Abstract 5467: Therapeutic potential of antibody-drug conjugate with PARP1 selective inhibitor as a payload: A promising therapeutic approach for potent antitumor efficacy with reduced toxicity

Abstract Poly (ADP-ribose) polymerase inhibitors (PARPi) have been extensively studied as anticancer agents that selectively induce cancer cell death by disabling complementary DNA repair pathways. Despite PARPi’s initial effectiveness, tumors often develop drug resistance, limiting the long-term effectiveness of these drugs. Combining PARPi with chemotherapeutics or other DNA damage response inhibitors have been explored to enhance the efficacy and overcome resistance. However, these combinations had significantly more side effects, highlighting the need for innovative therapeutic approaches that preserve anti-tumor efficacy while minimizing side effects. Incorporating PARPi as a payload within an antibody-drug conjugate (ADC) may offer a promising strategy for targeted delivery to tumor cells, to overcome drug resistance and to reduce systemic toxicity. To establish proof-of-concept, a TROP2 antibody was conjugated with a PARP1 selective inhibitor using a cleavable linker. In vitro cytotoxicity assays were conducted in MDA-MB-436, MDA-MB-468, and HCC1937 cell lines to compare the effects with the naked mAb, ADC, and free payload. An in vivo efficacy study was conducted using the MDA-MB-436 subcutaneous xenograft model in NOD-SCID mice. The PARPi payload was confirmed to be PARP1 selective via surface plasmon resonance and trapping assays. In vitro, ADC demonstrated potent cytotoxicity in MDA-MB-436 cells, which are known to be PARPi-sensitive with low levels of TROP2 expression, with an IC50 value of approximately 1 nM, whereas the naked mAb showed no cytotoxicity. In contrast, MDA-MB-468 and HCC1937 cells (with high levels of TROP2 expression and homologous recombination proficiency) showed cytotoxicity, only with free payload at high concentrations. In vivo, ADC and the free payload induced tumor regression and sustained antitumor effects, whereas the naked TROP2 mAb showed no efficacy. Hematological analysis reveals that the ADC-treated groups showed improved side effects compared to the free payload group. This study highlights the potential of a PARP1 selective inhibitor as an ADC payload, utilizing ADC as a drug delivery system, to achieve substantial antitumor activity with reduced side effects in vitro and in vivo. These findings emphasize the enhanced safety of PARP1i-based ADC compared to standalone PARP1 inhibitor, enabling novel strategies such as combination therapies or dual-payload ADC apporaches to effectively overcome drug resistance. Citation Format: Jina Koo, Jeong Eun Kim, Hyeon Woong Park, Won Sik Lee, Myongjae Lee. Therapeutic potential of antibody-drug conjugate with PARP1 selective inhibitor as a payload: A promising therapeutic approach for potent antitumor efficacy with reduced toxicity [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 5467.