SMP-656: A self-catalyzed ring-opening hydrolysis linker-based ADC with enhanced stability and antitumor efficacy.

Maleimide-based conjugation, the predominant strategy in approved antibody-drug conjugates (ADCs), is susceptible to retro-Michael deconjugation, resulting in premature transfer of the linker-payload moiety to serum proteins rather than free payload release and reduced therapeutic index. Here, we report SuperHydra, a self-hydrolyzing maleimide linker that undergoes rapid post-conjugation ring-opening hydrolysis to irreversibly stabilize the thiosuccinimide linkage and suppress retro-Michael deconjugation. Incorporation of SuperHydra into the HER2-targeting ADC SMP-656, comprising the antibody Inetetamab and the microtubule inhibitor Eribulin, resulted in markedly enhanced plasma stability while preserving HER2 binding, internalization, Fc-mediated effector function, and bystander killing. SMP-656 exhibited potent antigen-dependent cytotoxicity, retained activity in DS-8201a-resistant tumor models, and achieved durable antitumor efficacy in multiple HER2-positive xenograft models. In cynomolgus monkeys, SMP-656 demonstrated favorable pharmacokinetic properties and an acceptable safety profile. Collectively, these findings establish SMP-656 as a promising HER2-targeting ADC, support its ongoing clinical evaluation in HER2-expressing solid tumors, and highlight the potential of the SuperHydra linker as a versatile platform for improving the stability and overall performance of maleimide-based ADCs.