DXC011, a novel dual-payload antibody-drug conjugate targeting folate receptor alpha

Folate Receptor alpha (FRalpha) is highly expressed in epithelial ovarian cancer and selected solid tumors, making it an attractive target for antibody-drug conjugates (ADCs). Although an FRalpha-directed ADC Elahere has already achieved clinical approval, this microtubule inhibitor-based agent faces challenges, such as ocular toxicity, narrow therapeutic windows, and limited activity beyond ovarian cancer. To address these limitations, we developed DXC011, a next-generation FRalpha-targeting ADC engineered to enhance antitumor efficacy while improving tolerability. DXC011 comprises DXA011, a humanized IgG1 antibody specific for FRalpha, an optimized cleavable linker and a dual functional payload. This dual-payload strategy introduces complementary cytotoxic mechanisms and may help overcome resistance associated with single-mechanism ADCs. DXC011 demonstrated potent activity across multiple FRalpha-expressing in vitro and in vivo tumor models, encompassing ovarian cancer as well as additional solid tumor types. Beyond established ovarian cancer settings, DXC011 showed notable efficacy in gastrointestinal tumor models, supporting its potential for broader clinical application. Moreover, DXC011 displayed favorable tolerability in mouse, with an improved safety profile relative to microtubule inhibitor-based ADC while maintaining robust antitumor potency. Collectively, these findings indicate that DXC011 offers an improved therapeutic index and may enable expanded indication coverage. DXC011 represents a novel FRalpha-targeted dual-payload ADC that achieves potent and broad antitumor activity with enhanced tolerability, supporting its advancement toward clinical development.