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.
Adam P. Curnock, Giovanna Bossi, Jyothi Kumaran, Lindsay J. Bawden, Rita Figueiredo, Rajeevkumar Tawar, Katherine Wiseman, Emma Henderson, Sec Julie Hoong, Veronica Gonzalez, Hemza Ghadbane, David E.O. Knight, Ronan O’Dwyer, David X. Overton, Christina M. Lucato, Nicola M.G. Smith, Carlos R. Reis, Keith Page, Lorraine M. Whaley, Michelle L. McCully, Stephen Hearty, Tara M. Mahon, Peter Weber
Target cell–bound PD-1 antibody ImmTAAI molecules exhibit superior inhibition of TCR complex signaling over PD-L1 ImmTAAI molecules.