Tumor-Specific Activation of an EGFR-Targeting Probody Enhances Therapeutic Index
| Autor: | Fei Han, Shouchun Liu, Stephen James Moore, Jennifer Richardson, Jason Gee, Annie Yang, Olga Vasiljeva, Margaret Nguyen, Luc R. Desnoyers, Kenneth R. Wong, Kate Markham, Elizabeth Menendez, Kathy Kamath, Tony W. Liang, Jeanne Grace Flandez, Daniel R. Hostetter, James W. West, Chihunt Wong, Paul H. Bessette, Henry B. Lowman, Michael Krimm, Patrick S. Daugherty, Jason Gary Sagert |
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| Rok vydání: | 2013 |
| Předmět: |
Antibodies
Neoplasm Cetuximab Mice Nude Pharmacology Antibodies Monoclonal Humanized Mice Therapeutic index In vivo Neoplasms medicine Animals Humans Prodrugs Epidermal growth factor receptor Cell Proliferation Skin Tumor microenvironment biology business.industry General Medicine medicine.disease Immunohistochemistry Xenograft Model Antitumor Assays Primary tumor ErbB Receptors Macaca fascicularis biology.protein business Ex vivo medicine.drug |
| Zdroj: | Science Translational Medicine. 5 |
| ISSN: | 1946-6242 1946-6234 |
| DOI: | 10.1126/scitranslmed.3006682 |
| Popis: | Target-mediated toxicity constitutes a major limitation for the development of therapeutic antibodies. To redirect the activity of antibodies recognizing widely distributed targets to the site of disease, we have applied a prodrug strategy to create an epidermal growth factor receptor (EGFR)-directed Probody therapeutic-an antibody that remains masked against antigen binding until activated locally by proteases commonly active in the tumor microenvironment. In vitro, the masked Probody showed diminished antigen binding and cell-based activities, but when activated by appropriate proteases, it regained full activity compared to the parental anti-EGFR antibody cetuximab. In vivo, the Probody was largely inert in the systemic circulation of mice, but was activated within tumor tissue and showed antitumor efficacy that was similar to that of cetuximab. The Probody demonstrated markedly improved safety and increased half-life in nonhuman primates, enabling it to be dosed safely at much higher levels than cetuximab. In addition, we found that both Probody-responsive xenograft tumors and primary tumor samples from patients were capable of activating the Probody ex vivo. Probodies may therefore improve the safety profile of therapeutic antibodies without compromising efficacy of the parental antibody and may enable the wider use of empowered antibody formats such as antibody-drug conjugates and bispecifics. |
| Databáze: | OpenAIRE |
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