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Cytokine traps: multi-component, high-affinity blockers of cytokine action

Nature Medicine volume 9, pages 47–52 (2003)Cite this article

Abstract

Cytokines can initiate and perpetuate human diseases, and are among the best-validated of therapeutic targets. Cytokines can be blocked by the use of soluble receptors; however, the use of this approach for cytokines such as interleukin (IL)-1, IL-4, IL-6 and IL-13 that use multi-component receptor systems is limited because monomeric soluble receptors generally exhibit low affinity or function as agonists. We describe here a generally applicable method to create very high-affinity blockers called 'cytokine traps' consisting of fusions between the constant region of IgG and the extracellular domains of two distinct cytokine receptor components involved in binding the cytokine. Traps potently block cytokines in vitro and in vivo and represent a substantial advance in creating novel therapeutic candidates for cytokine-driven diseases.

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Figure 1: Cytokine trap.
Figure 2: Traps are potent blockers of cytokine action in vitro.
Figure 3: Binding affinity analysis of IL-1 and IL-4 trap.
Figure 4: Traps persist in circulation for many days.
Figure 5: IL-1 trap blocks the action of IL-1β in vivo.
Figure 6: IL-4 trap blocks in vivo effects of IL-4.

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Acknowledgements

We thank L. Schleifer and P.R. Vagelos for support; X. Wang, L. LaForge, A. Rafique, L. Kovac, H. Wang, E. Pasnikowski, W. Cheng, T. Sterlacci, A. Hijarunguru, A. Sweeney, E. Skop, M. Gunthart, A. Apedo, C. Sheng, S. Valluzzo, A. Coppi, W. Tu, K. Stafford, M. LaFond, K. Audo, M. Karow, P. Krueger, W. Mikulka, J. Martin and Y. Wei for their contributions; S. Staton and V. Lan for graphics; and the Regeneron scientific community and W.P. Jencks for his contribution.

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Author notes

  1. Aris N. Economides and Laura Rocco Carpenter: A.N.E. and L.R.C. contributed equally to this study.

Authors and Affiliations

  1. Department of BioMolecular Science, Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA

    Aris N. Economides, Laura Rocco Carpenter, John S. Rudge, George D. Yancopoulos & Neil Stahl

  2. Department of Preclinical Pharmacology, Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA

    Vivien Wong & Ellen M. Koehler-Stec

  3. Department of Protein Chemistry Sciences, Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA

    Christopher Hartnett, Erica A. Pyles, Xiaobing Xu & Thomas J. Daly

  4. Department of Protein Expression Sciences, Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA

    Michael R. Young & James P. Fandl

  5. Department of Preclinical Manufacturing and Process Development, Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA

    Frank Lee, Scott Carver, Jennifer McNay & Kevin Bailey

  6. Department of Pharmacokinetics, Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA

    Swayampakula Ramakanth & Renta Hutabarat

  7. Department of Protein Biochemistry, Regeneron Pharmaceuticals, Inc., Tarrytown, New York, USA

    Tammy T. Huang & Czeslaw Radziejewski

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  1. Aris N. Economides
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Correspondence to Neil Stahl.

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All authors are employees of Regeneron Pharmaceuticals, Inc.

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Economides, A., Carpenter, L., Rudge, J. et al. Cytokine traps: multi-component, high-affinity blockers of cytokine action. Nat Med 9, 47–52 (2003). https://doi.org/10.1038/nm811

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