Preclinical Development – Biomolecular
2019 PharmSci 360
Tumor-associated antigen (TAA) x CD3 bispecifics have been shown to recruit T cells to mediate cytotoxicity against tumor cells. The pharmacodynamics and tolerability of TAA x CD3 bispecifics are impacted by multiple aspects of TAA biology such as tumor load, cell surface antigen density, and normal tissue expression. Here we present our XmAb bispecific antibody platform, utilizing a proprietary heterodimeric Fc domain, to generate TAA x CD3 bispecifics in a monovalent:monovalent (1:1) Fab-scFv-Fc format and a bivalent:monovalent (2:1) mixed-valency Fab2-scFv-Fc format. We have engineered multiple examples of well-behaved bivalent:monovalent (2:1) TAA x CD3 bispecifics that exhibit selective cytotoxicity of high versus low antigen density cell lines that mimic tumor versus normal tissue, respectively. The selectivity exhibited by the 2:1 format potentially empowers TAA x CD3 bispecifics to address an expanded set of tumor antigens.