Bispecific Antibodies for Multiple Myeloma: A Review of Targets, Drugs, Clinical Trials, and Future Directions

Abstract

Multiple myeloma (MM) is a plasma cell malignancy and the second most common hematological neoplasm in adults, comprising 1.8% of all cancers. With an annual incidence of ∼30,770 cases in the United States, MM has a high mortality rate, leading to 12,770 deaths per year. MM is a genetically complex, highly heterogeneous malignancy, with significant inter-and intra-patient clonal variability. Recent years have witnessed dramatic improvements in the diagnostics, classification, and treatment of MM. However, patients with high-risk disease have not yet benefited from therapeutic advances. Highrisk patients are often primary refractory to treatment or relapse early, ultimately resulting in progression toward aggressive end-stage MM, with associated extramedullary disease or plasma cell leukemia. Therefore, novel treatment modalities are needed to improve the outcomes of these patients. Bispecific antibodies (BsAbs) are immunotherapeutics that simultaneously target and thereby redirect effector immune cells to tumor cells. BsAbs have shown high efficacy in B cell malignancies, including refractory/relapsed acute lymphoblastic leukemia. Various BsAbs targeting MM-specific antigens such as B cell maturation antigen (BCMA), CD38, and CD138 are currently in pre-clinical and clinical development, with promising results. In this review, we outline these advances, focusing on BsAb drugs, their targets, and their potential to improve survival, especially for high-risk MM patients. In combination with current treatment strategies, BsAbs may pave the way toward a cure for MM.

Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True

“…BCMA on malignant plasma cells and CD3 on T cells are the two main targets exploited to design anti-MM BiAbs. Other BiAbs targeting different antigens on the plasma cell surface and/or involving different immune effectors have been reviewed elsewhere [91].…”

CAR T cells better than BiTEs

“…For instance, in multiple myeloma (MM), there are a host of emerging BiTEs as well as CAR T cells targeting several different MM antigens, including B-cell maturation antigen, CD38, and CD138, among others. [46][47][48] CD20 represents another attractive target for B-cell lymphomas, and certainly both CD20 targeted BiTEs and combinatorial CD19-CD20 CAR T-cell constructs 49 are actively being tested. Further experiences with these novel approaches will provide greater insight into the merits and limitations of CAR T cells vs BiTEs beyond B-ALL, but the framework set forth will likely apply.…”

Drug Conjugated and Bispecific Antibodies for Multiple Myeloma: Improving Immunotherapies off the Shelf

“…Bispecific T cell redirecting antibodies (BsAbs) are engineered to bind specific and selected tumor-associated antigens and the CD3 component of the T cell receptor (TCR), resulting in the immune-synapsis formation, T cell activation, and ultimately in T cell mediated killing of the neoplastic cell [ 46 , 47 ]. There are several advantages of this type of immunotherapeutic approach, primarily a Mayor Histocompatibility Complex (MHC) independent T cell activation, since T cell activation is independent of antigen presentation [ 48 ].…”

“…There are several advantages of this type of immunotherapeutic approach, primarily a Mayor Histocompatibility Complex (MHC) independent T cell activation, since T cell activation is independent of antigen presentation [ 48 ]. Moreover, BsAbs retain the ability to activate T cells without co-stimulatory signals by APC cells through TCR-CD3 clustering, also reducing the risk of become anergic due to TCR stimulation in the absence of costimulatory signals [ 47 , 49 ]. Finally, BsAbs can exert their cytotoxic properties even in the presence of low tumor antigens levels, a common occurrence in malignant cells evading immune-surveillance [ 50 ] ( Figure 3 ).…”