Functional Characterization of an scFv-Fc Antibody that Immunotherapeutically Targets the Common Cancer Cell Surface Proteoglycan CSPG4
| Autor: | Koichi Sakakura, Takahiro Tsuchikawa, Alessandra Favole, Soldano Ferrone, Simon C. Watkins, Elvira Favoino, Akihiro Katayama, Susan Silver, Ling Yu, Xinhui Wang, Yangyang Wang, Toshiro Kageshita |
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| Rok vydání: | 2011 |
| Předmět: |
Cancer Research
Lung Neoplasms MAP Kinase Signaling System medicine.drug_class medicine.medical_treatment Immunoblotting Mice SCID Monoclonal antibody Article Epitope Epitopes Mice Cancer immunotherapy Antibody Specificity Cell Movement Peptide Library Cell Line Tumor Neoplasms medicine Animals Humans Melanoma Cell Proliferation Microscopy Confocal biology Survival Analysis Xenograft Model Antitumor Assays Tumor Cell Biology Fragment crystallizable region Molecular biology Oncology CSPG4 Cancer cell Cancer research biology.protein Female Proteoglycans Immunotherapy Mitogen-Activated Protein Kinases Antibody Protein Binding Single-Chain Antibodies |
| Zdroj: | Cancer Research. 71:7410-7422 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-10-1134 |
| Popis: | Cell surface chondroitin sulfate proteoglycan 4 (CSPG4) is an attractive target for antibody-based cancer immunotherapy because of its role in tumor cell biology, its high expression on malignant cells including cancer-initiating cells, and its restricted distribution in normal tissues. The clinical use of CSPG4 has been hampered by the lack of a CSPG4-specific chimeric, humanized, or fully human monoclonal antibody. To overcome this limitation, we generated a CSPG4-specific fully human single-chain antibody termed scFv-FcC21 and characterized its specificity and antitumor activity. Viable CSPG4+ melanoma cells were used in a screen of a human scFv phage display library that included CDR3 engineered to optimize antibody binding sites. The scFv antibody isolated was then recombinantly engineered with a human immunoglobulin G1 Fc region to construct the fully human antibody scFv-FcC21, which recognized tumors of neuroectodermal origin, various types of carcinomas, mesotheliomas, and sarcomas as well as myeloid leukemias. scFv-FcC21 inhibited in vitro growth and migration of tumor cells and in vivo growth of human tumor xenografts. These effects were mediated by inhibition of the activation of extracellular signal–regulated kinase and focal adhesion kinase signaling pathways that are critical for tumor cell growth and migration, respectively. Our findings define the CSPG4-specific fully human scFv-FcC21 antibody as a candidate therapeutic agent to target the many types of tumors that express CSPG4. Cancer Res; 71(24); 7410–22. ©2011 AACR. |
| Databáze: | OpenAIRE |
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