments, the smoldering MM does not manifest in physical symptoms that affect the subject. In some embodiments, the MM is a hyperdiploid MM in which malignant cells have more chromosomes than normal. In some embodiments, the MM is a hypodiploid MM in which malignant cells have fewer chromosomes than normal. In some embodiments, the MM is a light chain myeloma. In some embodiments, the MM is a non-secretory myeloma. In some embodiments, the MM comprises a solitary plasmacytoma. In some embodiments, the MM comprises an extramedullary plasmacytoma. In some embodiments, the MM has progressed from MGUS. In some embodiments, the MM is an immunoglobulin G (IgG) myeloma. In some embodiments, the MM is an immunoglobulin A (IgA) myeloma. In some embodiments, the MM is an immunoglobulin M (IgM) myeloma. In some embodiments, the MM is an immunoglobulin D (IgD) myeloma. In some embodiments, the MM is an immunoglobulin E (IgE) myeloma. In some embodiments, the MM is an active myeloma.

[0138] In some embodiments, the subject in need of a treatment, wherein the treatment comprises administering the multispecific binder molecule, has multiple myeloma. In some embodiments, the subject has been diagnosed with active MM and has not begun an initial MM treatment. In some embodiments, the subject has been diagnosed with active MM and, aftercompleting a period of treatment, has maintained a period of remission. In some embodiments, the subject has received one or more treatments for MM. In some embodiments, the subject has received two or more treatments for MM. In some embodiments, the subject has received three or more treatments for MM. In some embodiments, the subject has received four or more treatments for MM. In some embodiments, the subject has relapsed with MM symptoms one or more times following a treatment for MM. In some embodiments, the subject has relapsed with MM symptoms two or more times following a treatment for MM. In some embodiments, the subject has relapsed with MM symptoms three or more times following a treatment for MM. In some embodiments, the subject has relapsed with MM symptoms four or more times following a treatment for MM. In some embodiments, the subject has MM that is refractory to a previously effective treatment. In some embodiments, the refractory myeloma is non-responsive to a therapy or progresses within 60 days of the last line of therapy administered. In some embodiments, the subject has relapsed refractory multiple myeloma (RRMM).

[0139] In some embodiments, the administering an effective amount of the multispecific binder molecule increases the overall survival (OS) rate of the subject. In some embodiments, the multispecific binder molecule is administered systemically or locally. In some embodiments, the multispecific binder molecule administered systemically is administered by intravenous injection. In some embodiments, the multispecific binder molecule is administered systemically by infusion. In some embodiments, the multispecific binder molecule is administered systemically by drip infusion. In some embodiments, the multispecific binder molecule is administered systemically by pump infusion.

[0140] In some embodiments, the immune response induced against a tumor cell leads to targeted depletion of a plurality of tumor cells. In some embodiments, cytotoxic immune effector cells are activated following the induction of the immune response. In some embodiments, cytotoxic immune effector cells are able to penetrate the immunoprotected BM microenvironment. In some embodiments, cytotoxic immune effector cells are able to penetrate the immunoprotected BM microenvironment and target malignant plasma cells for lysis. In some embodiments, cytotoxic immune effector cells are able to reduce tumor burden in the subject following the administering. In some embodiments, cytotoxic immune effector cells are able to produce a partial response (PR) in the subject following the administering. In some embodiments, cytotoxic immune effector cells are able to produce a very good partial response (VGPR) in the subject following the administering. In some embodiments, cytotoxic immune effector cells are able to produce a complete remission (CR) in the subject following the administering. In some embodiments, cytotoxic immune effector cells are able to produce a stringent complete remission (sCR) in the subject following the administering.

[0141] In some embodiments, the administering improves one or more MM symptoms of the subject. In some embodiments, the one or more MM symptoms comprise pain, bone pain, nausea, constipation, frequent urination, loss of appetite, mental fogginess or confusion, fatigue, frequent infections, weight loss, weakness in extremities, leg numbness, excessive thirst, blood clots, nosebleed, bleeding gums, bruising, cloudy vision, hyperviscosity of blood, low platelet count, weakened bones, bone fractures, shortness of breath, dizziness, anemia, kidney damage, kidney dysfunction, or amyloidosis, or any combination thereof. In some embodiments, the administering significantly lowers a concentration of M protein in the blood of the subject. In some embodiments, the administering significantly lowers a concentration of M protein in the urine of the subject. In some embodiments, the administering significantly lowers a serum concentration of M protein in the subject to below about 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, or 10 g / L. In some embodiments, the administering improves anemia in the subject. In some embodiments, the administering improves anemia in the subject to a level about at least about 10 g / dL of a level of hemoglobin. In some embodiments, the administering improves hypercalcemia in the subject. In some embodiments, the administering improves hypercalcemia in the subject to a corrected calcium level of below about 2.7 mmol / L. In some embodiments, the administering improves kidney dysfunction in the subject. In some embodiments, the administering improves an involved / uninvolved light chain ratio in the subject to below 100. In some embodiments, the administering improves lytic bone lesions identified through X-ray, PET, MRI, or CT scanning. In some embodiments, the administering improves compression fractures. In some embodiments, the administering significantly decreases a number of plasma cells in a bone marrow sample of the treated subject. In some embodiments, the administering significantly decreases a number of plasma cells in a bone marrow sample of the treated subject so that the percentage of plasma cells versus total cells in the BM sample is less than about 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 49, 48, 47, 46, 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, or 5 %. In some embodiments, the administering decreases a measurement of P2 microglobulin in the subject to less than about 7.5, 7.4, 7.3, 7.2, 7.1, 7.0, 6.9, 6.8, 6.7, 6.6, 6.5, 6.4, 6.3, 6.2, 6.1, 6.0, 5.9, 5.8, 5.7, 5.6, 5.5, 5.4, 5.3, 5.2, 5.1, 5.0, 4.9, 4.8, 4.7, 4.6, 4.5, 4.4, 4.3, 4.2, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.5, 3.4, 3.3, 3.2, 3.1, 3.0, 2.9, 2.8, 2.7, 2.6, or 2.5 mg / L. In some embodiments, the administering decreases a level of serum albumin to below about 3.5 g / dL. In some embodiments, the administering significantly decreases a serum level of LDH in the subject.Pharmaceutically Acceptable Excipients, Carriers, And Diluents

[0142] Compositions comprising the modified antibodies and multispecific binder molecules of the current disclosure are included in a pharmaceutical composition comprising one or more pharmaceutically acceptable excipients, carriers, and diluents. In some embodiments, the antibodies of the current disclosure are administered suspended in a sterile solution. In some embodiments, the antibodies of the current disclosure are administered suspended in an isotonic solution. In some instances, the pharmaceutical formulation includes one or more salts in an amount required to bring osmolality of the composition into an acceptable range. Such salts include those having sodium, potassium or ammonium cations and chloride, citrate, ascorbate, borate, phosphate, bicarbonate, sulfate, thiosulfate or bisulfite anions; suitable salts include sodium chloride, potassium chloride, sodium thiosulfate, sodium bisulfite and ammonium sulfate. In certain aspects, the solution comprises about 0.9% NaCl. In certain aspects, the solution comprises about 5.0% dextrose. In certain aspects, the solution further comprises one or more of buffers, for example, acetate, citrate, histidine, succinate, phosphate, bicarbonate and Tri s(hydroxymethyl)aminom ethane; surfactants, for example, polysorbate 80 (Tween 80), polysorbate 20 (Tween 20); polyol / disaccharide / polysaccharides, for example, glucose, dextrose, mannose, mannitol, sorbitol, sucrose, and dextran 40; amino acids, for example, glycine or arginine; antioxidants, for example, ascorbic acid, methionine; or chelating agents, for example, EDTA or EGTA.

[0143] In certain aspects, the modified antibodies and multispecific binder molecules of the current disclosure are shipped and / or stored lyophilized and can then be reconstituted before administration. In certain aspects, lyophilized antibody formulations comprise a bulking agent such as, mannitol, sorbitol, sucrose, trehalose, dextran 40, or combinations thereof. The lyophilized formulation can be contained in a vial comprised of glass or other suitable non- reactive material. The antibodies when formulated, whether reconstituted or not, can be buffered at a certain pH, generally less than about 7.5. In certain aspects, the pH can be between 4.5 and 7.5, 4.5 and 7.0, 4.5 and 6.5, 4.5 and 6.0, or 5.5 or 5.0.Definitions

[0144] Unless defined otherwise, all terms of art, notations and other technical and scientific terms or terminology used herein are intended to have the same meaning as is commonly understood by one of ordinary skill in the art to which the claimed subject matter pertains. In some cases, terms with commonly understood meanings are defined herein for clarity and / or forready reference, and the inclusion of such definitions herein should not necessarily be construed to represent a substantial difference over what is generally understood in the art.

[0145] Throughout this specification, the terms “multispecific binder molecule” and “multispecific binding molecule” are used interchangeably.

[0146] Throughout this specification, the terms “tetraspecific binder molecule” and “tetraspecific binding molecule” are used interchangeably.

[0147] Throughout this specification, the terms “T cell” and “T-cell” are used interchangeably.

[0148] Throughout this specification, the terms “T cells” and “T-cells” are used interchangeably.

[0149] Throughout this application, various embodiments may be presented in a range format. It should be understood that the description in range format is merely for convenience and brevity and should not be construed as an inflexible limitation on the scope of the disclosure. Accordingly, the description of a range should be considered to have specifically disclosed all the possible subranges as well as individual numerical values within that range. For example, description of a range such as from 1 to 6 should be considered to have specifically disclosed subranges such as from 1 to 3, from 1 to 4, from 1 to 5, from 2 to 4, from 2 to 6, from 3 to 6 etc., as well as individual numbers within that range, for example, 1, 2, 3, 4, 5, and 6. This applies regardless of the breadth of the range.

[0150] As used in the specification and claims, the singular forms “a”, “an” and “the” include plural references unless the context clearly dictates otherwise. For example, the term “a sample” includes a plurality of samples, including mixtures thereof.

[0151] The terms “determining,” “measuring,” “evaluating,” “assessing,” “assaying,” and “analyzing” are often used interchangeably herein to refer to forms of measurement. The terms include determining if an element is present or not (for example, detection). These terms can include quantitative, qualitative or quantitative and qualitative determinations. Assessing can be relative or absolute. “Detecting the presence of’ can include determining the amount of something present in addition to determining whether it is present or absent depending on the context.

[0152] The terms “subject,” “individual,” or “patient” are often used interchangeably herein. A “subject” can be a biological entity containing expressed genetic materials. The biological entity can be a plant, animal, or microorganism, including, for example, bacteria, viruses, fungi, and protozoa. The subject can be tissues, cells and their progeny of a biological entity obtained in vivo or cultured in vitro. The subject can be a mammal. The mammal can be a human. The subject may be diagnosed or suspected of being at high risk for a disease. In some cases, the subject is not necessarily diagnosed or suspected of being at high risk for the disease.

[0153] The term “in vitro” is used to describe an event that takes places contained in a container for holding laboratory reagent such that it is separated from the biological source from which the material is obtained. In vitro assays can encompass cell-based assays in which living or dead cells are employed. In vitro assays can also encompass a cell-free assay in which no intact cells are employed.

[0154] As used herein, the term “about” a number refers to that number plus or minus 10% of that number. The term “about” a range refers to that range minus 10% of its lowest value and plus 10% of its greatest value.

[0155] As used herein, the terms “treatment” or “treating” are used in reference to a pharmaceutical or other intervention regimen for obtaining beneficial or desired results in the recipient. Beneficial or desired results include but are not limited to a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may refer to eradication or amelioration of symptoms or of an underlying disorder being treated. Also, a therapeutic benefit can be achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. A prophylactic effect includes delaying, preventing, or eliminating the appearance of a disease or condition, delaying, or eliminating the onset of symptoms of a disease or condition, slowing, halting, or reversing the progression of a disease or condition, or any combination thereof. For prophylactic benefit, a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease may undergo treatment, even though a diagnosis of this disease may not have been made.

[0156] The term “antibody” herein is used in the broadest sense and includes monoclonal antibodies, including intact antibodies and functional (antigen-binding) antibody fragments thereof, including fragment antigen-binding (Fab) fragments, F(ab’)2 fragments, Fab' fragments, Fv fragments, recombinant IgG (rlgG) fragments, single chain antibody fragments, including single chain variable fragments (sFv or scFv), and single domain antibodies (e.g., sdAb, sdFv, nanobody) fragments. The term encompasses genetically engineered and / or otherwise modified forms of immunoglobulins, such as intrabodies, peptibodies, chimeric antibodies, fully human antibodies, humanized antibodies, and heteroconjugate antibodies, tandem di-scFv, tandem tri- scFv. Unless otherwise stated, the term “antibody” should be understood to encompass functional antibody fragments thereof. The term also encompasses intact or full- length antibodies, including antibodies of any class or sub-class, including IgG and sub-classes thereof, IgM, IgE, IgA, and IgD. The antibody can comprise a human IgGl constant region. The antibody can comprise a human IgG4 constant region. An antibody includes, but is not limitedto, full-length and native antibodies, as well as fragments and portion thereof retaining the binding specificities thereof, such as any specific binding portion thereof including those having any number of, immunoglobulin classes and / or isotypes (e.g., IgGl, IgG2, IgG3, IgG4, IgM, IgA, IgD, IgE and IgM); and biologically relevant (antigen-binding) fragments or specific binding portions thereof, including but not limited to Fab, F(ab’)2, Fv, and scFv (single chain or related entity). A monoclonal antibody is generally one within a composition of substantially homogeneous antibodies; thus, any individual antibodies comprised within the monoclonal antibody composition are identical except for possible naturally occurring mutations that may be present in minor amounts. A monoclonal antibody can comprise a human IgGl constant region or a human IgG4 constant region.

[0157] The terms “complementarity determining region,” and “CDR,” which are synonymous with “hypervariable region” or “HVR,” are known in the art and refer to non-contiguous sequences of amino acids within antibody variable regions, which confer antigen specificity and / or binding affinity. In general, there are three CDRs in each heavy chain variable region (CDR-H1, CDR-H2, CDR-H3) and three CDRs in each light chain variable region (CDR-L1, CDR-L2, CDR-L3). CDR-H1, CDR-H2, CDR-H3 are also referred to as HCDR1, HCDR2, and...

Claims

CLAIMSWhat is claimed is:

1. A multispecific binder molecule, comprising three distinct tumor antigen binding moieties (a-c) comprising: a) a TNFRSF17 (BCMA) binding moiety, b) a GPRC5D binding moiety, and c) a FcRH5 binding moiety; and d) an immune cell engager.

2. The multispecific binder molecule of claim 1, wherein the immune cell engager comprises a T cell binding moiety, an NK cell binding moiety, or an NKT cell binding moiety.

3. The multispecific binder molecule of claim 1, wherein the immune cell engager comprises a T cell binding moiety.

4. The multispecific binder molecule of claim 3, wherein the T cell binding moiety comprises a CD3 binding moiety.

5. The multispecific binder molecule of claim 4, wherein at least one of the three distinct tumor antigen binding moieties is an antibody or antigen binding fragment thereof.

6. The multispecific binder molecule of claim 5, wherein the antibody or antigen binding fragment thereof is a human antibody, a humanized antibody, or antigen binding fragment thereof.

7. The multispecific binder molecule of claim 5, wherein the antibody or antigen binding fragment thereof comprises a chimeric antibody, a monoclonal antibody, a monovalent Fab’, a divalent Fab2, a single-chain variable fragment (scFv), a diabody, a minibody, a nanobody, a single-domain antibody (sdAb), a camelid antibody, or antigen binding fragment thereof.

8. The multispecific binder molecule of claim 5, comprising a first immunoglobulin chain constant region and a second immunoglobulin chain constant region.

9. The multispecific binder molecule of claim 8, wherein the TNFRSF17 (BCMA) binding moiety and the GPRC5D binding moiety are linked to the first immunoglobulin chain constant region, and wherein the CD3 binding moiety and the FcRH5 binding moiety are linked to the second immunoglobulin chain constant region.

10. The multispecific binder molecule of claim 8, wherein the TNFRSF17 (BCMA) binding moiety and the CD3 binding moiety are linked to the first immunoglobulin chain constant region, and wherein the GPRC5D binding moiety and the FcRH5 binding moiety are linked to the second immunoglobulin chain constant region.

11. The multispecific binder molecule of claim 8, wherein the TNFRSF17 (BCMA) binding moiety and the FcRH5 binding moiety are linked to the first immunoglobulin chain constant region, and wherein the GPRC5D binding moiety and the CD3 binding moiety are linked to the second immunoglobulin chain constant region.

12. The multispecific binder molecule of claim 5, wherein the a) TNFRSF17 (BCMA) binding moiety, b) GPRC5D binding moiety, c) FcRH5 binding moiety, and d) CD3 binding moiety, comprise an antibody or antigen binding fragment thereof, wherein the antibody or antigen binding fragment thereof comprises Fab’, scFv, IgG-scFv, nanobody, mini-antibody, minibody, scFv-CH3 KiH, or scFv-KiH.

13. The multispecific binder molecule of claim 8, wherein the first or second immunoglobulin chain constant region comprises a heavy chain constant region of IgGl, IgG2, and IgG4, or a variant thereof.

14. The multispecific binder molecule of claim 8, wherein the first or second immunoglobulin chain constant regions form a IgGl heavy chain or a variant thereof.

15. The multispecific binder molecule of claim 14, wherein the TNFRSF17 (BCMA) binding moiety is coupled to the N-terminus of the IgGl heavy chain or a variant thereof.

16. The multispecific binder molecule of claim 14, wherein the TNFRSF17 (BCMA) binding moiety is coupled to the C-terminus of the IgGl heavy chain or a variant thereof.

17. The multispecific binder molecule of claim 14, wherein the GPRC5D binding moiety is coupled to the N-terminus of the IgGl heavy chain or a variant thereof.

18. The multispecific binder molecule of claim 14, wherein the GPRC5D binding moiety is coupled to the C-terminus of the IgGl heavy chain or a variant thereof.

19. The multispecific binder molecule of claim 14, wherein the FcRH5 binding moiety is coupled to the N-terminus of the IgGl heavy chain or a variant thereof.

20. The multispecific binder molecule of claim 14, wherein the FcRH5 binding moiety is coupled to the C-terminus of the IgGl heavy chain or a variant thereof.

21. The multispecific binder molecule of claim 14, wherein the CD3 binding moiety is coupled to the N-terminus of the IgGl heavy chain or a variant thereof.

22. The multispecific binder molecule of claim 14, wherein the CD3 binding moiety is coupled to the C-terminus of the IgGl heavy chain or a variant thereof.

23. The multispecific binder molecule of claim 14, wherein the IgGl heavy chain comprises a mutation that reduces FcyR binding.

24. The multispecific binder molecule of claim 23 wherein the mutation comprises N297A mutation.

25. The multispecific binder molecule of claim 14, wherein at least one of the three distinct tumor antigen binding moieties is coupled to an immunoglobulin kappa light chain domain.

26. The multispecific binder molecule of claim 14, wherein at least one of the three distinct tumor antigen binding moieties is coupled to an immunoglobulin lambda light chain domain.

27. The multispecific binder molecule of claim 14, wherein one of the three distinct tumor antigen binding moieties is coupled to an immunoglobulin lambda light chain domain and another of the three distinct tumor antigen binding moieties is coupled to an immunoglobulin kappa light chain domain.

28. The multispecific binder molecule of claim 4, wherein the TNFRSF17 (BCMA) binding moiety is derived from Teclistamab, AMG 701, Alnuctamab, Belantamab mafodotin, Elranatamab, Linvoseltamab, ABBV-383, HPN217, ISB 2001, GSK287916, MEDI2228, TNB- 383B, REGN545, or AMG 420.

29. The multispecific binder molecule of claim 4, wherein the GPRC5D binding moiety is derived from Talquetamab or RG6234.

30. The multispecific binder molecule of claim 4, wherein the FcRH5 binding moiety is derived from Cevostamab or DFRF4539A.

31. The multispecific binder molecule of claim 4, wherein the CD3 binding moiety is derived from AMG 701, Alnuctamab, Elranatamab, Linvoseltamab, Teclistamab, ABBV-383, HPN217, XmAb969, ISB1347, Talquetamab, RG6234, Cevostamab, SAR442257, F182112, or ISB 2001.

32. A method for inducing an immune response against a tumor cell, comprising contacting the tumor cell with the multispecific binder molecule of any one of claims 1-31.

33. The method of claim 32, wherein the contacting induces proximity between the tumor cell and one or more immune effector cells.

34. The method of claim 32, wherein the contacting supports formation of a cytolytic immunological synapse between the tumor cell and one or more immune effector cells.

35. The method of claim 33, wherein the one or more immune effector cells comprise one or more activated T cells.

36. The method of claim 35, wherein the one or more activated T cells release primary cytokines that induce the activation of other immune cell types wherein the other immune cell types comprise macrophages, dendritic cells, monocytes, NK cells, or any combination thereof.

37. The method of claim 36, wherein the other immune cell types produce elevated levels of secondary cytokines, wherein the secondary cytokines comprise IL6, IL10, IL5, or any combination thereof.

38. The method of claim 33, wherein the one or more immune effector cells induce apoptosis in a target tumor cell.

39. The method of claim 36, wherein the one or more immune effector cells induce pyroptosis in a target tumor cell.

40. The method of claim 33, wherein the one or more immune effector cells release one or more cytotoxic proteases of the granzyme family following the contacting.

41. The method of claim 40, wherein the one or more cytotoxic proteases of the granzyme family comprise Granzyme B (GrB).

42. The method of claim 33, wherein the one or more immune effector cells release one or more lytic proteins following the contacting.

43. The method of claim 42, wherein the one or more lytic proteins comprise perforin.

44. The method of claim 34, wherein the contacting engages a T cell receptor (TCR) on one or more T cells.

45. The method of claim 44, wherein the one or more T cells comprise naive T cells, helper T cells, cytotoxic T cells, or any combination thereof.

46. The method of claim 45, wherein the one or more T cells receive a co-stimulatory signal resulting in T cell proliferation, differentiation, and survival.

47. The method of claim 45, wherein the contacting induces co-stimulation independent polyclonal T-cell activation.

48. The method of claim 32, wherein the tumor cell is a multiple myeloma tumor cell.

49. A method for treating a cancer in a subject in need thereof, comprising administering a therapeutically effective amount of the multispecific binder molecule of any one of claims 1-31 to the subject.

50. The method of claim 49, wherein the cancer is a hematological cancer.

51. The method of claim 50, wherein the cancer is multiple myeloma.

52. The method of claim 51, wherein the therapeutically effective amount reduces a risk of the subject developing cytokine release syndrome (CRS) following the administering.

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