一种新型协同双载荷 FRalpha ADC（CTPH-08），通过改善 MTD 和 MED 有望为低 IHC+ 卵巢癌患者带来获益

Dual-payload antibody drug conjugates (ADCs) have achieved increasing traction as a next-generation ADC technology to improve the therapeutic window of single-payload ADCs. By integrating two different payloads having distinct modes of actions, dual-payload ADC platforms can offer opportunities to counter tumor heterogeneity, or to reduce the likelihood of resistance that often emerges with the single-payload ADCs. We have pursued novel dual-payload ADC formats that can provide synergistic activity as well as minimal overlapping toxicity due to complementary acting mechanisms from two different payloads. A few combinations of payloads have been found to demonstrate synergistic cytotoxicity, which have been successfully incorporated into ADCs to confirm the novel dual-payload ADC(AD 2 C) concept. Although folate receptor-alpha (FRalpha) represents a clinically validated antigen as highlighted by the approval of Elahere, clinical benefit is yet to remain limited due to dose-limiting toxicities and suboptimal response durability. To address these shortcomings, we have generated dual-payload FRalpha ADC (AD 2 C) designed to enhance anti-tumor activity without exacerbating systemic toxicity. This presentation covers a comprehensive characterization of FRalpha AD 2 C including in vitro cytotoxicity for cancer cells with different levels of FRalpha expression, in vivo anti-tumor activities in FRalpha-positive CDX models, in vivo stability of FRalpha AD 2 C via pharmacokinetic assessment in rats, and preliminary safety evaluation in mice. We are currently advancing dual-payload FRalpha ADC(AD 2 C) toward PDX efficacy studies and GLP toxicology studies in order to proceed to Ph1 IND filing in due course.