A majority of ovarian and non-small cell lung adenocarcinoma cancers overexpress folate receptor a (FRa). Here, we report the development of an anti-FRa antibody-drug conjugate (ADC), consisting of a FRa-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-FRa monoclonal antibodies, we selected the humanized antibody M9346A as the best antibody for targeted delivery of a

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... d payload into FRa-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 0 -deacetyl-N 2 0 -(4-mercapto-4-methyl-1-oxopentyl)-maytansine (DM4) exhibited the most potent antitumor activity in several FRa-expressing xeno-graft tumor models. The level of expression of FRa 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 FRa 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 FRa-negative cells situated near FRa-positive cells (bystander cytotoxic activity), indicating its ability to eradicate tumors with heterogeneous expression of FRa. Together, these findings support the clinical development of IMGN853 as a novel targeted therapy for patients with FRaexpressing tumors.