Derivation of AZD5335, a novel FRα-targeted TOP1i-loaded ADC, for the treatment of FRα-expressing cancers

Abstract Purpose: Folate receptor alpha (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 ADCs 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 to an Elahere-analog. 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 (2.5mg/kg) achieved an overall response rate of 82% in ovarian cancer patient-derived xenografts (n=17). Anti-tumor responses were observed in models expressing both high and low levels of FRα. Specifically within FRα low models, AZD5335 demonstrated superiority over an Elahere-analog. 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.