IMGN853, a Folate Receptor-α (FRα)-Targeting Antibody-Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors.

A majority of ovarian and non-small cell lung adenocarcinoma cancers overexpress folate receptor alpha (FR alpha). Here, we report the development of an anti-FR alpha antibody-drug conjugate (ADC), consisting of a FR alpha-binding antibody attached to a highly potent maytansinoid that induces cell-cycle arrest and cell death by targeting microtubules. From screening a large panel of anti-FR alpha monoclonal antibodies, we selected the humanized antibody M9346A as the best antibody for targeted delivery of a maytansinoid payload into FR alpha-positive cells. We compared M9346A conjugates with various linker/maytansinoid combinations, and found that a conjugate, now denoted as IMGN853, with the N-succinimidyl 4-(2-pyridyldithio)-2-sulfobutanoate (sulfo-SPDB) linker and N-2'-deacetyl-N-2'-(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4) exhibited the most potent antitumor activity in several FR alpha-expressing xenograft tumor models. The level of expression of FR alpha on the surface of cells was a major determinant in the sensitivity of tumor cells to the cytotoxic effect of the conjugate. Efficacy studies of IMGN853 in xenografts of ovarian cancer and non-small cell lung cancer cell lines and of a patient tumor-derived xenograft model demonstrated that the ADC was highly active against tumors that expressed FR alpha at levels similar to those found on a large fraction of ovarian and non-small cell lung cancer patient tumors, as assessed by immunohistochemistry. IMGN853 displayed cytotoxic activity against FR alpha-negative cells situated near FR alpha-positive cells (bystander cytotoxic activity), indicating its ability to eradicate tumors with heterogeneous expression of FR alpha. Together, these findings support the clinical development of IMGN853 as a novel targeted therapy for patients with FR alpha expressing tumors. (C) 2015 AACR.