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

  • Clin Cancer Res. 2025 Dec 15;31(24):5261-5275. doi: 10.1158/1078-0432.CCR-25-1749.
Jason J Zoeller  1 ,  Ravinder Tammali  1 ,  Roger B Dodd  2 ,  Neki V Patel  3 ,  Alma Andoni  1 ,  Ina Bisha  4 ,  Shane Cronin  1 ,  Ana De Almeida  5 ,  Nancy Lee  1 ,  John H Meekin 3rd  1 ,  Isabella Tilmont  1 ,  Diana Gasper  1 ,  Lingyun Lan  1 ,  Megan Cox  1 ,  Tima Thomas  1 ,  Christopher Ward  1 ,  Jon Chesebrough  1 ,  Judith Anderton  2 ,  Frances Neal  2 ,  Zenon Zenonos  2 ,  Harini Shandilya  2 ,  K Phin Chooi  3 ,  Kathryn Pugh  3 ,  Ali Saleh  3 ,  Jixin Wang  1 ,  Pat Mitchell  5 ,  Humaira Naseer  2 ,  Kevin Beaumont  2 ,  John Hood  2 ,  Claire Myers  1 ,  Simon Christ  4 ,  Iris Dino  4 ,  Xhenifer Guza  4 ,  Tillmann Falck  4 ,  Michael Lehmann  1 ,  Rebecca Sargeant  2 ,  Lisa Godfrey  2 ,  Benedicte Recolin  2 ,  Tim Brier  2 ,  Simon Turner  2 ,  Edward Rosfjord  1 ,  Paula G Fraenkel  5 ,  Sabina Cosulich  2 ,  Marco Gymnopoulos  1 ,  Elaine Hurt  1 ,  Puja Sapra  1
Affiliations
  • 1. AstraZeneca, Gaithersburg, Maryland.
  • 2. AstraZeneca, Cambridge, United Kingdom.
  • 3. AstraZeneca, London, United Kingdom.
  • 4. AstraZeneca, Munich, Germany.
  • 5. AstraZeneca, Waltham, Massachusetts.
PMID: 41091103 DOI: 10.1158/1078-0432.CCR-25-1749
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.

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