AF12198, A NOVEL LOW-MOLECULAR-WEIGHT ANTAGONIST, SELECTIVELY BINDS THE HUMAN TYPE-I INTERLEUKIN (IL)-1 RECEPTOR AND BLOCKS IN-VIVO RESPONSES TO IL-1

Interleukin-1 (IL-1) -alpha and -beta are potent regulators of inflamm atory responses, The naturally occurring interleukin-1 receptor antago nist (IL-1ra) is effective in vitro and in vivo in modulating biologic al responses to IL-1, We have previously reported the discovery of IL- 1 antagonist peptides from the search of phage display libraries, Furt her characterization of this group of peptides has led to a 15-mer, AF 12198, Ac-FEWTPGWYQJYALPL-NH2 (J represents the unnatural amino acid, 2-azetidine-1-carboxylic acid), with both in vitro and in vivo IL-1 an tagonist activity, AF12198 selectively binds the human type I IL-1 rec eptor but not the human type II receptor or the murine type I receptor , In vitro, AF12198 inhibits IL-1-induced IL-8 production by human der mal fibroblasts with a half-maximal inhibition concentration or IC50 o f 25 nM and IL-1-induced intercellular adhesion molecule-1 (ICAM-1) ex pression by endothelial cells with an IC50 of 9 nM. When given as an i ntravenous infusion to cynomolgus monkeys, AF12198 blocks ex vitro IL- 1 induction of IL-6 and down modulates in vivo induction of IL-6. This is the first small molecule to show IL-1 receptor antagonist activity in vivo.