Human TNF mutants with selective activity on the p55 receptorHuman TNF mutants with selective activity on the p55 receptor
Faculty of Pharmaceutical, Biomedical and Veterinary Sciences . Biomedical Sciences
Proteinchemistry, proteomics and epigenetic signalling(PPES)
Nature. - London
361(1993):6409, p. 266-268
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 cytokines14. But clinical trials in cancer patients have on the whole been disappointing57, and it has been estimated that a TNF dose would be effective only at 525 times the maximum tolerated dose4. High TNF concentrations give a much more pronounced antitumour activity in mice1,810, in which murine TNF is about 50-fold more systemically toxic than human TNF11,12. But there is little or no species specificity in cytotoxicity of murine TNF and human TNF on human as well as on murine cell lines13,14. This dual action of TNF may be explained by the existence of two types of receptor for TNF15,16: the smaller, TNF-R55, is present on most cells and particularly on those susceptible to the cytotoxic action of TNF17; the larger, TNF-R55, is also present on many cell types15,16, especially those of myeloid origin, and is strongly expressed on stimulated T and B lymphocytes18. In mice, human TNF binds only to murine TNF-R55 (ref. 15), which can then mediate cytotoxic activity on malignant cells1517,19. 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 activated1,11,20. 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 still 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.