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.
Lindsay Edwards– Pandion Therapeutics
Daniel Rios– Pandion Therapeutics
Salvatore Alioto– Pandion Therapeutics
Bridget Larkin– Pandion Therapeutics
Timothy Kiprono– Pandion Therapeutics
Nathan Higginson-Scott– Director Therapeutics Protein Technologies, Pandion Therapeutics
Joanne Viney– Chief Scientific Officer, Pandion Therapeutics
Kevin Otipoby– Director Immunology, Pandion Therapeutics