(AstraZeneca) AZD5863: a specific, potent, affinity-optimized Claudin 18.2 and CD3 binding T cell-engager that elicits low cytokine release and is capable of bystander killing

Background

Claudin 18.2 (CLDN18.2), a tetraspanin family member essential for the formation of tight junctions,¹ is highly expressed in gastric, pancreatic and esophageal adenocarcinomas, with physiological expression restricted to gastric mucosal epithelial cells.² CLDN18.2 is a validated therapeutic target; zolbetuximab, a CLDN18.2-directed monoclonal antibody, demonstrated clinical benefit in combination with chemotherapy in CLDN18.2-high gastric cancer.^{3 4} Similarly, CLDN18.2-targeting chimeric antigen receptor T cells and antibody-drug conjugates have shown efficacy in gastric cancers,^5–7 and other modalities, including T cell-engagers (TCE), are also in clinical development. Here we describe AZD5863, a CLDN18.2 and cluster of differentiation 3 (CD3)-targeting TCE designed with bivalent high-affinity binding to CLDN18.2 and monovalent low-affinity binding to CD3 to reduce class-associated toxicities, such as cytokine release syndrome, while maintaining potent and specific antitumor activity.