Derivation of AZD5335, a Novel FRα-Targeted TOP1i-Loaded ADC, for the Treatment of FRα-Expressing Cancers

Abstract Purpose: Folate receptor α (FRα) is expressed in most ovarian cancers. However, only patients with high expression levels are eligible for Elahere, an FRα-targeted microtubule inhibitor antibody–drug conjugate (ADC). Efficacy limitations and safety concerns underscore the need to develop next-generation FRα-targeted ADC to treat tumors expressing variable levels of FRα and incorporate different payloads to reduce safety risks. Herein, we present the characterization of AZD5335, a novel FRα-targeted topoisomerase-1 inhibitor ADC. Experimental Design: The efficacy of AZD5335 was assessed and correlated with FRα expression using cell- and patient-derived models. Focusing on models with low FRα, AZD5335 was directly compared with an Elahere analogue. Additionally, AZD5335 was evaluated in a model of acquired Elahere resistance. Combined treatments, including AZD5335 plus either standard-of-care drugs or a PARP1 inhibitor, were also explored. Results: A single dose of AZD5335 (2.5 mg/kg) achieved an overall response rate of 82% in patient-derived ovarian cancer xenografts (n = 17). Antitumor responses were observed in models expressing both high and low levels of FRα. Specifically within FRα-low models, AZD5335 demonstrated superiority over an Elahere analogue. In the context of acquired Elahere resistance, AZD5335 treatments resulted in complete tumor regressions. Additionally, combining AZD5335 with standard-of-care drugs or a PARP1 inhibitor resulted in enhanced efficacy and sustained durability. Two clinical case studies that demonstrated significant AZD5335 responses in tumors exhibiting high and low FRα expression are also provided. Conclusions: AZD5335 is a promising next-generation ADC capable of targeting ovarian cancers with both high and low FRα expression. AZD5335 demonstrates efficacy in overcoming Elahere resistance and supports combined treatment strategies.