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Conversion of CTLA-4 from Inhibitor to Activator of T Cells with a Bispecific Tandem Single-Chain Fv Ligand¹

Joaquín Madrenas^2,*, Luan A. Chau^*, Wendy A. Teft^*, Paul W. Wu, Jason Jussif, Marion Kasaian, Beatriz M. Carreno and Vincent Ling^3,

^* Federation of Clinical Immunology Societies Centre for Clinical Immunology and Immunotherapeutics, Robarts Research Institute, and Departments of Microbiology and Immunology, and Medicine, University of Western Ontario, London, Ontario, Canada; and Wyeth Research, Cambridge, MA 02140

Abs or their recombinant fragments against surface receptors of the Ig superfamily can induce or block the receptors’ native function depending on whether they induce or prevent the assembly of signalosomes on their cytoplasmic tails. In this study, we introduce a novel paradigm based on the observation that a bispecific tandem single-chain variable region fragment ligand of CTLA-4 by itself converts this inhibitory receptor into an activating receptor for primary human T lymphocytes. This reversal of function results from increased recruitment of the serine/threonine phosphatase 2A to the cytoplasmic tail of CTLA-4, consistent with a role of this phosphatase in the regulation of CTLA-4 function, and assembly of a distinct signalosome that activates an lck-dependent signaling cascade and induces IL-2 production. Our data demonstrate that the cytoplasmic domain of CTLA-4 has an inherent plasticity for signaling that can be exploited therapeutically with recombinant ligands for this receptor.

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