@article{10.1172/jci.insight.152468, author = {Adam P. Curnock AND Giovanna Bossi AND Jyothi Kumaran AND Lindsay J. Bawden AND Rita Figueiredo AND Rajeevkumar Tawar AND Katherine Wiseman AND Emma Henderson AND Sec Julie Hoong AND Veronica Gonzalez AND Hemza Ghadbane AND David E.O. Knight AND Ronan O’Dwyer AND David X. Overton AND Christina M. Lucato AND Nicola M.G. Smith AND Carlos R. Reis AND Keith Page AND Lorraine M. Whaley AND Michelle L. McCully AND Stephen Hearty AND Tara M. Mahon AND Peter Weber}, journal = {JCI Insight}, publisher = {The American Society for Clinical Investigation}, title = {Cell-targeted PD-1 agonists that mimic PD-L1 are potent T cell inhibitors}, year = {2021}, month = {10}, volume = {6}, url = {https://insight.jci.org/articles/view/152468}, abstract = {The PD-1/PD-L1 pathway is a key immune checkpoint that regulates T cell activation. There is strong rationale to develop PD-1 agonists as therapeutics against autoimmunity, but progress in this area has been limited. Here, we generated T cell receptor (TCR) targeting, PD-1 agonist bispecifics called ImmTAAI molecules that mimic the ability of PD-L1 to facilitate the colocalization of PD-1 with the TCR complex at the target cell–T cell interface. PD-1 agonist ImmTAAI molecules specifically bound to target cells and were highly effective in activating the PD-1 receptor on interacting T cells to achieve immune suppression. Potent PD-1 antibody ImmTAAI molecules closely mimicked the mechanism of action of endogenously expressed PD-L1 in their localization to the target cell–T cell interface, inhibition of proximal TCR signaling events, and suppression of T cell function. At picomolar concentrations, these bispecifics suppressed cytokine production and inhibited CD8+ T cell–mediated cytotoxicity in vitro. Crucially, in soluble form, the PD-1 ImmTAAI molecules were inactive and, hence, could avoid systemic immunosuppression. This study outlines a promising new route to generate more effective, potent, tissue-targeted PD-1 agonists that can inhibit T cell function locally with the potential to treat autoimmune and chronic inflammatory diseases of high unmet need.}, number = {20}, doi = {10.1172/jci.insight.152468}, url = {https://doi.org/10.1172/jci.insight.152468}, }