Abstract IA023: Dual-drug ADC platform for effective and safe cancer treatment

Abstract

Abstract Breast tumor heterogeneity presents significant treatment challenges, particularly in overcoming drug resistance and tumor relapse driven by heterogeneous gene expression variability. Antibody-drug conjugates (ADCs) have demonstrated therapeutic success, yet intratumor heterogeneity remains a hurdle. We investigated dual-drug ADCs as a promising approach to address this clinical challenge. Our conjugates achieved potent and antigen-specific cytotoxicity, favorable pharmacokinetic properties, and high tolerability. In xenograft models with heterogeneous HER2 expression, our anti-HER2 dual-drug ADC significantly outperformed co-administration of two separate single-drug ADCs, demonstrating enhanced capacity to surmount tumor heterogeneity and resistance. Additionally, we developed a novel glutamic acid-glycine-citrulline (EGCit) linker, which enhances ADC hydrophilicity and stability in circulation. This EGCit linker also resists neutrophil protease degradation, a factor implicated in ADC-associated neutropenia. Compared to currently approved ADCs, our EGCit-based ADC exhibited reduced blood and liver toxicity, alongside superior antitumor efficacy in preclinical xenograft studies. These findings underscore the potential of our technology platform for advancing safer, more effective treatments for breast and other refractory cancers. Citation Format: Kyoji Tsuchikama. Dual-drug ADC platform for effective and safe cancer treatment [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr IA023.