Background/Purpose: 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 mainly found on activated lymphocytes. Ample evidence links the PD1 pathway to autoimmune diseases, ranging from genetic evidence, correlations between PD1 expression and disease severity in patients, and autoimmune-like immune-related adverse events (irAE) from blocking PD1 pathway therapies in oncology. Consequently, the activation of the PD1 pathway through agonist antibodies holds promise as a therapeutic approach in autoimmune disease. With the first PD1 targeting drugs entering the rheumatoid arthritis clinical trial space, there is a need to increase our understanding of the mechanistic underpinnings of agonist PD1 antibody (Ab) on T cells to support further drug development. Here we assess the impact of various Ab configurations on the potential of novel PD1 Ab to inhibit T cell activation in vitro.

Methods: PD1 Abs were assessed for affinity and capacity to interfere with endogenous ligands interaction. Selected anti-PD1 reagents were expressed with different molecule configurations and tethering partners. Naïve and activated CD4+ T cells were cultured with soluble or scaffold/bead-bound PD1 Abs and anti-CD3 to determine inhibitory potential on proliferation and cytokine production. Antigen stimulation-based studies in PBMC were used to assess impact in a multi-cellular setting. Potential to promote Treg development was assessed in naïve CD4+ T cells stimulated with anti-CD3 coated beads and recombinant interleukin 2.

Results: In purified T cell assays, several of the anti-PD1 molecules showed clear impact of tethering on the agonist capacity. Importantly, inhibition of T cell function and Treg development was observed when the PD1 Abs were bound to the same scaffold (cis), but not on separate scaffolds (trans). Some PD1 Abs that showed agonism in the purified T cell assay failed to do so in the PBMC assay, and some architectures, such as the PD1xCD4 tetrapod, shifted from agonist to antagonist.

Conclusion: Our data indicate that more potent agonist effects correlated with close proximity engagement of PD1 and T cell receptor. Therefore, strategies that preserve or enhance the natural behavior of PD1 localization to immune synapses are likely to yield more successful agonists.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/distinct-pd-1-receptor-engagement-leads-to-different-pharmacodynamic-effects/