A Novel FGFR3-Targeting Antibody-Drug Conjugate Induces Tumor Cell Apoptosis through the cGAS-STING Pathway in Bladder Cancer.

Antibody-drug conjugates (ADCs) emerge as a potent cancer therapeutic strategy by enabling precise antigen recognition and efficient intracellular delivery of cytotoxic payloads. In this study, 7-ethyl-9-fluorocamptothecin (A2), a camptothecin derivative, which demonstrates potent tumor-suppressive effects across cellular models, patient-derived organoids (PDOs), and cell line-derived xenograft/patient-derived xenograft (CDX/PDX) models is identified. Through pull-down/mass spectrometry analysis, MAD2L1 is identified as the direct target of A2. A2 specifically binds to the Lys73 site of MAD2L1, activating the cGAS-STING pathway and thereby inducing apoptosis in bladder cancer cells. To address the dose-limiting toxicity caused by A2's insufficient targeting capability, LZU-WZLYCS01, a novel FGFR3-targeting ADC for bladder cancer with A2 as its cytotoxic payload is developed. LZU-WZLYCS01 exhibits precise FGFR3-dependent targeting, with significantly reduced antitumor activity in both FGFR3-knockout cell models and xenograft models. Moreover, in vivo fluorescence imaging demonstrates the potent tumor-targeting capability of LZU-WZLYCS01. LZU-WZLYCS01 demonstrates remarkable bystander effects in an in vitro co-culture model, along with potent tumor growth inhibition in PDOs and CDX/PDX models while maintaining favorable safety. Notably, LZU-WZLYCS01 shows superior antitumor efficacy to gemcitabine-cisplatin (GC) chemotherapy and maintains significant activity in GC-resistant PDX models. These findings present a promising therapeutic candidate for targeted bladder cancer treatment.