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 soluble cytokine receptors and anticytokine antibodies is considered for the treatment of cytokine-dependent diseases. The pleiotropic cytokine interleukin-6 (IL-6) is a target for immunointervention in numerous pathologic situations, including multiple myeloma, B-cell lymphoma, and rheumatoid arthritis. An antitumor response was obtained in the treatment of a patient with multiple myeloma. A controversial issue is to evaluate whether the carrier effect of the CBPs might limit their efficiency in blocking the target cytokine. We analyzed the pharmacokinetics of radiolabeled IL-6 in mice treated with various combinations of anti-IL-6 antibodies. We show that injection of one or two antibodies led to the stabilization of the cytokine. Conversely, simultaneous treatment with three anti-IL-6 antibodies, binding to three distinct epitopes, induced the rapid uptake of the trimeric immune complexes by the liver 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 molecule and should help in the design of antibody-based clinical trials by overcoming the problem of the accumulation of the cytokine in the form of monomeric immune complexes.