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

Siler H Panowski,Amy Chen,Bing Kuang,Wei Chen,Kevin C Lindquist,Pavel Strop,Michael Mirsky,Laura Aschenbrenner,Jeffrey L Wolf,Kathy Delaria,Allison G Chunyk,Cris Kamperschroer,Sherman M Chin,Tao Geng,Yik Andy Yeung,Santiago Farias,Arvind Rajpal,Ingrid Pardo,Yi Zhang,Marjorie Bateman,Barbra J Sasu,Edward Pascua,Russell G Dushin,Bora Han,Tracy C Kuo,David L Shelton ,Thomas Martin ,Javier Chaparro‐Riggers ,Thomas Van Blarcom ,Bernard S Buetow

doi:10.1158/1535-7163.mct-19-0007

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 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.

Highlights

Multiple myeloma is a disease of malignant plasma cells and despite recent advances in treatment options, relapse is inevitable and patients become refractory to treatment [1,2,3,4], highlighting the clear need for additional treatment approaches
Antibodies formatted into CD3 bispecifics demonstrated effective binding to myeloma cell lines and human T cells, indicating that the bispecific format did not affect recognition of either epitope (Fig. 1C)
A high-affinity B-cell maturation antigen (BCMA) clone was selected for further studies as both BCMA CD3 bispecific and BCMA antibody–drug conjugates (ADC)

Summary

Introduction

Multiple myeloma is a disease of malignant plasma cells and despite recent advances in treatment options, relapse is inevitable and patients become refractory to treatment [1,2,3,4], highlighting the clear need for additional treatment approaches. Two exciting approaches of current focus that may benefit myeloma patients are CD3 targeting bispecific antibodies and antibody–drug conjugates CD3 bispecific antibodies function by redirection of T lymphocytes, highly potent immune cells capable of killing cancer cells and virally infected cells through perforin/granzyme release [13,14,15]. One way to circumvent the need for this precise interaction is by T-cell redirection through the use of bispecific molecules that bridge TAAs and CD3 [9, 11]. ADCs combine the specificity of monoclonal antibodies with the potency of cytotoxic payloads

Methods

Results

Conclusion