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

Area of Science:

• Immunology
• Molecular Biology
• Drug Discovery

Background:

• The PD-1/PD-L1 pathway is a critical immune checkpoint regulating T cell activation.
• Developing PD-1 agonists for autoimmune diseases is promising but challenging.
• Existing approaches face limitations in achieving targeted immune suppression.

Purpose of the Study:

• To create novel T cell receptor (TCR) targeting, PD-1 agonist bispecifics (ImmTAAI molecules).
• To mimic PD-L1's function in colocalizing PD-1 with the TCR complex at the cell interface.
• To develop potent, tissue-targeted PD-1 agonists for autoimmune and inflammatory diseases.

Main Methods:

• Generation of ImmTAAI molecules, bispecifics targeting TCR and PD-1.
• Assessing ImmTAAI binding to target cells and activation of PD-1 on T cells.
• Evaluating ImmTAAI's mechanism of action, including TCR signaling inhibition and T cell function suppression in vitro.
• Testing the activity of soluble versus cell-bound ImmTAAI molecules.

Main Results:

• ImmTAAI molecules specifically bound target cells and activated PD-1 on T cells, inducing immune suppression.
• These bispecifics effectively mimicked endogenous PD-L1's mechanism at the target cell-T cell interface.
• Picomolar concentrations of ImmTAAI suppressed cytokine production and CD8+ T cell cytotoxicity.
• Soluble ImmTAAI molecules showed inactivity, preventing systemic immunosuppression.

Conclusions:

• ImmTAAI molecules represent a novel strategy for potent, tissue-targeted PD-1 agonism.
• This approach effectively inhibits T cell function locally, with potential for treating autoimmune diseases.
• The study provides a promising new route for developing therapeutics for unmet medical needs in inflammation.