Abstract 5652: Preclinical development of LUA011, a novel CDH17/cMET bispecific ADC with enhanced antitumor efficacy and mitigated gastrointestinal toxicity.

Abstract Background: CDH17 is an emerging ADC target in gastrointestinal (GI) cancers due to its overexpression in colorectal, gastric and pancreatic tumors. However, CDH17-directed ADCs suffer on-target GI toxicities. cMET is a clinically validated target in GI malignancies with limited expression in some normal tissues. Expression profiling shows that CDH17 and cMET are frequently co-expressed in GI tumors, while seldomly co-expressed in normal tissues. Therefore, targeting both CDH17 and c-Met might improve therapeutic index and maintain or even enhance efficacy. Here we report the preclinical development of LUA011, a bispecific ADC targeting both CDH17 and cMET, with a proprietary TOPO1i payload conjugated to the antibody via a glycan-based platform. Results: LUA011 was selected from a panel of bispecific ADC formats based on a comprehensive evaluation of pharmacokinetic properties, in vivo efficacy, and overall developability. Both LUA011 and its unconjugated bispecific antibody moiety exhibited strong binding to CDH17-positive and cMET-positive GI cancer cell lines, with EC50 values in the nanomolar range. Rapid internalization of the antibody component was observed in multiple GI cancer cell lines expressing CDH17 and/or cMET. In vitro, LUA011 demonstrated potent and specific cytotoxicity against cell lines positive for CDH17, cMET, or both targets, with enhanced activity compared to CDH17 mono-specific ADCs in CDH17 and cMet dual-positive cell lines. LUA011 demonstrated significantly superior antitumor efficacy over CDH17- and cMET-targeting monospecific ADCs across multiple gastrointestinal CDX and PDX models with varying target expression levels. This enhanced activity was consistently observed even when compared to its own CDH17-parental ADC and a benchmark CDH17-specific ADC conjugated with the same linker-payload, underscoring that the therapeutic advantage stems from the bispecific format and the synergistic effect of dual targeting CDH17 and cMET. LUA011 exhibited high stability in human and cynomolgus monkey plasma, with minimal payload release and maintained DAR. In cynomolgus monkeys, LUA011 displayed favorable pharmacokinetics and a promising safety profile, with a maximum tolerated dose exceeding 30 mg/kg. Conclusions: LUA011 is a novel bispecific ADC targeting both CDH17 and c-Met with favorable physicochemical properties, strong target binding, cellular internalization and potent antitumor activity in preclinical GI cancer models. Its dual targeting activity, along with its optimized payload, conjugation method, and DAR value, contribute to its strong anti-tumor efficacy, improved therapeutic index, and reduced GI toxicities. Further investigation is warranted to advance this promising ADC into clinical development. Citation Format: Guoyin Huang, Ken Qin, Man Wu, Lei Han, Ying Huang, Wei Zheng, Xiaoshuang Yan, luchan deng, Hai Wu, Wenshu Huang, Shuyong Zhao, Ling Zhang, Yang Yang, Hua Ying, Weikang Tao. Preclinical development of LUA011, a novel CDH17/cMET bispecific ADC with enhanced antitumor efficacy and mitigated gastrointestinal toxicity 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 5652.