title: IMGN853, a Folate Receptor-α (FRα)-Targeting Antibody-Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors.
abstract: A majority of ovarian and non-small cell lung adenocarcinoma cancers overexpress folate receptor α (FRα). Here, we report the development of an anti-FRα antibody-drug conjugate (ADC), consisting of a FRα-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-FRα monoclonal antibodies, we selected the humanized antibody M9346A as the best antibody for targeted delivery of a maytansinoid payload into FRα-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 FRα-expressing xenograft tumor models. The level of expression of FRα 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 FRα 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 FRα-negative cells situated near FRα-positive cells (bystander cytotoxic activity), indicating its ability to eradicate tumors with heterogeneous expression of FRα. Together, these findings support the clinical development of IMGN853 as a novel targeted therapy for patients with FRα-expressing tumors.
authors.affiliation: Department of Cell Biology, ImmunoGen, Inc., Waltham, Massachusetts. olga.ab@immunogen.com.
authors.forename: Olga
authors.initials: O
authors.lastname: Ab
authors.affiliation: Department of Pharmacology Toxicology, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Kathleen R
authors.initials: KR
authors.lastname: Whiteman
authors.affiliation: Department of Cell Biology, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Bartle
authors.affiliation: Department of Biochemistry, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Xiuxia
authors.initials: X
authors.lastname: Sun
authors.affiliation: Department of Biochemistry, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Rajeeva
authors.initials: R
authors.lastname: Singh
authors.affiliation: Department of Antibody Engineering, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Daniel
authors.initials: D
authors.lastname: Tavares
authors.affiliation: Department of Biomarkers, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Alyssa
authors.initials: A
authors.lastname: LaBelle
authors.affiliation: Department of Bioanalytical Science, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Gillian
authors.initials: G
authors.lastname: Payne
authors.affiliation: Department of Translational Research and Development, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Lutz
authors.affiliation: Department of Pharmacology Toxicology, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Jan
authors.initials: J
authors.lastname: Pinkas
authors.affiliation: Department of Cell Biology, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Victor S
authors.initials: VS
authors.lastname: Goldmacher
authors.affiliation: Research and Development, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: Thomas
authors.initials: T
authors.lastname: Chittenden
authors.affiliation: Research and Development, ImmunoGen, Inc., Waltham, Massachusetts.
authors.forename: John M
authors.initials: JM
authors.lastname: Lambert
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000276:immunology / Q000494:pharmacology; D024201:Bystander Effect / Q000187:drug effects; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D058975:Folate Receptor 1 / Q000037:antagonists & inhibitors* / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates / Q000276:immunology / Q000494:pharmacology*; D008453:Maytansine / Q000031:analogs & derivatives / Q000276:immunology / Q000494:pharmacology; D008819:Mice, Nude; D016513:Mice, SCID; D058990:Molecular Targeted Therapy / Q000379:methods; D009369:Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D016896:Treatment Outcome; D047368:Tumor Burden / Q000187:drug effects / Q000276:immunology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058975:Folate Receptor 1; D018796:Immunoconjugates; D008453:Maytansine; C000607289:mirvetuximab soravtansine