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Dominant-Negative Inhibitors of Soluble TNF Attenuate Experimental Arthritis without Suppressing Innate Immunity to Infection

Jonathan Zalevsky^*, Thomas Secher, Sergei A. Ezhevsky^*, Laure Janot, Paul M. Steed^*, Christopher O’Brien^*, Araz Eivazi^*, James Kung^*, Duc-Hanh T. Nguyen^*, Stephen K. Doberstein^*, François Erard, Bernhard Ryffel and David E. Szymkowski^1,*

^* Xencor, Monrovia, CA 91016; and Institut Transgenose, Centre National de la Recherche Scientifique, Orléans, France

TNF is a pleiotropic cytokine required for normal development and function of the immune system; however, TNF overexpression also induces inflammation and is associated with autoimmune diseases. TNF exists as both a soluble and a transmembrane protein. Genetic studies in mice have suggested that inflammation in disease models involves soluble TNF (solTNF) and that maintenance of innate immune function involves transmembrane TNF (tmTNF). These findings imply that selective pharmacologic inhibition of solTNF may be anti-inflammatory and yet preserve innate immunity to infection. To address this hypothesis, we now describe dominant-negative inhibitors of TNF (DN-TNFs) as a new class of biologics that selectively inhibits solTNF. DN-TNFs blocked solTNF activity in human and mouse cells, a human blood cytokine release assay, and two mouse arthritis models. In contrast, DN-TNFs neither inhibited the activity of human or mouse tmTNF nor suppressed innate immunity to Listeria infection in mice. These results establish DN-TNFs as the first selective inhibitors of solTNF, demonstrate that inflammation in mouse arthritis models is primarily driven by solTNF, and suggest that the maintenance of tmTNF activity may improve the therapeutic index of future anti-inflammatory agents.

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 Address correspondence and reprint requests to Dr. David E. Szymkowski, Xencor, 111 W. Lemon Avenue, Monrovia, CA 91016. E-mail address: david.szymkowski{at}xencor.com

² Abbreviations used in this paper: TACE, TNF- converting enzyme; CAIA, collagen-antibody induced arthritis; CIA, collagen-induced arthritis; CHO, Chinese hamster ovary; DN-TNF, dominant-negative inhibitor of TNF; PEG, polyethylene glycol; solTNF, soluble TNF; tmTNF, transmembrane TNF.

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The JI 2007 179: 1411-1412. [Full Text]