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Science 26 September 2003:
Vol. 301. no. 5641, pp. 1895 - 1898
DOI: 10.1126/science.1081297
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Reports

Inactivation of TNF Signaling by Rationally Designed Dominant-Negative TNF Variants

Paul M. Steed,* Malú G. Tansey,*{dagger} Jonathan Zalevsky,* Eugene A. Zhukovsky, John R. Desjarlais, David E. Szymkowski, Christina Abbott, David Carmichael, Cheryl Chan, Lisa Cherry, Peter Cheung, Arthur J. Chirino, Hyo H. Chung, Stephen K. Doberstein, Araz Eivazi, Anton V. Filikov, Sarah X. Gao, René S. Hubert, Marian Hwang, Linus Hyun, Sandhya Kashi, Alice Kim, Esther Kim, James Kung, Sabrina P. Martinez,{dagger} Umesh S. Muchhal, Duc-Hanh T. Nguyen, Christopher O'Brien, Donald O'Keefe, Karen Singer, Omid Vafa, Jost Vielmetter, Sean C. Yoder, Bassil I. Dahiyat{ddagger}

Tumor necrosis factor (TNF) is a key regulator of inflammatory responses and has been implicated in many pathological conditions. We used structure-based design to engineer variant TNF proteins that rapidly form heterotrimers with native TNF to give complexes that neither bind to nor stimulate signaling through TNF receptors. Thus, TNF is inactivated by sequestration. Dominant-negative TNFs represent a possible approach to anti-inflammatory biotherapeutics, and experiments in animal models show that the strategy can attenuate TNF-mediated pathology. Similar rational design could be used to engineer inhibitors of additional TNF superfamily cytokines as well as other multimeric ligands.

Xencor, 111 West Lemon Avenue, Monrovia, CA 91016, USA.



* These authors contributed equally to this work.

{dagger} Present address: Department of Physiology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA.

{ddagger} To whom correspondence should be addressed. E-mail: baz{at}xencor.com

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