Abstract 2873: Preclinical development of SMP-656: An eribulin-SuperHydraTM linker based ADC

Abstract Background: To date, 15 ADCs have been globally approved, 9 of which employ Michael addition reactions between maleimide and the free thiol groups of antibodies. This reaction is characterized by high selectivity, mild conditions, and rapid kinetics. However, the retro-Michael addition reaction in vivo can reverse this process, leading to payload detachment, which compromises the drug’s efficacy and safety. The SuperHydraTM linker promotes maleimide ring-opening via ortho effects, preventing retro-Michael deconjugation and enhancing ADC stability. Consequently, ADCs with the SuperHydraTM linker demonstrate remarkable efficacy, safety, and better stability as represented by our clinical stage candidate, SMP-656, a HER2-eribulin ADC. Methods: SuperHydra™ linkers were designed with varying ortho groups, distances, and pro-hydrolysis group optimizations. A medium hydrolysis-rate linker was chosen for SMP-656 to balance stability during CMC stages with controlled hydrolysis in circulation, ensuring ADC homogeneity. Comparative studies of SMP-656 vs. DS-8201a were performed in vitro and in vivo. Additionally, we evaluated SMP-656's cytotoxicity against DS-8201a-induced resistant cells and cells overexpressing the DXd efflux pump. Bystander effects, critical for DS-8201a efficacy, were assessed for SMP-656. Repeat-dose PK and toxicology studies in non-human primates provided PK data and HNSTD. Results: SMP-656 demonstrated significantly higher efficacy than DS-8201a in various cancer cell lines, including DS-8201a-resistant gastric cancer and HER2-low breast cancer cells. It retained potency in resistant models where DS-8201a was ineffective, highlighting its potential for treating resistant and HER2-low patients.In vivo studies showed that SMP-656 achieved higher tumor growth inhibition rates than DS-8201a, with only half the DAR and one-third the dosing amount. This translates to superior tumor inhibition with one-sixth the toxin dosage, highlighting its enhanced safety profile. In NCI-N87 xenografts model, SMP-656 extended tumor inhibition to 62 days at an equivalent payload dose 0.08 mpk (single dose), compared to DS-8201a's 23 days. SMP-656 also demonstrated significant bystander effects, addressing tumor heterogeneity.Repeat-dose PK studies showed high concordance between ADC and total antibody concentration curves, confirming SuperHydraTM linker stability. Additionally, SMP-656 achieved an HNSTD of 10 mpk, representing the highest safety profile among eribulin-based ADCs known to date. Conclusions: The SuperHydraTM linker enabled SMP-656 to combine superior stability, efficacy, and safety with the ability to overcome DS-8201a resistance. SMP-656 represents the safest and most effective eribulin-based ADC and is currently in Phase I clinical trials, showing promising tolerability and efficacy. Citation Format: Jinkun Huang, Chenglong Wu, Chaoyang Feng, Xiaojie Heng, Tingting Yang, Rang Gao, Tianyi Ke. Preclinical development of SMP-656: An eribulin-SuperHydraTM linker based ADC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2873.