Abstract Antibody-drug conjugates (ADCs) targeting Nectin-4 have emerged as a promising therapeutic approach particularly in urothelial carcinoma (UCs). However, currently available Nectin-4 directed ADCs are often limited by narrow therapeutic index and dose-limiting toxicities. SBE303 is a novel Nectin-4 targeting ADC engineered to improve the therapeutic window by combining a highly specific anti-Nectin-4 antibody conjugated with a potent novel topoisomerase I inhibitor via a proprietary beta-glucuronide-based cleavable linker, OHPASTM. For nonclinical characterization of SBE303, a comprehensive set of pharmacology, pharmacokinetics, and toxicology studies was performed. In vitro studies have shown that the antibody of SBE303 exhibits specific binding to the human Nectin-4. Upon binding, SBE303 internalizes into cancer cells, which then traffics to the lysosomal compartment where payload is released via beta-glucuronidase cleavage of the linker. Released payload induces DNA topoisomerase I inhibition, triggering cytotoxicity in various cancer cells. The antitumor efficacy of SBE303 was evaluated across multiple Nectin-4 positive cell-derived xenograft models including UC. SBE303 treatment resulted in marked and statistically significant tumor growth inhibition compared to vehicle controls on week 3, supporting the broad therapeutic potential in solid cancers. Pharmacokinetic properties were evaluated in mice, rats, and monkeys. Comparable profiles between SBE303 and total antibody showed the linker stability in systemic circulation, supported by minimal free payload exposure. Novel free payload showed low risk of drug-drug interaction potential for metabolic enzymes and drug transporters. In repeat-dose toxicity study in cynomolgus monkeys, IV administration of SBE303 was well tolerated at 40 mg/kg/dose. No severe systemic toxicity or unexpected target-related findings were observed, including skin toxicity. SBE303-related findings were limited to minimal-to-moderate changes and were reversible at the end of the recovery period. The absence of significant histopathologic changes indicated a favorable systemic safety profile. These nonclinical findings support the advancement of SBE303into clinical development with a favorable therapeutic index based on higher tolerated doses and wider exposure margins compared to known approved anti-Nectin4 ADC. A first-in-human study is expected to initiate in 2026. Citation Format: Ji Yeon Kim, Sungwoo Hyung, Hyun-Ji Choi, Songhyun Lim, Jae Hee Lee, Seokuee Kim, Donghyun Kim, So-Shin Ahn, Donghoon Shin. Nonclinical characterization of SBE303: A nectin-4 targeted antibody drug conjugate (ADC) with novel topoisomerase 1 inhibitor shows a favorable safety margin 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 1815.
Kim et al. (Fri,) studied this question.