A phase I/II study of BDC-4182, a claudin18.2-targeting next generation immune-stimulating antibody conjugate (ISAC), in patients with advanced gastric and gastroesophageal cancer

초록

Background: Claudin 18.2 (CLDN18.2) 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. BDC-4182 induced immunologic memory and epitope spreading as evidenced by rejection of tumor cells that no longer express the target antigen (CLDN18.2) following re-challenge. Trial design: This is a first-in-human Phase 1 dose escalation and Phase 2 expansion study of BDC-4182. Up to 122 subjects with advanced gastric and gastro-esophageal patients will be enrolled. Dose cohorts ranging from 0.75 mg/kg up to 18 mg/kg will be tested during dose escalation. Primary objectives are to define safety and tolerability and to determine the recommended phase 2 dose (RP2D) of BDC-4182 as a single agent. Secondary objectives will evaluate the preliminary anti-tumor activity of BDC-4182, analyze PK characteristics of BDC-4182, and evaluate the immunogenicity of BDC-4182 as a single agent. Exploratory analyses will also be conducted to explore potential biomarkers in blood and tumor tissue associated with exposure, efficacy, or safety of BDC-4182, and to investigate and define CLDN18 expression in tumor tissue. This study is being conducted in Australia, South Korea, and Taiwan.