Background: T cells play an important role in the development and progression of many autoimmune diseases. Inhibition of T cells and their effector mechanisms has therefore been an area of great therapeutic interest. PD1 (CD279) is a CD28/CTLA4 family coinhibitory receptor that is upregulated when cells are activated. Several lines of evidence link the PD1 pathway to autoimmune diseases, including genetics, correlations between PD1 expression and disease severity in patients, and autoimmune-like immune-related adverse events upon antagonizing the PD1 pathway in oncology. Consequently, the activation of the PD1 pathway through agonist antibodies holds promise as a therapeutic approach in autoimmune diseases. Several PD1 agonists have or are currently being tested in rheumatoid arthritis, psoriasis, alopecia areata, and ulcerative colitis clinical trials, with the goal to engage this endogenous regulatory mechanism. However, the molecular mechanism of how PD1 agonistic molecules work remains unclear.

Objectives: To increase our understanding of PD1 agonist antibodies mechanism of action on PD1 expressing cells by comparing activities of several PD1-agonistic antibodies.

Methods: Selected PD1 agonistic antibodies were profiled for binding affinity and ability to interfere with endogenous receptor-ligand interaction through biochemical assays. The functional effects of different PD1 agonistic antibodies were studied in vitro by assessing proliferation capacity and cytokine levels using human T cells.

Results: Antibodies that block PD1 receptor-ligand interaction led to enhanced lymphocyte activation and increased cytokine production as expected. Further, some, but not all, PD1 agonistic molecules that do not block PD1 receptor-ligand interaction exhibited potential enhancement of proinflammatory cytokine production.

Conclusion: Our data indicate that PD1 antibodies may become antagonistic under specific situations, leading to an increased inflammatory load in the local environment. Additional analyses will be helpful to further elucidate the molecular mechanism of how agonistic antibodies function, and their propensity to become antagonistic under particular conditions.

REFERENCES: NIL.

Acknowledgements: NIL.

Disclosure of Interests: Yevgeniya Orlovsky Johnson and Johnson Innovative Medicine, Johnson and Johnson Innovative Medicine, Ling-Yang Hao Johnson and Johnson Innovative Medicine, Johnson and Johnson Innovative Medicine, Melissa Swiecki Johnson and Johnson Innovative Medicine, Johnson and Johnson Innovative Medicine, Suzanne Cole Johnson and Johnson Innovative Medicine, Johnson and Johnson Innovative Medicine, Supratik Dutta Johnson and Johnson Innovative Medicine, Johnson and Johnson Innovative Medicine, Ian White Johnson and Johnson Innovative Medicine, Johnson and Johnson Innovative Medicine.