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PMID: 14512626 Published · ppublish English Journal Article

Inactivation of TNF signaling by rationally designed dominant-negative TNF variants.

Science (New York, N.Y.) ·Vol. 301 ·No. 5641 ·2003-09-26 ·Pages 1895-8

Steed PM, Tansey MG, Zalevsky J, Zhukovsky EA, Desjarlais JR, Szymkowski DE, Abbott C, Carmichael D, Chan C, Cherry L, Cheung P, Chirino AJ, Chung HH, Doberstein SK, Eivazi A, Filikov AV, Gao SX, Hubert RS, Hwang M, Hyun L, Kashi S, Kim A, Kim E, Kung J, Martinez SP, Muchhal US, Nguyen DH, O'Brien C, O'Keefe D, Singer K, Vafa O, Vielmetter J, Yoder SC, Dahiyat BI

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.

MeSH Terms

Amino Acid Substitution Animals Antigens, CD/metabolism Apoptosis Arthritis, Experimental/drug therapy Biopolymers Caspases/metabolism Cell Line Cell Nucleus/metabolism Computer Simulation Disease Progression Enzyme-Linked Immunosorbent Assay Female Galactosamine/pharmacology HeLa Cells Humans Liver/drug effects NF-kappa B/metabolism Point Mutation Protein Engineering Rats Receptors, Tumor Necrosis Factor/metabolism Receptors, Tumor Necrosis Factor, Type I Receptors, Tumor Necrosis Factor, Type II Signal Transduction Transcription Factor RelA Transcription, Genetic Tumor Necrosis Factor-alpha/antagonists & inhibitors,genetics,metabolism,pharmacology

Chemicals

Antigens, CD Biopolymers NF-kappa B Receptors, Tumor Necrosis Factor Receptors, Tumor Necrosis Factor, Type I Receptors, Tumor Necrosis Factor, Type II Transcription Factor RelA Tumor Necrosis Factor-alpha Galactosamine Caspases

Authors & Affiliations

34 authors, click to expand affiliations / ORCID

Steed Paul M

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

Tansey Malú G

Zalevsky Jonathan

Zhukovsky Eugene A

Desjarlais John R

Szymkowski David E

Abbott Christina

Carmichael David

Chan Cheryl

Cherry Lisa

Cheung Peter

Chirino Arthur J

Chung Hyo H

Doberstein Stephen K

Eivazi Araz

Filikov Anton V

Gao Sarah X

Hubert René S

Hwang Marian

Hyun Linus

Kashi Sandhya

Kim Alice

Kim Esther

Kung James

Martinez Sabrina P

Muchhal Umesh S

Nguyen Duc-Hanh T

O'Brien Christopher

O'Keefe Donald

Singer Karen

Vafa Omid

Vielmetter Jost

Yoder Sean C

Dahiyat Bassil I

Article Info

Journal

Science (New York, N.Y.)

Abbr.

Science

ISSN

1095-9203

DOI

10.1126/science.1081297

Published

2003-09-26

Pages

1895-8

Language

English

Region

United States

NLM ID

0404511

Subset

External Links

PubMed source DOI: 10.1126/science.1081297 View journal details

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Inactivation of TNF signaling by rationally designed dominant-negative TNF variants.

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