An Integrin β6–Targeted Antibody–Drug Conjugate Optimized for Intravesical Delivery to Treat Non–Muscle-Invasive Bladder Cancer

Abstract Non–muscle-invasive bladder cancer (NMIBC) accounts for 75% of all new bladder cancer diagnoses. Despite new therapeutic treatment options aiming to replace Bacillus Calmette–Guérin (BCG), the standard of care for 40+ years, high rates of failure and recurrence of disease remain in patients with NMIBC. Integrins are a large family of cell surface receptors involved in key biological processes such as cellular adhesion, motility, and cytokinesis, and integrin β-6 (IB6) has emerged as a clinically relevant target due to its restricted expression in normal adult epithelial tissues and elevated levels in solid tumors. IB6 is being actively tested in lung cancer with the antibody–drug conjugate (ADC) sigvotatug vedotin. In this study, we introduce PF-08052667, an IB6-directed ADC that has been optimized for local delivery via intravesical dosing in patients with NMIBC. PF-08052667 leverages the high and consistent expression of IB6 in NMIBC tumors for efficient ADC internalization. In PF-08052667, an average of 8 monomethyl auristatin E molecules are attached to an IB6-specific humanized IgG1 antibody via a glucuronide linker shown to increase potency in vitro. PF-08052667 efficacy was further optimized when administered after a bladder prewash, which improved ADC delivery to the bladder tissue. The combination of highly potent PF-08052667 with bladder prewash demonstrated enhanced in vivo efficacy while maintaining minimal systemic exposure and no systemic toxicity. Together, the results position PF-08052667 as a potential first-in-class ADC optimized for intravesical delivery and support further clinical examination in an ongoing phase I trial testing safety and efficacy in BCG-unresponsive and BCG-exposed NMIBC (NCT07206225).