Abstract 6930: Preclinical efficacy of BCG018, an ADC targeting ITGB6 and incorporating a topoisomerase I inhibitor payload, was demonstrated to be effective in PDX models

Abstract Integrin αvβ6 is a heterodimer composed of αv and β6 subunits that is primarily found on the surfaces of epithelial cells and is known to be upregulated during the epithelial-mesenchymal transition (EMT). Its overexpression in various solid tumors, which correlates with poor patient prognosis, makes it a promising target for ADC therapy. However, the large size and complexity of the integrin family present significant challenges in developing specific antibodies. In our studies, we identified the anti-ITGB6-B antibody, which selectively binds to ITGB6 over other beta integrins. This specificity was established using fully human common light chain RenLite mice with ITGB6 knockout. The anti-ITGB6-B antibody demonstrated good binding affinity for both ITGB6 and its heterodimer αvβ6, outperforming the benchmark, as confirmed by SPR and ELISA experiments. Furthermore, anti-ITGB6-B exhibited excellent binding characteristics across multiple tumor cell lines, effectively targeting cells with varying levels of ITGB6 expression. Importantly, its internalization activity was found to be comparable to or greater than that of the benchmark, enhancing its potential for therapeutic applications. Notably, the anti-ITGB6-B did not block the interaction of ITGB6 with its ligand LAP in ELISA assays, indicating its potential as a targeted therapy without disrupting critical signaling pathways. The anti-ITGB6-B also exhibited excellent physicochemical properties and developability, making it a promising candidate for further development in ADC therapy. The anti-ITGB6-B was then conjugated to vcMMAE. The resulting conjugate demonstrated superior efficacy to that of the benchmark ADC in PDX models, regardless of ITGB6 expression levels. Additionally, the BCG018, which is anti-ITGB6-B conjugated with a novel topoisomerase I inhibitor (BLD1102), showed superior efficacy to benchmark ADC in models of pancreatic, colorectal, and NSCLC PDX or CDX xenografts. Overall, BCG018 conjugates offer a promising strategy for targeting integrin αvβ6 in solid tumors with specific and potent efficacy. Citation Format: Yi Yang, Mengran Li, Chengzhang Shang, . Preclinical efficacy of BCG018, an ADC targeting ITGB6 and incorporating a topoisomerase I inhibitor payload, was demonstrated to be effective in PDX models 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 6930.