Folate Receptor α-Targeted 89Zr-M9346A Immuno-PET for Image-Guided Intervention with Mirvetuximab Soravtansine in Triple-Negative Breast Cancer

Folate receptor alpha (FR alpha) is a well-studied tumor biomarker highly expressed in many epithelial tumors such as breast, ovarian, and lung cancers. Mirvetuximab soravtansine (IMGN853) is the antibody-drug conjugate of FR alpha-binding humanized monoclonal antibody M9346A and cytotoxic maytansinoid drug DM4. IMGN853 is currently being evaluated in multiple clinical trials, in which the immunohistochemical evaluation of an archival tumor or biopsy specimen is used for patient screening. However, limited tissue collection may lead to inaccurate diagnosis due to tumor heterogeneity. Herein, we developed a zirconium-89 (Zr-89)-radiolabeled M9346A (Zr-89-M9346A) as an immuno-positron emission tomography (immuno-PET) radiotracer to evaluate FR alpha expression in triple-negative breast cancer (TNBC) patients, providing a novel means to guide intervention with therapeutic IMGN853. In this study, we verified the binding specificity and immunoreactivity of Zr-89-M9346A by in vitro studies in FR alpha(high) cells (HeLa) and FR alpha(low) cells (OVCAR-3). In vivo PET/computed tomography (PET/CT) imaging in HeLa xenografts and TNBC patient-derived xenograft (PDX) mouse models with various levels of FR alpha expression demonstrated its targeting specificity and sensitivity. Following PET imagin, the treatment efficiencies of IMGN853, pemetrexed, IMGN853 + pemetrexed, paclitaxel, and saline were assessed in FR alpha(high) and FR alpha(low) TNBC PDX models. The correlation between Zr-89-M9346A tumor uptake and treatment response using IMGN853 in FR alpha(high) TNBC PDX model suggested the potential of Zr-89-M9346A PET as a noninvasive tool to prescreen patients based on the in vivo PET imaging for IMGN853-targeted treatment.