RECEPTOR-SELECTIVE MUTANTS OF TUMOR-NECROSIS-FACTOR IN THE THERAPY OFCANCER - PRECLINICAL STUDIES

The use of TNF-mutants that are selective agonists of the TNF-R55 is o ne strategy that is being explored to broaden the therapeutic margin o f TNF. Several problems still have to be overcome before they can be u sed in clinical trials. Regarding the sensitizing effect of some infec tions and some tumours, we identified IFN-gamma as a mediator in BCG- but not in tumour-induced sensitization. In both models, the vessel wa ll is most probably the key tissue as alpha-LFA-1 antibodies could pro tect against lethality. Studies in primates showed that an unexpected feature, namely, the longer half-life of such mutants, might interfere with this strategy. Recent observations also indicate that the mechan ism of tolerance-induction, another way to separate antitumour and tox ic effects of TNF, might reside in the functional ablation of the TNF- R75. Using IL-6(0/0) knockout mice, we could not find any causal role for IL-6 in TNF-mediated lethality, this in contrast to results obtain ed previously with neutralizing antibodies. Finally, we identified the acute phase protein alpha(1)-acid glycoprotein as a protein with prot ective properties towards TNF-induced lethality and liver damage. (C) 1994 Wiley-Liss, Inc.