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: Olga Ab, Kathleen R Whiteman, Laura M Bartle, Xiuxia Sun, Rajeeva Singh, Daniel Tavares, Alyssa LaBelle, Gillian Payne, Robert J Lutz, Jan Pinkas, Victor S Goldmacher, Thomas Chittenden, John M Lambert
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 14 Issue 7 Pg. 1605-13 (Jul 2015) ISSN: 1538-8514 [Electronic] United States
• PMID: 25904506 (Publication Type: Journal Article)
• Copyright: ©2015 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal
• Antibodies, Monoclonal, Humanized
• Folate Receptor 1
• Immunoconjugates
• Maytansine
• mirvetuximab soravtansine

Topics

• Animals
• Antibodies, Monoclonal (immunology, pharmacology)
• Antibodies, Monoclonal, Humanized (immunology, pharmacology)
• Bystander Effect (drug effects)
• Cell Line, Tumor
• Cytotoxicity, Immunologic (drug effects)
• Female
• Folate Receptor 1 (antagonists & inhibitors, immunology)
• Humans
• Immunoconjugates (immunology, pharmacology)
• Maytansine (analogs & derivatives, immunology, pharmacology)
• Mice, Nude
• Mice, SCID
• Molecular Targeted Therapy (methods)
• Neoplasms (drug therapy, immunology, metabolism)
• Treatment Outcome
• Tumor Burden (drug effects, immunology)
• Xenograft Model Antitumor Assays