Abstract 6755: Discovery of the synergistic dual-payload antibody-drug conjugate (CTPH-02) by combination of MMAE and novel payloads

Abstract Many ADC drugs in clinical trials are showing poor performance without providing sufficient dose due to dose-limiting toxicity, which is rooted from on-target toxicity related to payload itself. There are many efforts to increase the therapeutic index (TI) of ADC, but research on discovering novel payloads based on unique anticancer mechanisms of action is relatively limited. We have developed unique ADC platform technology by adopting multi-drug payloads concept, where we aim to achieve three different goals, (1) increasing MTD and lowering MED (2) showing cytotoxic activity in antigen low-expressed cell lines (3) overcoming resistance cell lines with better cytotoxic effects. This study began with the search for a drug combination that could maintain or increase efficacy of MMAE even with lower dose of MMAE. Drugs with various mechanisms of action were tested to select a combination that showed a high synergy effect with MMAE, and a cell cycle regulating drug was found to offer the most synergistic combination efficacy with MMAE. By conjugating a dual-payload with two-different mechanisms of action to HER2 antibody(trastuzumab), the resulting ADC(CTPH-02) was confirmed to show synergistic effect in terms of cytotoxicity. Very excitingly, CTPH-02 shows significantly high synergistic efficacy in the case of cell lines with low HER2 antigen expression. These findings based on the right combination of two-different payloads open a new paradigm for ADC drug design strategies in cancer therapy in order to provide treatment options to wider range of cancer patients such as low TPS % with low IHC score. Citation Format: Chang-Sun Lee, Myeong Joo Kim, Da hyun Kim, Soyeon Lim, Jiwoo Lee, Eunseok Choi, Wonbin Ha, Han ah Kim, Jaebeom Park, Seung Chan Kim. Discovery of the synergistic dual-payload antibody-drug conjugate (CTPH-02) by combination of MMAE and novel payloads [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 6755.