15357163mct190007-sup-214777_2_supp_5623706_pt18tt.pdf (881.15 kB)
Figure S5 from Preclinical Efficacy and Safety Comparison of CD3 Bispecific and ADC Modalities Targeting BCMA for the Treatment of Multiple Myeloma
journal contributionposted on 2023-04-03, 16:08 authored by Siler H. Panowski, Tracy C. Kuo, Yi Zhang, Amy Chen, Tao Geng, Laura Aschenbrenner, Cris Kamperschroer, Edward Pascua, Wei Chen, Kathy Delaria, Santiago Farias, Marjorie Bateman, Russell G. Dushin, Sherman M. Chin, Thomas J. Van Blarcom, Yik Andy Yeung, Kevin C. Lindquist, Allison G. Chunyk, Bing Kuang, Bora Han, Michael Mirsky, Ingrid Pardo, Bernard Buetow, Thomas G. Martin, Jeffrey L. Wolf, David Shelton, Arvind Rajpal, Pavel Strop, Javier Chaparro-Riggers, Barbra J. Sasu
Pharmacokinetics of BCMA bispecific and ADC in cynomolgus monkeys.
ARTICLE ABSTRACTThe 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 on-target 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.