Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Logo for

Science 301 (5641): 1895-1898

Copyright © 2003 by the American Association for the Advancement of Science

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}

Abstract: 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.

Back to Top

* 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


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Inhibition of soluble tumor necrosis factor is therapeutic in Huntington's disease.
H.-Y. Hsiao, F.-L. Chiu, C.-M. Chen, Y.-R. Wu, H.-M. Chen, Y.-C. Chen, H.-C. Kuo, and Y. Chern (2014)
Hum. Mol. Genet.
   Abstract »    Full Text »    PDF »
Peripheral elevation of TNF-{alpha} leads to early synaptic abnormalities in the mouse somatosensory cortex in experimental autoimmune encephalomyelitis.
G. Yang, C. N. Parkhurst, S. Hayes, and W.-B. Gan (2013)
PNAS 110, 10306-10311
   Abstract »    Full Text »    PDF »
Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination.
R. Brambilla, J. J. Ashbaugh, R. Magliozzi, A. Dellarole, S. Karmally, D. E. Szymkowski, and J. R. Bethea (2011)
Brain 134, 2736-2754
   Abstract »    Full Text »    PDF »
Transmembrane tumour necrosis factor is neuroprotective and regulates experimental autoimmune encephalomyelitis via neuronal nuclear factor-{kappa}B.
E. Taoufik, V. Tseveleki, S. Y. Chu, T. Tselios, M. Karin, H. Lassmann, D. E. Szymkowski, and L. Probert (2011)
Brain 134, 2722-2735
   Abstract »    Full Text »    PDF »
Solution of the Structure of the TNF-TNFR2 Complex.
Y. Mukai, T. Nakamura, M. Yoshikawa, Y. Yoshioka, S.-i. Tsunoda, S. Nakagawa, Y. Yamagata, and Y. Tsutsumi (2010)
Science Signaling 3, ra83
   Abstract »    Full Text »    PDF »
Virally infected and matured human dendritic cells activate natural killer cells via cooperative activity of plasma membrane-bound TNF and IL-15.
L. Vujanovic, D. E. Szymkowski, S. Alber, S. C. Watkins, N. L. Vujanovic, and L. H. Butterfield (2010)
Blood 116, 575-583
   Abstract »    Full Text »    PDF »
Protein design in biological networks: from manipulating the input to modifying the output.
A. M. Van der Sloot, C. Kiel, L. Serrano, and F. Stricher (2009)
Protein Eng. Des. Sel. 22, 537-542
   Abstract »    Full Text »    PDF »
Immunochemical termination of self-tolerance.
J. Grunewald, M.-L. Tsao, R. Perera, L. Dong, F. Niessen, B. G. Wen, D. M. Kubitz, V. V. Smider, W. Ruf, M. Nasoff, et al. (2008)
PNAS 105, 11276-11280
   Abstract »    Full Text »    PDF »
DR4-selective Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Variants Obtained by Structure-based Design.
V. Tur, A. M. van der Sloot, C. R. Reis, E. Szegezdi, R. H. Cool, A. Samali, L. Serrano, and W. J. Quax (2008)
J. Biol. Chem. 283, 20560-20568
   Abstract »    Full Text »    PDF »
Dominant-Negative Inhibitors of Soluble TNF Attenuate Experimental Arthritis without Suppressing Innate Immunity to Infection.
J. Zalevsky, T. Secher, S. A. Ezhevsky, L. Janot, P. M. Steed, C. O'Brien, A. Eivazi, J. Kung, D.-H. T. Nguyen, S. K. Doberstein, et al. (2007)
J. Immunol. 179, 1872-1883
   Abstract »    Full Text »    PDF »
A Virus-Like Particle-Based Vaccine Selectively Targeting Soluble TNF-{alpha} Protects from Arthritis without Inducing Reactivation of Latent Tuberculosis.
G. Spohn, R. Guler, P. Johansen, I. Keller, M. Jacobs, M. Beck, F. Rohner, M. Bauer, K. Dietmeier, T. M. Kundig, et al. (2007)
J. Immunol. 178, 7450-7457
   Abstract »    Full Text »    PDF »
Blocking soluble tumor necrosis factor signaling with dominant-negative tumor necrosis factor inhibitor attenuates loss of dopaminergic neurons in models of Parkinson's disease..
M. K. McCoy, T. N. Martinez, K. A. Ruhn, D. E. Szymkowski, C. G. Smith, B. R. Botterman, K. E. Tansey, and M. G. Tansey (2006)
J. Neurosci. 26, 9365-9375
   Abstract »    Full Text »    PDF »
PanR1, a Dominant Negative Missense Allele of the Gene Encoding TNF-{alpha} (Tnf), Does Not Impair Lymphoid Development..
S. Rutschmann, K. Hoebe, J. Zalevsky, X. Du, N. Mann, B. I. Dahiyat, P. Steed, and B. Beutler (2006)
J. Immunol. 176, 7525-7532
   Abstract »    Full Text »    PDF »
Designed tumor necrosis factor-related apoptosis-inducing ligand variants initiating apoptosis exclusively via the DR5 receptor.
A. M. van der Sloot, V. Tur, E. Szegezdi, M. M. Mullally, R. H. Cool, A. Samali, L. Serrano, and W. J. Quax (2006)
PNAS 103, 8634-8639
   Abstract »    Full Text »    PDF »
Differential Requirements for Soluble and Transmembrane Tumor Necrosis Factor in the Immunological Control of Primary and Secondary Listeria monocytogenes Infection.
K. Musicki, H. Briscoe, S. Tran, W. J. Britton, and B. M. Saunders (2006)
Infect. Immun. 74, 3180-3189
   Abstract »    Full Text »    PDF »
Multimeric Soluble CD40 Ligand and GITR Ligand as Adjuvants for Human Immunodeficiency Virus DNA Vaccines.
G. W. Stone, S. Barzee, V. Snarsky, K. Kee, C. A. Spina, X.-F. Yu, and R. S. Kornbluth (2006)
J. Virol. 80, 1762-1772
   Abstract »    Full Text »    PDF »
JNK and Tumor Necrosis Factor-{alpha} Mediate Free Fatty Acid-induced Insulin Resistance in 3T3-L1 Adipocytes.
M. T. A. Nguyen, H. Satoh, S. Favelyukis, J. L. Babendure, T. Imamura, J. I. Sbodio, J. Zalevsky, B. I. Dahiyat, N.-W. Chi, and J. M. Olefsky (2005)
J. Biol. Chem. 280, 35361-35371
   Abstract »    Full Text »    PDF »
Interference with Heparin Binding and Oligomerization Creates a Novel Anti-Inflammatory Strategy Targeting the Chemokine System.
Z. Johnson, M. H. Kosco-Vilbois, S. Herren, R. Cirillo, V. Muzio, P. Zaratin, M. Carbonatto, M. Mack, A. Smailbegovic, M. Rose, et al. (2004)
J. Immunol. 173, 5776-5785
   Abstract »    Full Text »    PDF »
Computational Design of Variant TNF Molecules: A Novel Methodology for Inhibition of Proinflammatory Cascades.
E. Abraham (2003)
Sci. STKE 2003, pe51
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882