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Cutting Edge: Mechanism of Enhancement of In Vivo Cytokine Effects by Anti-Cytokine Monoclonal Antibodies¹

James D. Phelan^*, Tatyana Orekov^, and Fred D. Finkelman^2,,,

^* Immunobiology Graduate Program, University of Cincinnati College of Medicine, Cincinnati, OH 45267; Cincinnati Veterans Affairs Medical Center, Cincinnati, OH 45220; Division of Immunology, University of Cincinnati College of Medicine, Cincinnati, OH 45267; and Division of Immunobiology, Children’s Hospital Medical Research Foundation, Cincinnati, OH 45229.

Inhibitory anti-cytokine mAbs are used to treat cytokine-mediated disorders. Recently, however, S4B6, an anti-IL-2 mAb that blocks IL-2 binding to IL-2R, a receptor component that enhances affinity but is not required for signaling, was shown to enhance IL-2 agonist effects in vivo. We evaluated how S4B6 enhances IL-2 effects and whether a similar mechanism allows mAbs to IL-4 to enhance IL-4 effects. Induction of T cell proliferation by IL-2/S4B6 complexes did not require complex dissociation and was IL-2R independent. S4B6 increased IL-2 agonist effects by increasing in vivo half-life, not by focusing IL-2 onto cells through Fc receptors. In contrast to IL-2/S4B6 complexes, anti-IL-4 mAb enhancement of in vivo IL-4 effects required IL-4/anti-IL-4 mAb complex dissociation. Thus, agonist effects observed with high doses of anti-IL-2 mAb are most likely only applicable for mAbs that maintain cytokine half-life without blocking binding to receptor signaling components.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ Our work was supported by a Merit Award from the Department of Veterans Affairs and National Institutes of Health Grants RO1 AI55848 and P01 HL076383.

² Address correspondence and reprint requests to Dr. Fred D. Finkelman, Division of Immunology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0563. E-mail address: ffinkelman{at}pol.net

³ Abbreviations used in this paper: Treg, regulatory T cell; FcRn, neonatal Fc receptor.

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