JCI Insight (Oct 2021)

Cell-targeted PD-1 agonists that mimic PD-L1 are potent T cell inhibitors

  • 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

Journal volume & issue
Vol. 6, no. 20

Abstract

Read online

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.

Keywords