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

JCI Insight. 2021 Oct 22;6(20):e152468. doi: 10.1172/jci.insight.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.

Keywords: Adaptive immunity; Autoimmune diseases; Autoimmunity; Drug therapy; Immunology.

MeSH terms

  • Humans
  • Immune Checkpoint Inhibitors / therapeutic use*
  • Immunotherapy / methods*
  • Programmed Cell Death 1 Receptor / metabolism*
  • Receptors, Antigen, T-Cell / antagonists & inhibitors*

Substances

  • Immune Checkpoint Inhibitors
  • Programmed Cell Death 1 Receptor
  • Receptors, Antigen, T-Cell

Grants and funding

All work was funded internally