Abstract 3400A: Development and application of an immunohistochemistry-based clinical assay for evaluating Folate Receptor Alpha (FRα) expression in a phase I clinical trial of IMGN853
Authors: Zhao Jianhua , LaBelle Alyssa , Ab Olga , Acosta Krista , Yates Al , Zhou Yinghui , Romanelli Angela 
Published: August 2015

Abstract
A biomarker-based patient selection strategy, coupled with the co-development of a companion diagnostic, is key to the successful development of molecularly targeted cancer therapeutics. IMGN853 is a Folate Receptor Alpha (FRα)-targeting antibody-drug conjugate (ADC) consisting of an anti-FRα antibody linked to DM4, a highly cytotoxic maytansinoid, via a cleavable disulfide linker. FRα is a glycosyl-phosphatidylinositol-linked membrane protein commonly over-expressed in several solid tumor types including epithelial ovarian cancer (EOC), endometrial cancer and lung adenocarcinoma, with limited expression in normal tissues. Previously reported preclinical data demonstrated regression or significant inhibition of tumor growth by the conjugate in tumor models with clinically relevant levels of FRα expression. IMGN853 is currently in a phase I clinical trial for safety and tolerability in patients with FRα-positive solid tumors. Preliminary evidence of clinical activity has been observed in patients receiving IMGN853 treatment.
Immunohistochemistry (IHC) is one of the most widely adopted techniques in clinical labs for semi-quantitative determination of protein expression in different cellular compartments. We have developed an IHC assay to support the FRα-expression based patient selection strategy in the clinical development of IMGN853. To this end, a novel murine monoclonal antibody with high specificity for human FRα was generated. This antibody, 353-2.1, is compatible with formalin fixed and paraffin embedded (FFPE) tissue samples and can recognize the same pool of FRα molecules as IMGN853, making it an ideal candidate for a companion diagnostic for IMGN853. The antibody was used to develop and optimize an assay that covers a broad dynamic range of FRα expression, allowing discrimination among high, moderate and low levels of expression. Data from tissue microarrays that cover a broad range of normal and tumor tissue types, as well as additional prevalence data in selected tumor types, were used to validate this assay. They also demonstrate that the FRα-expression data generated using this assay are consistent with previous findings. This clinical FRα IHC assay has been successfully used to measure FRα expression in more than 100 patient tumor samples submitted for testing in the ongoing IMGN853 phase I trial. A summary of FRα staining pattern and expression level data from these patients will be presented, as well as the prevalence in each tumor type.
Citation Format: Jianhua Zhao, Alyssa LaBelle, Olga Ab, Krista Acosta, Al Yates, Yinghui Zhou, Angela Romanelli. Development and application of an immunohistochemistry-based clinical assay for evaluating Folate Receptor Alpha (FRα) expression in a phase I clinical trial of IMGN853. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3400A. doi:10.1158/1538-7445.AM2015-3400A