Antibodies and bispecifics for multiple myeloma: effective effector therapy

Abstract

The therapeutic landscape in multiple myeloma (MM) has changed dramatically over the last 2 decades. With the introduction of novel immunotherapies, patients with MM can expect deeper responses, longer remissions, and improved overall survival. Since its approval by the US Food and Drug Administration in 2015, the monoclonal antibody specific for CD38, daratumumab, has been incorporated into both frontline and relapsed treatment regimens. Its role as a maintenance therapy is currently being explored. Subsequently, a variety of novel antibody therapeutics have evolved from the success of daratumumab, using similar concepts to target the malignant plasma cell clone. Noteworthy naked monoclonal antibodies include isatuximab, another agent directed against CD38, and elotuzumab, an agent directed against SLAM family member 7. Antibody-drug conjugates, complex molecules composed of an antibody tethered to a cytotoxic drug, target malignant cells and deliver a lethal payload. The first to market is belantamab mafodotin, which targets B-cell maturation antigen (BCMA) on malignant plasma cells and delivers a potent microtubule inhibitor, monomethyl auristatin F. Additionally, bispecific T-cell antibodies are in development that engage the immune system directly by simultaneously binding CD3 on T cells and a target epitope-such as BCMA, G-protein coupled receptor family C group 5 member D (GPRC5d), and Fc receptor homologue 5 (FcRH5)-on malignant cells. Currently, teclistamab, an anti-BCMA bispecific, is closest to approval for commercial use. In this review, we explore the evolving landscape of antibodies in the treatment of MM, including their role in frontline and relapse settings.

Graphical abstract

Figure 1.

Characteristics of ADCs. The components of the ADC and its target antigen influence the efficacy and safety profile. Preferably, target antigens should only be found on malignant cells, be abundantly expressed, be capable of internalization, and not be shed from the cellular membrane. The cytotoxic drug (payload or warhead) is the ultimate effector component, inducing direct cell killing either by inhibiting microtubule formation or directly damaging cellular DNA. It should be highly potent in the subnanomolar range and preferably nonpermeable to avoid damage to surrounding tissues. The linker connects the warhead to the antibody. These should be stable in circulation and cleavable upon lysosomal degradation. The conjugation chemistry of the linker determines the drug:antibody ratio, which critically influences the ADC potency. ADCC, antibody-dependent T-cellular cytotoxicity, Fab, fragment antigen-binding region.

Figure 2.

Characteristics of BsAbs. IgG-like BsAbs include an Fc region, while non–IgG-like BsAbs consist of only Fab (fragment antigen-binding) variable regions and linkers. Since the Fc portion provides stability and longevity to the molecule in circulation, most non–IgG-like BsAbs require more frequent dosing to maintain therapeutic plasma levels; they also lack the Fc-mediated effector functions such as antibody-dependent T-cellular cytotoxicity and complement-dependent cytotoxicity. Several BsAbs, both IgG-like and non–IgG-like, are under development for the treatment of MM. BiAb, bispecific antibodies.