IMGN853, a Folate Receptor-alpha (FRalpha)-Targeting Antibody-Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRalpha-Expressing Tumors.
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Ab O, Whiteman KR, Bartle LM, Sun X, Singh R, Tavares D, LaBelle A, Payne G, Lutz RJ, Pinkas J, Goldmacher VS, Chittenden T, Lambert JM
IMGN853, a Folate Receptor-alpha (FRalpha)-Targeting Antibody-Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRalpha-Expressing Tumors.
Mol Cancer Ther. 2015 Jul;14(7):1605-13. doi: 10.1158/1535-7163.MCT-14-1095. Epub 2015 Apr 22.
- PubMed ID
- 25904506 [ View in PubMed]
- Abstract
A majority of ovarian and non-small cell lung adenocarcinoma cancers overexpress folate receptor alpha (FRalpha). Here, we report the development of an anti-FRalpha antibody-drug conjugate (ADC), consisting of a FRalpha-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-FRalpha monoclonal antibodies, we selected the humanized antibody M9346A as the best antibody for targeted delivery of a maytansinoid payload into FRalpha-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 FRalpha-expressing xenograft tumor models. The level of expression of FRalpha 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 FRalpha 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 FRalpha-negative cells situated near FRalpha-positive cells (bystander cytotoxic activity), indicating its ability to eradicate tumors with heterogeneous expression of FRalpha. Together, these findings support the clinical development of IMGN853 as a novel targeted therapy for patients with FRalpha-expressing tumors.
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- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Mirvetuximab soravtansine Folate receptor alpha Protein Humans YesBinderDetails - Drug Reactions
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