Abstract 3617: Evaluation of folate receptor 1 (FOLR1) expression by calibrated immunohistochemistry identifies candidate tumor subtypes for targeting by IMGN853, an anti-FOLR1-maytansinoid conjugate

Abstract

Abstract Background: The folate receptor α (FOLR1) is a GPI-linked glycoprotein reported to be highly expressed in cancers including ovarian, renal, brain, lung, and breast carcinomas, while having restricted distribution in normal tissues, including kidney and lung. This expression profile suggests that FOLR1 may be an attractive target for development of a therapeutic antibody-drug conjugate. The antibody maytansinoid conjugate (AMC), IMGN853, consists of a FOLR1-binding monoclonal antibody, M9346A, conjugated to the maytansinoid, DM4, attached via the cleavable sulfo-SPDB linker. IMGN853 exhibited potent anti-tumor activity in preclinical studies, supporting its development as a treatment for FOLR1-expressing cancers. Objective: The aim of the study was to identify potential patient populations for treatment with IMGN853 by determining the level, cellular distribution, and incidence of FOLR1 expression in carcinomas. Methods: A calibrated immunohistochemical (IHC) staining method was developed for assessing FOLR1 expression in formalin-fixed paraffin-embedded (FFPE) tissues. Staining conditions were established wherein the intensity of FOLR1 membrane staining observed in tumor tissues could be related to FFPE cell pellet controls, prepared from human tumor cell lines expressing known levels of FOLR1 (quantified by flow cytometry). This calibrated IHC staining method was applied to FOLR1-positive controls and a panel of tumor tissues including ovarian, renal, brain, lung, and breast carcinomas. The extent, pattern, and intensity of immunostaining were evaluated for each tissue, and the level of FOLR1 expression was estimated using comparison to the cell pellet controls. Results: Biopsy samples from patients with ovarian cancer and non-small cell lung adenocarcinoma or bronchiolalveolar carcinomas of the lung express significant levels of membrane-associated FOLR1. Expression in these indications was frequently observed exhibiting high, homogeneous, and cell membrane-localized patterns – properties considered favorable for AMC-targeting. In particular, a high percentage of the most common subtypes of ovarian cancer, serous (79%) and endometrioid (70%), expressed high (> 260,000 antigen sites per cell) and homogeneous levels of FOLR1. Likewise, a high percentage of the non-small cell lung adenocarcinoma (54%) and bronchioloalveolar carcinoma (100%) subtypes also expressed high (> 260,000 antigens per cell) levels. In contrast, FOLR1 expression in most non-small cell lung squamous carcinomas was undetectable. These findings support the development of IMGN853 for treatment of ovarian carcinomas and NSCL adenocarcinoma and bronchiolalveolar carcinomas, and provide a potential approach for assessing FOLR1 expression in patient tumors during clinical development. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3617. doi:10.1158/1538-7445.AM2011-3617