# A Novel FGFR3‐Targeting Antibody‐Drug Conjugate Induces Tumor Cell Apoptosis through the cGAS–STING Pathway in Bladder Cancer

## TL;DR

A new antibody-drug conjugate targeting bladder cancer cells shows strong tumor-killing effects by activating a specific pathway and outperforms standard chemotherapy.

## Contribution

A novel FGFR3-targeting ADC with A2 as a payload is developed, inducing apoptosis via the cGAS–STING pathway in bladder cancer.

## Key findings

- LZU-WZLYCS01 shows potent tumor-targeting and bystander effects in preclinical models.
- The ADC demonstrates superior antitumor efficacy compared to gemcitabine-cisplatin chemotherapy.
- It maintains activity in chemotherapy-resistant PDX models and shows favorable safety.

## Abstract

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.

LZU‐WZLYCS01 is a novel FGFR3‐targeting ADC for bladder cancer with 7‐ethyl‐9‐fluorocamptothecin (A2) as its cytotoxic payload. LZU‐WZLYCS01 intracellularly releases A2, which targets MAD2L1 to activate the cGAS‐STING pathway and induce tumor cell apoptosis. LZU‐WZLYCS01 demonstrates potent antitumor efficacy across cellular models, PDOs, and CDX/PDX models. This breakthrough may provide a new strategic option for the precision therapy of bladder cancer.