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Human TNF mutants with selective activity on the p55 receptor
X Van Ostade1, P Vandenabeele, B Everaerdt
1Laboratory of Molecular Biology, University of Gent, Belgium.
Nature
|January 21, 1993
Summary
Tumor necrosis factor (TNF) shows promise against cancer but causes toxicity. New TNF mutants target TNF-R55 receptors, enhancing anti-cancer effects while reducing systemic toxicity in humans.
Area of Science:
- Immunology
- Molecular Biology
- Oncology
Background:
- Tumor necrosis factor (TNF) exhibits potent anti-cancer activity, often enhanced by interferon, but clinical applications are limited by dose-limiting systemic toxicity.
- Two TNF receptors, TNF-R55 and TNF-R75, mediate distinct biological effects, with TNF-R55 linked to cytotoxicity and TNF-R75 to systemic toxicity.
Purpose of the Study:
- To develop human TNF mutants that selectively activate TNF-R55 for enhanced anti-tumor efficacy with reduced systemic toxicity.
- To investigate the role of TNF receptor binding in mediating both anti-tumor and toxic effects.
Main Methods:
- Engineering human TNF mutants with altered binding affinities for TNF-R75 while retaining TNF-R55 interaction.
- Evaluating the cytotoxic activity of TNF mutants on malignant cell lines.
- Assessing anti-tumor efficacy and systemic toxicity of TNF mutants in preclinical models.
Main Results:
- Developed human TNF mutants that bind TNF-R55 but not TNF-R75.
- Demonstrated that TNF-R55 activation is sufficient for cytotoxic activity against transformed cells.
- One representative mutant showed retained anti-tumor activity in human cancer xenografts in mice, suggesting reduced systemic toxicity.
Conclusions:
- Selective activation of TNF-R55 using engineered TNF mutants offers a promising strategy for cancer therapy.
- These mutants are expected to provide a therapeutic window with reduced systemic toxicity in humans while maintaining direct anti-tumor effects.