PHARMACOKINETIC STUDY OF ANTI-INTERLEUKIN-6 (IL-6) THERAPY WITH MONOCLONAL-ANTIBODIES - ENHANCEMENT OF IL-6 CLEARANCE BY COCKTAILS OF ANTI-IL-6 ANTIBODIES

The use of inhibiting cytokine-binding-proteins (CBPs) such, as solubl e cytokine receptors and anticytokine antibodies is considered for the treatment of cytokine-dependent diseases. The pleiotropic cytokine in terleukin-6 (IL-6) is a target for immunointervention in numerous path ologic situations, including multiple myeloma, B-cell lymphoma, and rh eumatoid arthritis. An antitumor response was obtained in the treatmen t of a patient with multiple myeloma. A controversial issue is to eval uate whether the carrier effect of the CBPs might limit their efficici ency in blocking the target cytokine. We analyzed the pharmacokinetics of radiolabeled IL-6 in mice treated with various combinations of ant i-IL-6 antibodies. We show that injection of one or two antibodies led to the stabilization of the cytokine. Conversely, simultaneous treatm ent with three anti-IL-6 antibodies, binding to three distinct epitope s, induced the rapid uptake of the trimeric immune complexes by the li ver and the elimination of IL-6 from the central compartment. The use of cocktails of three antibodies binding simultaneously to a cytokine thus provides a new means of enhancing the clearance of the target mol ecule and should help in the design of antibody-based clinical trials by overcoming the problem of the accumulation of the cytokine in the f orm of monomeric immune complexes. (C) 1995 by The American Society of Hematology.