Background Claudin (CLDN) 18.2 is a transmembrane tight junction protein with expression restricted to the gastric mucosal epithelia where CLDN18.2 protects against paracellular acid leakage and associated gastritis. CLDN18.2 overexpression has been observed in several tumor types, including gastric, esophageal, and pancreatic cancer. Loss of cell polarity in these tumors results in CLDN18.2 localization to surfaces that are more readily accessible to biologics and effector cells. This expression pattern makes CLDN18.2 a compelling target for immune-stimulating antibody conjugates (ISACs) that combine the specificity of tumor-targeting antibodies with the potency and durability of immune activation.

BDC-4182 is a next generation ISAC consisting of a CLDN18.2-targeting antibody covalently attached to a novel toll-like receptor (TLR)7/8 agonist via a non-cleavable linker. In preclinical models, systemic delivery of ISACs has been shown to broadly activate the innate and adaptive immune system, leading to complete tumor regression, immunologic memory and epitope spreading to eliminate tumors cells that no longer express the target antigen. Herein, we describe the activity of CLDN18.2 ISAC in multiple tumor models and its safety profile in non-human primates (NHP).

Methods In vivo assessment of anti-tumor activity was performed with a mouse active surrogate of BDC-4182 (BDC-4182.S) using xenograft and syngeneic tumor models with different levels of CLDN18.2 expression. The tolerability of BDC-4182 was tested in a non-GLP NHP study.

Results BDC-4182 elicits robust CLDN18.2 antigen-dependent activation of human dendritic cells, leading to the secretion of proinflammatory cytokines such as TNFα and IL-12p70. BDC-4182.S led to significant tumor regression in both xenograft and syngeneic mouse models and elicited T cell-dependent immunological memory with epitope spreading. BDC-4182.S also outperformed cytotoxic CLDN18.2 ADCs, exhibiting a greater ability to inhibit growth of low CLDN18.2 expressing tumors. In a non-GLP NHP study, BDC-4182 was tolerated at the highest dose tested (12 mg/kg) with no significant histopathological changes in the stomach and other organs of interest.

Conclusions BDC-4182, a CLDN18.2-targeted ISAC, demonstrates potent antigen dependent activation of the immune system, compelling anti-tumor activity, induction of immunologic memory with epitope spreading, favorable activity compared to cytotoxic CLDN18.2 ADCs and an acceptable safety profile in preclinical studies. BDC-4182 is expected to begin FIH trials in 2025.