Abstract 5810: The impact of scaffold, linker, homogeneity and payload selection on the efficacy and tolerability of anti-tubulin ADCs

Abstract Antibody-drug conjugates (ADCs) achieve targeted drug delivery to a tumor and have demonstrated clinical success in many tumor types. The properties of an ADC, including its activity and safety profile, can be highly influenced by its characteristics and individual components, commonly viewed as the antibody, payload, linker, and drug-to-antibody ratio (DAR). However, multiple other characteristics can also significantly influence an ADC’s overall drug-like properties, including DAR homogeneity, method of bioconjugation, hydrophilicity, and charge balance. Due to the multiparametric nature of ADC platform optimization, there are few examples in preclinical research, and even fewer in the clinical realm, where comparisons across platforms have been investigated for the same target, both preclinically and clinically, to elucidate how deliberate modifications in molecular design can improve drug-like properties and clinical outcomes. To that end, here we describe the improvements observed in preclinical characteristics, as well as their translational relevance to corresponding clinical characteristics. Two anti-NaPi2b ADCs were produced using two different platforms, XMT-1536 (Dolaflexin platform) and XMT-1592 (Dolasynthen platform), conjugated to the same antibody and employing the same payload. The Dolasynthen platform was deliberately designed, taking into account preclinical and clinical learnings from earlier ADC platforms, to improve both safety and efficacy. In addition, comparisons to clinically approved anti-tubulin ADC platforms are made to provide further context. Citation Format: Scott D. Collins, Natalie Keirstead, Marc Damelin, Dorin Toader, Katsu Ishida, Niyanta N. Kumar, Kelly L. Lancaster, Kalli C. Catcott, Annika Yau, Mohan Bala, Timothy B. Lowinger. The impact of scaffold, linker, homogeneity and payload selection on the efficacy and tolerability of anti-tubulin ADCs abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 5810.