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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.
Abstract:
The remarkable ability of tumour necrosis factor (TNF), especially in combination with interferon, selectively to kill or inhibit malignant cell lines is so far unmatched by any other combination of cytokines. But clinical trials in cancer patients have on the whole been disappointing, and it has been estimated that a TNF dose would be effective only at 5-25 times the maximum tolerated dose. High TNF concentrations give a much more pronounced antitumour activity in mice, in which murine TNF is about 50-fold more systemically toxic than human TNF. But there is little or no species specificity in cytotoxicity of murine TNF and human TNF on human as well as on murine cell lines. This dual action of TNF may be explained by the existence of two types of receptor for TNF: the smaller, TNF-R55, is present on most cells and particularly on those susceptible to the cytotoxic action of TNF; the larger, TNF-R75, is also present on many cell types, especially those of myeloid origin, and is strongly expressed on stimulated T and B lymphocytes. In mice, human TNF binds only to murine TNF-R55 (ref. 15), which can then mediate cytotoxic activity on malignant cells. As human TNF does not bind to murine TNF-R75, the latter must be responsible for the much enhanced systemic toxicity of murine TNF. Human TNF can, however, become toxic in mice when a second pathway is activated. There is no reciprocal situation in the human system: human and murine TNF bind almost equally well to the two human TNF receptors. Here we describe human TNF mutants that sill interact with the human TNF-R55 receptor but which have largely lost their ability to bind to human TNF-R75. Activation of TNF-R55 is sufficient to trigger cytotoxic activity towards transformed cells. One representative human TNF mutant retains its antitumour activity in nude mice carrying tumours derived from human cancers. Under the appropriate conditions, such human TNF mutants are expected to induce less systemic toxicity in man, while still exerting their direct antitumour effect.
Insights
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.