Monoclonal and Bispecific Anti-BCMA Antibodies in Multiple Myeloma

Abstract

B-cell maturation antigen (BCMA), a member of the tumor necrosis factor receptor superfamily, is universally expressed by normal and neoplastic plasma cells and plays a critical role in the proliferation, survival and tumor progression in multiple myeloma (MM). B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) have been recognized as proliferation ligands for BCMA in the bone marrow microenvironment. Soluble BCMA levels in the serum correlates with disease phase and tumor burden and is a predictor of progression-free survival (PFS) and overall survival (OS). Recently, the introduction of new monoclonal antibodies against CD38 (Daratumumab and Isatuximab) and SLAM7 (Elotuzumab) has changed the therapeutic approach to MM, improving the response rate and the time to progression, both in newly diagnosed and refractory/relapsed patients. Among the surface antigens on MM cells, BCMA is a suitable target for the design of new antibody-based strategies. Experimental approaches targeting BCMA are currently being investigated and include antibody-drug conjugates (ADCs), bispecific antibodies (bsAbs) and genetically engineered T-cells with chimeric antigen receptors (CAR). In this review we summarize the more recent findings about BCMA biologic rationale as a therapeutic target and report the updated results of preclinical and clinical studies focused on ADCs and bsAbs targeting BCMA.

Immunotherapy in Acute Myeloid Leukemia: Where We Stand

“…In this scenario, the class of bispecific antibodies (bsAbs), also known as dual-targeting molecules, includes antibodies or single chain variable fragments (scFv) derived from the Fab fragment of the IgG immunoglobulin, composed of the VH and VL domains attached with a linker, to physically bridge two or more cells (58). Several formats of bsAbs have been investigated in AML: BiTe (Bispecific T-cell engager), BiKe (Bispecific killer cell engager), TriKe (Trispecific killer cell engager), Tandem Diabodies (TandAbs), and dual affinity retargeting antibodies (DARTs) (57,(59)(60)(61).…”

Novel Experimental Drugs for Treatment of Multiple Myeloma

“…The new frontier of immunotherapy in MM is the use of a smart technique that can boost the immune system against MM cells. 53 B-cell maturation antigen (BCMA) is the most used target because of its important functions in the proliferation, survival, and tumor progression in MM. 54 …”

Mechanisms of Action of the New Antibodies in Use in Multiple Myeloma

“…Two formats of bsAbs have been extensively studied in MM: BiTE (Bispecific T-cell engager, developed by Amgen, Thousand Oaks, CA, USA) ( 10 , 184 , 190 , 194 ) and DuoBody (developed by Genmab A/S, Copenhagen, Denmark). In the BiTE molecules, binding domains are two single‐chain variable fragment (scFv) regions, arised from mAbs, joined by a flexible peptide linker: one, to recognize tumor‐expressed antigens, and another to engage effector T-cells.…”

“…Monoclonal antibodies (mAbs) are a group of agents with immune-based mechanism of actions that in recent years have changed the management of newly diagnosed and relapsed/refractory MM (RRMM) ( 6 , 9 ). Moreover, the development of a new generation of mAbs, including antibody-drug conjugates (ADCs) and bispecific antibodies (bsAbs) has the potential to additional improve the clinical outcome of MM patients ( 6 , 10 ). Isotype dictates mAbs activity ( 11 ), and most anti-MM mAbs are IgG antibodies.…”