Cell-targeted PD-1 agonists are potent NK cell inhibitors

Harriet C Pope¹Ana L Chiodetti²Alice Newey²Guillaume Rieunier²David X Overton²Eduardo Mateos-Diaz²Tara M Mahon²Giovanna Bossi²Hussein Al-Mossawi²Charlotte Viant^2*

• ¹University of Bath, Bath, United Kingdom
• ²Immunocore Holdings plc, Abingdon, United Kingdom

The Programmed cell death protein 1 (PD-1) is a key regulatory immune checkpoint and a major target for therapeutic intervention. In oncology, antibodies blocking the PD-1 pathway are used to activate immune cells to promote antitumour immunity while in immune-mediated inflammatory diseases, PD-1 agonist molecules have the potential to achieve immune suppression.NK cells are a specialised population of innate lymphocytes able to recognize a large range of distressed cells including damaged tissues in autoimmune and inflammatory conditions. Of note, NK cells can upregulate PD-1 expression upon activation and their effector functions can be modulated by the PD-1 pathway signalling.We have generated a novel targeted bispecific PD-1 molecule, to achieve tissue-specific immune suppression for the treatment of immune-mediated inflammatory diseases. These targeted PD-1 agonists have shown potent T cell inhibition and here we describe an additional effect on NK cell activation. We show that PD-1 pathway activation modifies NK cell gene expression and decreases their inflammatory and cytotoxic functions. Targeted PD-1 agonist molecules, inhibiting T cells and NK cells in a tissue-specific manner offer a new promising treatment for autoimmune and inflammatory diseases.