Abstract LB025: First disclosure of AZD5335, a TOP1i-ADC targeting low and high FRα-expressing ovarian cancer with superior preclinical activity vs FRα-MTI ADC
Authors: Gymnopoulos Marco , Thomas Tima , Gasper Diana , Anderton Judith , Tammali Ravinder , Rosfjord Ed , Durham Nick , Ward Chris , Myers Claire , Wang Jixin , Zhong Wenyan , Christ Simon , Meinecke Lina , Nekolla Katharina , Monasor Laura Sebastian , Dodd Roger , Patel Neki , Albertella Mark , Zeron-Medina Jorge , Fraenkel Paula , Sapra Puja 
Published: April 2023

Abstract
Folate receptor alpha (FRα) is a cell surface GPI-anchored protein overexpressed in several solid tumors with highest prevalence in ovarian cancer and lung adenocarcinoma but restricted expression in normal tissues. An antibody drug conjugate (ADC) with a microtubule inhibitor (MTI) payload recently received accelerated approval from the FDA for FRα-expressing platinum-resistant ovarian cancer. We describe for the first time the preclinical activity of AZD5335, an FRα-targeting antibody conjugated to AZ’s proprietary topoisomerase 1 inhibitor (TOP1i) payload, AZ14170132, with a homogeneous drug-to-antibody ratio of 8 (DAR8) and potential benefits vs an MTI-based ADC. AZD5335’s primary mechanism of action is to deliver TOP1i payload into FRα-expressing cancer cells, leading to DNA damage and apoptotic cell death. The TOP1i payload mediates bystander killing, which is important for targeting tumors with less than uniformly positive expression. Here, we report that a single dose of AZD5335 at 2.5 mg/kg was sufficient to provide a robust and durable anti-tumor response in FRα-expressing ovarian cancer cell line xenografts (CDX) with a tumor growth inhibition (TGI) of 75%-94% and median best tumor volume reduction &gt;30% in 14/17 (82%) ovarian cancer patient-derived xenografts (PDX) evaluated. FRα-expression levels (by IHC and deep-learning based image analysis) correlated with efficacy in the tested PDX models, and we observed that AZD5335 was also active in models with low levels of target expression (75% of cells with FRα staining of 2+), expected to be representative of patients who would be ineligible for treatment with the MTI-ADC. Furthermore, AZD5335 demonstrated superior activity vs an FRα-MTI benchmark ADC with respect to anti-tumor activity and duration of response in two PDX models with low-to-medium FRα expression at equal or higher drug doses (e.g., in OV0857-CIS: 96% TGI vs 24% TGI at 5 mg/kg and 95% TGI vs 2% TGI at 2.5 mg/kg of a single IV dose AZD5335 and FRα-MTI, respectively). These data indicate that AZD5335 is a promising therapeutic candidate for the treatment of ovarian cancers across the spectrum of FRα-expression.
Citation Format: Marco Gymnopoulos, Tima Thomas, Diana Gasper, Judith Anderton, Ravinder Tammali, Ed Rosfjord, Nick Durham, Chris Ward, Claire Myers, Jixin Wang, Wenyan Zhong, Simon Christ, Lina Meinecke, Katharina Nekolla, Laura Sebastian Monasor, Roger Dodd, Neki Patel, Mark Albertella, Jorge Zeron-Medina, Paula Fraenkel, Puja Sapra. First disclosure of AZD5335, a TOP1i-ADC targeting low and high FRα-expressing ovarian cancer with superior preclinical activity vs FRα-MTI ADC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB025.