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Pharmacokinetic study of anti-interleukin-6 (IL-6) therapy with monoclonal
antibodies: enhancement of IL-6 clearance by cocktails of anti-IL-6
antibodies
FA Montero-Julian, B Klein, E Gautherot and H Brailly
Immunotech S.A., Marseilles, France.
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.
Volume 85,
Issue 4,
pp. 917-924,
02/15/1995
Copyright © 1995 by The American Society of Hematology
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