Abstract A110: Proteasome inhibitor (PI) ADC: A novel broad spectrum payload platform

Abstract Antibody-drug conjugates (ADCs) are a therapeutic modality that combines the targeting precision of monoclonal antibodies with the potent cytotoxicity of small-molecule drugs. Despite recent progress of ADC technology in treatment of cancer, efficacy and safety profile of ADCs is often limited by the characteristics of the payloads, highlighting the need for continued innovation in payload selection strategies. To address the unmet needs, we developed a novel class of ADC payload platform employing a novel payload class that disrupts proteostasis by inhibiting a critical component of the cellular protein degradation machinery. Upon internalization, the proteasome inhibitor (PI) payload can block tumor specific protein degradation pathway such as inhibitor of kappa B (IkB) degradation in hematologic malignancies or can induce the accumulation of misfolded and damaged proteins, leading to apoptotic cell death- particularly effective in tumor cells with high protein turnover. Various antibodies were conjugated with PI payload using different conjugation technologies, generating PI-ADCs for the treatment of solid tumors or hematologic malignancies. The resulting ADCs demonstrated efficient intracellular delivery and payload-dependent activity. Strong in vitro cytotoxicity and robust in vivo anti-tumor efficacy were observed across multiple preclinical tumor models, including those with limited sensitivity to existing ADC therapies. These findings highlight the potential of a new broad spectrum payload class to overcome resistance mechanisms and expand the therapeutic landscape of ADCs across diverse malignancies. Citation Format: Won-Gyun Ahn, Jaehee Jang, Seung-Joo Lee, Yong Soo Kim, Jaeseung Kim, Robert Huber, Uwe Koch, Johannes Bange, Martin Huber, Bert Klebl, Kiyean Nam. Proteasome inhibitor (PI) ADC: A novel broad spectrum payload platform [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A110.