Abstract Antibody-drug conjugates (ADCs) are an expanding class of targeted cancer therapies, and innovations in linker and payload chemistry are critical to improving therapeutic index and clinical outcomes. We present four complementary strategies designed to enhance ADC performance and manufacturability. First, a novel linker adapter, N-(ortho-hydroxyphenyl)-N-methylcarbamate, enables controlled side-chain modification and rapid payload release, resulting in pronounced tumor regression in colonic cancer xenograft models. Second, a Val-Ala-based double self-immolative linker-payload platform was developed to optimize hydroxyl group-containing payload integration. A trastuzumab-DXd ADC constructed using this platform demonstrated improved stability, cathepsin B sensitivity, potent bystander effect, and a broad therapeutic index in HER2-positive and -negative xenografts, with favorable safety profiles in preclinical toxicology studies. Additionally, we introduce a streamlined two-step synthesis of a disaccharide linker for glycosite-specific conjugation, reducing the traditional 15-step process and enabling cost-effective production of homogeneous ADCs with enhanced quality and consistency. Finally, we report the first ADC incorporating homocamptothecin as a payload, achieving antitumor activity comparable to Enhertu at 3 mg/kg while demonstrating improved tolerability in NCI-N87 xenograft models. Collectively, these innovations establish a versatile platform for next-generation ADCs, combining precision targeting, improved pharmacological properties, and scalable manufacturing to advance clinical oncology. Citation Format: Gengcheng Jack Yang, Xudong Wei. Transforming ADC development with novel linker architectures and payload optimization 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 4435.
Yang et al. (2026) studied this question.