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Molecular Determinants of Inverse Agonist Activity of Biologicals Targeting CTLA-4¹

Wendy A. Teft^*, and Joaquín Madrenas^2,*,,

^* FOCIS Centre for Clinical Immunology and Immunotherapeutics, Robarts Research Institute, London, Ontario, Canada; and Department of Microbiology and Immunology and Department of Medicine, University of Western Ontario, London, Ontario, Canada

Ligation of CD28 or CTLA-4 with some biologicals can activate T cells due to an unexpected superagonist or inverse agonist activity, respectively. The risk of such an outcome limits the therapeutic development of these reagents. Thus, identifying the molecular determinants of superagonist/inverse agonist properties for biologicals targeting costimulatory/inhibitory receptors has not only fundamental value but also important therapeutic implications. In this study, we show that ligation of CTLA-4 with either soluble B7.1 Ig (but not B7.2 Ig) or with a recombinant bispecific in-tandem single chain Fv known as 24:26 induces TCR-independent, T cell activation. Such an inverse agonist activity requires CD28 expression and high CTLA-4 expression and is not seen when CTLA-4 is ligated by membrane-bound B7.1 or B7.2. At the molecular level, the inverse agonist activity of B7.1 Ig or 24:26 correlates with their ability to induce the formation of unique dimer-based, CTLA-4 oligomers on the T cell surface and involves CTLA-4 signaling through its cytoplasmic domain. Our results provide a potential mechanism to explain and to predict inverse agonist activity for CTLA-4 ligands.

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 This work was supported by grants from the Canadian Institutes of Health Research and the Kidney Foundation of Canada. W.A.T. holds a Canadian Institutes for Health Research Doctoral Award and J.M. holds a Canada Research Chair in Transplantation and Immunobiology.

² Address correspondence and reprint requests to Dr. Joaquín Madrenas, Robarts Research Institute, P.O. Box 5015, 100 Perth Drive, London, Ontario, Canada. E-mail address: madrenas{at}robarts.ca

³ Abbreviations used in this paper: ScFv, single-chain Fv; SEE, staphylococcal enterotoxin E; DSS, disuccinimidyl suberate.

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