PO-432 Small molecules, peptides and antibodies – the comparison of PD-1/PD-L1 blocking potential in an in vitro immune checkpoint blockade assay

Abstract

IntroductionProgrammed cell death-1 (PD-1, CD279) protein is a surface receptor belonging to immunoglobulin superfamily. The receptor is expressed mostly on activated T cells and serves as an emergency brake for turning off the destructive action of these cells. Its natural ligand, PD-L1, is expressed on several types of immune cells to prevent from autoimmune reactions and provide T cell homeostasis. Due to its immunosuppressive function, PD-L1 is also utilised by a variety of cancer types to evade the deadly impact of activated T cells.In the recent years cancer immunotherapy utilising antibodies targeting PD-1/PD-L1 interaction has been proved to be exceptionally effective in multiple clinical studies. Due to extraordinary clinical outcome the use of both anti-PD-1 and anti-PD-L1 antibodies has been approved for the treatment of several cancer types. Despite great achievements of the use of therapeutic antibodies, a strikingly less progress has been done in the field of small molecules targeting this interaction. In this report the comparison of the in vitro activity of therapeutic antibodies, Bristol-Myers Squibb (BMS) small molecules and cyclic peptides is presented.Material and methodsFor the comparison of in vitro potential in blocking PD-1/PD-L1 axis, the PD-1/PD-L1 immune checkpoint blockade (ICB) assay (Promega) was utilised. Four therapeutic antibodies, i.e. nivolumab (Opdivo), pembrolizumab (Keytruda), atezolizumab (Tecentriq) and durvalumab (Imfinzi), two BMS small molecules (BMS-1001 and BMS-1166) and two BMS peptides (peptide-57 and peptide-71) were tested.Results and discussionsFor all the molecules tested the EC50 values of the immune checkpoint blocking activity were in sub-micromolar range. The experiments revealed the strongest ICB potential of the therapeutic antibodies, followed by cyclic peptides. The lowest activity was observed in the case of BMS small molecules.ConclusionAlthough the small molecules and cyclic peptides show the potential of blocking PD-1/PD-L1 interaction in vitro, the activity of therapeutic antibodies is still unrivalled. The optimisation of the structures of the compounds is required before proceeding to clinical trials.