Abstract 1770: Morab-202, a folate receptor alpha-targeted antibody-drug conjugate, shows a highly potent activity against a panel of FRA-expressing tumors

Abstract

Abstract Folate receptor alpha (FRA) is a membrane protein with high affinity for binding and transporting folate into cells. Overexpression of FRA may confer a growth advantage to tumors by increasing folate uptake and affecting cell proliferation via alternative cell signaling pathways (1). FRA levels have been found to be elevated in tumors of epithelial origin compared to normal tissue as cancers of the breast (including TNBC (2)), colon, lungs and ovary (3). In this study, we report the development of MORAb-202, an anti-FRA antibody-drug conjugate (ADC), consisting of a FRA-binding antibody (MORAb-003, farletuzumab) with a cathepsin-cleavable form of eribulin (eribulin mesylate, marketed as Halaven®), a highly potent anti-mitotic agent that induces cell-cycle arrest and cell death by targeting microtubules. We first study expression of FRA on a large panel of tumors patient-derived xenograft (PDX) and Cancer Cell Line-derived Xenograft (CDX). Then, we performed in vitro and in vivo anti-proliferation assays and compare antitumor activity of MORAb-202 with free eribulin accordingly to the FRA expression level. FRA expression was found to be determinant in the sensitivity of tumor cells to the cytotoxic effect of the ADC. Moreover, in case of high expression of FRA, MORAb-202 showed a higher antitumor activity compared with free eribulin. These results suggest that FRA expression could be used as a response-predictive biomarker for this targeted therapy. The ability to identify and treat patients with an effective therapy based on the known expression of the tumor marker is a key point in predictive medicine progress. These findings support the clinical development of MORAb-202 ADC as a novel targeted therapy for patients with FRA-expressing tumors. The ADC described in this abstract is investigational, as efficacy and safety have not been established. There is no guarantee that this ADC will be available commercially. 1-Siu MK et al., PLoS One. 2012;7(11) 2-Nacela BM. et al., PLoS One. 2015, 10(3) 3-Cheung A. et al., Oncotarget. 2016 7(32), 52553-52574 4-Arrowsmith J. & Miller P. 2011-2012. Nat. Rev. Drug Discov. 12, 569 (2013). 5-Paul S.M. et al. Nat. Rev. Drug Discov. 9, 203-214 (2010). 6-Hidalgo, M. et al. Cancer Discov. 4, 998-1013 (2014). Citation Format: Caroline Mignard, Coralie DURIX, Katherine Rybinski, Xin Cheng, Keiji Furuuchi, Earl Albone, Toshimitsu Uenaka, Marc Hillairet de Boisferon. Morab-202, a folate receptor alpha-targeted antibody-drug conjugate, shows a highly potent activity against a panel of FRA-expressing tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1770.