Abstract 1320: Interim results of clinical trial phase 1 of pan-mKARS or PTEN loss tumor targeting peptide drug conjugates (Maleimide-KGDEVD-Doxorubicin/Exatecan).

Abstract mKRAS and PTEN alterations are highly prevalent across multiple cancer types - occurring in approximately 45% of colorectal cancers (CRC) and up to 30-50% of non-small cell lung cancers (NSCLC) - yet they remain largely undruggable. These malignancies exhibit enhanced albumin metabolism and macropinocytosis to sustain their elevated metabolic demands, presenting a unique opportunity for selective, metabolism-guided drug delivery. We developed a next-generation platform of albumin-binding peptide drug conjugates (PDCs) to target mKRAS and/or PTEN loss tumors. The lead candidate, MPD-1 (Maleimide-KGDEVD-Doxorubicin), represents the first clinical-stage prototype in this series. MPD-1 couples a maleimide anchor for covalent albumin conjugation with a dual-cleavable KGDEVD linker that responds to both cathepsin B and caspase-3/7, enabling highly selective, apoptosis-responsive payload release within the tumor microenvironment. This dual-trigger mechanism ensures intracellular liberation of doxorubicin through lysosomal cathepsin B activity and secondary amplification via caspase-3/7 cleavage in neighboring apoptotic cells - sustaining cytotoxic activity through in-situ feedback amplification and a potent bystander effect. Preclinical studies demonstrated that MPD-1 exhibits strong antitumor efficacy in mKRAS-mutant colorectal and PTEN-loss NSCLC models, with approximately ten-fold lower systemic toxicity than free doxorubicin. Combination regimens with radiation, PARP inhibition, DNA-PK blockade, or immunotherapy yielded further synergistic effects. The ongoing Phase I clinical trial [NCT06944457] is open-label, single-center, dose-escalation and dose-finding trial to evaluate the MTD, RP2D and pharmacokinetics of MPD-1 in patients with advanced mKRAS and/or PTEN loss solid tumors. We are going to report the interim results of clinical study of MPD-1 as a first-in-class, caspase/cathepsin-responsive, albumin-binding peptide drug conjugate. We next engineered MPD-5 (Maleimide-KGDEVD-Exatecan) as a second-generation conjugate optimized for higher potency. MPD-5 extends the platform to topoisomerase I inhibition, and it showed superior efficacy in various mKRAS cancers and PTEN loss cancers. Acknowledgments: This research was supported by the Korea Drug Development Fund (HN21C0264). Citation Format: Byoungmo Kim, Ha Kyeoung Lee, Yun-Gun Ko, Kyu-pyo Kim, Youngro Byun, Sang Yoon Kim. Interim results of clinical trial phase 1 of pan-mKARS or PTEN loss tumor targeting peptide drug conjugates (Maleimide-KGDEVD-Doxorubicin/Exatecan) [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 1320.