Abstract 3169: Development of conformation selective ITGB6 ADC

Abstract Integrin β6 (ITGB6), an epithelial receptor upregulated in fibrotic diseases and epithelial-derived cancers, drives tumor progression by regulating immunosuppression, therapeutic resistance, and metastatic processes. Conventional antibodies lack conformational specificity, often resulting in on-target, off-tumor toxicity. To address this, we developed HC029, a novel activation-state-selective anti-ITGB6 monoclonal antibody and antibody-drug conjugate (ADC) designed to specifically target disease-specific ITGB6 conformation while sparing physiological state ITGB6 unaffected. HC029 binds to a unique conformational epitope exposed on activated ITGB6, achieving 100-fold selectivity for disease-specific ITGB6. Binding affinity increases proportionally with disease severity, as demonstrated by enhanced HC029 ITGB6 engagement in the presence of cancer associated fibroblast (CAF) and latency-associated peptide (LAP) predominantly present in tumor microenvironment. HC029 demonstrated weak and partial inhibition on pathological ITGB6 signaling pathway while preserving physiological ITGB6 function. Furthermore, HC029 incorporates an Fc-silenced human IgG1 which further mitigates off target toxicity. HC029 conjugated with camptothecin derivatives (HC029-CPT) retains ITGB6 conformation-dependent binding, selectively kills cancer cells in the presence of CAF and LAP while sparing cells under physiological conditions. In vivo, HC029-CPT demonstrated potent antitumor activity across multiple PDX and CDX in vivo models including NSCLC, HNSCC, and BLCA, with no significant weight loss or severe toxicity observed. Exploratory pharmacokinetic and toxicology studies in non-human primate demonstrated that HC029-CPT has a maximum tolerated dose (MTD) exceeding 60 mg/kg, with no drug-related mortality observed. Comprehensive evaluations revealed no significant hematological, biochemical, coagulation, or histopathological abnormalities in potential target organs. HC029-CPT exhibited typical ADC pharmacokinetics in cynomolgus monkeys, with dose-proportional exposure of the intact ADC, total antibody, and payload. The linker-payload was highly stable in both in vitro and in vivo studies, with minimal payload release (0.0001%) from the ADC in plasma. Combining ITGB6 disease state selectivity, unique conformational epitope, effector null Fc, extra stable linker payload and safety profile, HC029-CPT expects to achieve a much broader therapeutic window compared to conventional ITGB6 ADC targeting therapeutics. Citation Format: Xiaofei Zhou, Huijie Zhao, Liuge Gu, Guoping Jiang, Wenkai Zhao, Jiangbo Song, Teddy Yang, Ying Lei, Li Tong, Fei Peng, . Development of conformation selective ITGB6 ADC abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3169.