Biochemical and pharmacological characterization of human c-Met neutralizing monoclonal antibody CE-355621
| Autor: | Jitesh P. Jani, Gerrit Los, Kajiji Shama M, Bruce D. Cohen, Green Larry L, Kevin Coleman, Mary Campbell, Jinghai J. Xu, Elsa G. Barbacci-Tobin, Vahe Bedian, Konstantinos Tsaparikos, Jean-Martin Lapointe, Patrick Vincent, Boris A. Chrunyk, Neil R. Michaud, Stephen M. Hillerman, David F. Gebhard, Tim M. Coskran, George A. Karam, Margaret C. Dunn, Elisabeth Knauth, Stefan J. Steyn, Henry Putz, Gary Borzillo |
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| Rok vydání: | 2012 |
| Předmět: |
C-Met
Carcinogenesis medicine.drug_class Angiogenesis Immunology Mice Nude Cell Growth Processes Monoclonal antibody Proto-Oncogene Mas Epitope Receptor tyrosine kinase Mice chemistry.chemical_compound Report Morphogenesis medicine Animals Humans Immunology and Allergy Transgenes A549 cell biology Hepatocyte Growth Factor Immunodominant Epitopes Cell growth Antibodies Monoclonal Proto-Oncogene Proteins c-met Antibodies Neutralizing Xenograft Model Antitumor Assays Molecular biology chemistry NIH 3T3 Cells biology.protein Cancer research Hepatocyte growth factor medicine.drug |
| Zdroj: | mAbs. 4:710-723 |
| ISSN: | 1942-0870 1942-0862 |
| DOI: | 10.4161/mabs.22160 |
| Popis: | The c-Met proto-oncogene is a multifunctional receptor tyrosine kinase that is stimulated by its ligand, hepatocyte growth factor (HGF), to induce cell growth, motility and morphogenesis. Dysregulation of c-Met function, through mutational activation or overexpression, has been observed in many types of cancer and is thought to contribute to tumor growth and metastasis by affecting mitogenesis, invasion, and angiogenesis. We identified human monoclonal antibodies that bind to the extracellular domain of c-Met and inhibit tumor growth by interfering with ligand-dependent c-Met activation. We identified antibodies representing four independent epitope classes that inhibited both ligand binding and ligand-dependent activation of c-Met in A549 cells. In cells, the antibodies antagonized c-Met function by blocking receptor activation and by subsequently inducing downregulation of the receptor, translating to phenotypic effects in soft agar growth and tubular morphogenesis assays. Further characterization of the antibodies in vivo revealed significant inhibition of c-Met activity (≥ 80% lasting for 72-96 h) in excised tumors corresponded to tumor growth inhibition in multiple xenograft tumor models. Several of the antibodies identified inhibited the growth of tumors engineered to overexpress human HGF and human c-Met (S114 NIH 3T3) when grown subcutaneously in athymic mice. Furthermore, lead candidate antibody CE-355621 inhibited the growth of U87MG human glioblastoma and GTL-16 gastric xenografts by up to 98%. The findings support published pre-clinical and clinical data indicating that targeting c-Met with human monoclonal antibodies is a promising therapeutic approach for the treatment of cancer. |
| Databáze: | OpenAIRE |
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