IMGN853, a Folate Receptor-α (FRα)-Targeting Antibody-Drug Conjugate, Exhibits Potent Targeted Antitumor Activity against FRα-Expressing Tumors
| Autor: | Victor S. Goldmacher, Olga Ab, Gillian Payne, Laura M. Bartle, Thomas Chittenden, John M. Lambert, Kathleen R. Whiteman, Xiuxia Sun, Jan Pinkas, Robert J. Lutz, Daniel Tavares, Rajeeva Singh, Alyssa LaBelle |
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| Rok vydání: | 2014 |
| Předmět: |
Cytotoxicity
Immunologic Cancer Research Antibody-drug conjugate Immunoconjugates medicine.medical_treatment Mice Nude Mice SCID Pharmacology Biology Humanized antibody Maytansinoid Antibodies Monoclonal Humanized Targeted therapy chemistry.chemical_compound Cell Line Tumor Neoplasms medicine Cytotoxic T cell Animals Humans Folate Receptor 1 Maytansine Molecular Targeted Therapy Cancer Antibodies Monoclonal Bystander Effect medicine.disease Xenograft Model Antitumor Assays Tumor Burden Treatment Outcome Oncology chemistry Folate receptor Cancer research Female Ovarian cancer |
| Zdroj: | Molecular cancer therapeutics. 14(7) |
| ISSN: | 1538-8514 |
| Popis: | 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 N2′-deacetyl-N2′-(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. Mol Cancer Ther; 14(7); 1605–13. ©2015 AACR. |
| Databáze: | OpenAIRE |
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