Characterization of an IL-2 mimetic with therapeutic potential

Human interleukin-2 (IL-2) interacts with two types of functional receptors (IL-2R alpha beta gamma and IL-2R beta gamma) and acts on a broad range of target cells involved in inflammatory reactions and immune responses. IL-2 is also used in different clinical trials aimed at improving the treatment of some cancers and the recovery of CD4 Lymphocytes by HIV patients. The t herapeutic index of IL-2 is limited by various side effects dominated by th e vascular leak syndrome. We have shown that a chemically synthesised fragm ent of the IL-2 sequence can fold into a helical tetramer likely mimicking the quaternary structure of an hemopoietin. Indeed, peptide p1-30 (containi ng amino acids 1 to 30, including the sequence corresponding to the entire a helix A of IL-2) spontaneously folds into an a-helical homotetramer and s timulates the growth of T-cell lines expressing human IL-2R beta, whereas s horter versions of the peptide lack helical structure and are inactive. At the cellular level, p1-30 induces lymphokine-activated killer (LAK) cells a nd preferentially activates CD8 low lymphocytes and natural killer cells, w hich constitutively express IL-2R beta. A significant IFN-gamma production is also detected following p1-30 stimulation. A mutant form of p1-30 (Asp20 ->Lys) which is likely unable to induce vascular leak syndrome remains capa ble to generate LAK cells like the original p1-30 peptide. Altogether our d ata suggest that p1-30 has therapeutic potential.