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

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.