Abstract 1683: Enhancing therapeutic efficacy and overcoming resistance with a novel dual-payload antibody-drug conjugate technology

Abstract Antibody-Drug Conjugates (ADCs) are promising oncology therapeutics that deliver cytotoxic payloads selectively to tumors. However, their efficacy is often limited by tumor heterogeneity, acquired resistance to single-agent payloads and off-target toxicity caused by premature linker cleavage. There is a critical need for next-generation ADCs to address these issues and broaden the therapeutic use of such modality. To address these challenges, we developed MLINK Duo, a dual-payload ADC technology combining plasma stability and controlled tumor-specific dual payload release. This technology enables the conjugation of a diverse range of dual payloads to antibodies, including combinations of well-established cytotoxic agents such as DM1, DM4, MMAE, and exatecan, as well as innovative new payload combinations. Here we show a proof of concept using a trastuzumab MLINK Duo ADC simultaneously delivering MMAE and exatecan (TmAb-MLINK Duo-MMAE/exatecan) at different drug-to-antibody ratios. The payload release mechanism was characterized biochemically, and the ADC stability was evaluated in mouse and human plasma. The TmAb-MLINK Duo-MMAE/exatecan was characterized for efficacy, pharmacokinetics and safety in non-clinical models. We also provide proof of synergy with other new dual-payload ADCs. The MLINK Duo ADCs exhibited low aggregation, high stability in circulation with minimal premature payload release, suggesting an improved therapeutic window. The specific enzymatic cleavage mechanism of the MLINK Duo linker technology was confirmed, demonstrating effective payload release. Crucially, the TmAb-MLINK Duo-MMAE/exatecan showed enhanced anti-tumor activity in several Cell-Derived Xenograft (CDX) models, maintaining efficacy and achieving tumor regression in CDX models that were resistant to the corresponding mono-payload ADCs (MMAE-ADC or exatecan-ADC). In addition, other MLINK Duo ADCs demonstrated clear synergistic anti-tumor effects compared to the treatment with single-payload ADCs. The pharmacokinetic profile of the TmAb-MLINK Duo-MMAE/exatecan supported favorable dosing schedules, and preliminary safety data showed a tolerable profile, validating the platform's clinical viability. In conclusion, we have developed a novel, stable, and versatile linker technology enabling the generation of innovative ADCs, including a highly promising dual-payload (MMAE/exatecan) configuration. The tested MLINK Duo ADCs could overcome resistance mechanisms prevalent against mono-payload ADCs and demonstrate potent synergy in vivo. This technology marks an important advancement in antibody-drug conjugate (ADC) technology, providing a promising approach to overcoming tumor resistance and potentially improving clinical outcomes in cancer therapy. Further translational development is ongoing. AI was used to assist abstract writing Citation Format: Antoine Attinger, Léo Marx, Diana Bianca Rocha Gomes, Vincent Gerusz, Min Ma, Viktoriia Postupalenko, Alain Monjardet, Nicolas Quesnot, Christophe Chardonnens, René Wuttke, Noémie Luong. Enhancing therapeutic efficacy and overcoming resistance with a novel dual-payload antibody-drug conjugate technology [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 1683.