Preclinical Efficacy and Safety Comparison of CD3 Bispecific and ADC Modalities Targeting BCMA for the Treatment of Multiple Myeloma

Abstract

The restricted expression pattern of B-cell maturation antigen (BCMA) makes it an ideal tumor-associated antigen (TAA) for the treatment of myeloma. BCMA has been targeted by both CD3 bispecific antibody and antibody-drug conjugate (ADC) modalities, but a true comparison of modalities has yet to be performed. Here we utilized a single BCMA antibody to develop and characterize both a CD3 bispecific and 2 ADC formats (cleavable and noncleavable) and compared activity both in vitro and in vivo with the aim of generating an optimal therapeutic. Antibody affinity, but not epitope was influential in drug activity and hence a high-affinity BCMA antibody was selected. Both the bispecific and ADCs were potent in vitro and in vivo, causing dose-dependent cell killing of myeloma cell lines and tumor regression in orthotopic myeloma xenograft models. Primary patient cells were effectively lysed by both CD3 bispecific and ADCs, with the bispecific demonstrating improved potency, maximal cell killing, and consistency across patients. Safety was evaluated in cynomolgus monkey toxicity studies and both modalities were active based on ontarget elimination of B lineage cells. Distinct nonclinical toxicity profiles were seen for the bispecific and ADC modalities. When taken together, results from this comparison of BCMA CD3 bispecific and ADC modalities suggest better efficacy and an improved toxicity profile might be achieved with the bispecific modality. This led to the advancement of a bispecific candidate into phase I clinical trials.

Bispecific, T-Cell-Recruiting Antibodies in B-Cell Malignancies

“…PF-06863135 (PF-3135) is a humanized BsAb using a IgG2a backbone with mutations in the Fc part that promote heavy chain heterodimer formation and reduce Fcγ receptor binding (105). This BsAb showed potent anti-myeloma activity in both in vitro and in vivo models and its toxicity profile in cynomolgus monkeys was acceptable (105). PF-06863135 is currently undergoing a Phase I study to assess its safety and tolerability (NCT03269136) (106).…”

Current State of the Art and Prospects of T Cell-Redirecting Bispecific Antibodies in Multiple Myeloma

“…PF-3135 is a humanized IgG-like bispecific monoclonal antibody (IgG2a) that utilizes two arms to target BCMA and CD3. In preclinical studies, elranatamab was able to kill BCMA + MM tumor cells in vitro and in a MM mouse model [ 63 ]. Elranatamab was also capable of completely depleting BCMA + PCs in cynomolgus monkeys with a half-life of 4–6 days [ 26 , 63 ].…”

The Agony of Choice—Where to Place the Wave of BCMA-Targeted Therapies in the Multiple Myeloma Treatment Puzzle in 2022 and Beyond

“…BsAbs-targeting multiple myeloma cells have demonstrated encouraging results in preclinical studies in vitro, in mouse xenograft models, and in cynomolgus monkeys [ 47 , 48 , 49 , 50 , 51 , 52 ]. To date, more than 10 different BsAbs-targeting MM antigens have been clinically investigated, most of them directed to BCMA and CD3 with promising clinical data from phase 1/2 studies ( Table 2 ) [ 45 ].…”

“…Elranatamab (formerly known as PF-06863135) is a humanized anti-BCMA/CD3 BsAb with an IgG2a backbone [ 49 ]. Early clinical data for intravenous and subcutaneous administration showed activity in patients with RRMM.…”