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

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).