TY - JOUR AU - Curnock, Adam P. AU - Bossi, Giovanna AU - Kumaran, Jyothi AU - Bawden, Lindsay J. AU - Figueiredo, Rita AU - Tawar, Rajeevkumar AU - Wiseman, Katherine AU - Henderson, Emma AU - Hoong, Sec Julie AU - Gonzalez, Veronica AU - Ghadbane, Hemza AU - Knight, David E.O. AU - O’Dwyer, Ronan AU - Overton, David X. AU - Lucato, Christina M. AU - Smith, Nicola M.G. AU - Reis, Carlos R. AU - Page, Keith AU - Whaley, Lorraine M. AU - McCully, Michelle L. AU - Hearty, Stephen AU - Mahon, Tara M. AU - Weber, Peter T1 - Cell-targeted PD-1 agonists that mimic PD-L1 are potent T cell inhibitors PY - 2021/10/22/ AB - 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. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.152468 VL - 6 IS - 20 UR - https://doi.org/10.1172/jci.insight.152468 PB - The American Society for Clinical Investigation ER -