T cell function is regulated by complex signaling networks of interconnected activators and inhibitors. Blockade of inhibitory receptors such as PD-1 has emerged as a novel treatment for multiple forms of cancer. Rather than block the interaction of PD-1 with its endogenous ligands, we sought to develop antibodies that can activate this pathway to inhibit T cell activation and function.
We conducted our antibody screen against human, cynomolgus monkey, and mouse PD-1 to select for antibodies with species cross-reactivity. We then conducted functional screens for antagonism and agonism using a human PD-1 Jurkat reporter cell-based screen. We identified several classes of PD-1-specific antibodies with a range of functional activities. Approximately one-third of antibodies exhibited antagonist activity when in solution, but agonist activity when immobilized. Less than 1% of antibodies were antagonists in solution with no agonist. The observation that most PD-1 antibodies that are antagonists in solution also function as agonists when immobilized suggests a fundamental relationship between agonism and antagonism of the PD-1 pathway. Of particular interest to us were antibodies that displayed agonist activity yet did not antagonize PD-1/PD-L1 interactions. We further characterized the ability of this subset of antibodies to inhibit function of primary T cells.
In summary, we identified several classes of PD-1 antibodies that antagonize and/or agonize human and mouse PD-1 when in solution and/or when immobilized. We believe the subset of antibodies that can agonize PD-1 and attenuate T cell activation create an opportunity for developing new therapeutics for autoimmune and inflammatory diseases.