Abstract
We have generated the first TNFR1-selective antagonistic TNF mutant based on structural human TNF variants using our phage display technology. This TNF mutant did not activate TNFR1-mediated responses, although its affinity for TNFR1 was equivalent to human wild-type TNF (wtTNF). The TNF mutant neutralized wtTNF-induced TNFR1-mediated bioactivity without influencing TNFR2-mediated bioactivity. In hepatitis mouse models, the antagonistic TNF mutant significantly blocked liver injury caused by inflammation. These results indicate that antagonistic TNF mutants may be clinically useful for anti-TNF therapy and that phage display libraries of protein ligands can be used to select for receptor subtype-selective antagonists.
