ADENOVIRUS-MEDIATED GENE-TRANSFER OF A HUMAN IL-6 ANTAGONIST

IL-6 is a pleiotropic cytokine and plays a major role in inflammation and in the immune response. Altered serum levels of IL-6 have been des cribed in several pathologies such as myeloma, EBV-lymphoma and chroni c auto-immune disease. Here we report data on the utilization of a hIL -6 receptor superantagonist with a gene therapy approach. The superant agonist used in this work possesses very high affinity for the hIL-6 r eceptor, and is therefore an excellent candidate for the treatment of IL-6-dependent diseases. To obtain an efficient in vivo delivery metho d, we constructed a recombinant adenovirus expressing th IL-6 receptor superantagonist by inserting the cDNA, controlled by the RSV promoter , into a first generation replication-incompetent adenoviral vector. R ecombinant virus allowed correct expression of the transgene in vitro. Supernatants of infected cells specifically inhibited IL-6-induced tr anscriptional activation in hepatoma cells and blocked the IL-6-depend ent proliferation of human myeloma cells. After intravenous injection of the. recombinant virus into mice, nanomolar amounts of antagonist w ere Produced in the serum, and these were able. completely to inhibit IL-6 bioactivity. Gene transfer of such an antagonist offers a practic al means of imposing long-term blockade of IL-6 activity in vivo for i nvestigational and therapeutic purposes.