Impact of rheumatoid factors on the function of therapeutic monoclonals specific for PD-1/PD-L1

The efficacy of blocking antibodies against programmed death-1 (PD-1) and its ligand (PD-L1) is modulated by signalling through their Fc regions. The Fc region of anti-PD-1/PD-L1 antibodies, when cell-bound, represents a potential target for recognition by circulating rheumatoid factor (RF) autoantibodies. The resultant cell-associated immune complex may then provide different Fc signals to that of the PD-1/PD-L1 antibodies alone. However, little is known regarding the interaction of RF and therapeutic PD-1/PD-L1 antibodies. We report that PD-1 (pembrolizumab, nivolumab) and PD-L1 (avelumab) antibodies, when bound to their cellular targets, are recognised by both IgM-RF and IgA-RF components of RF⁺ patient serum. We further demonstrate that the presence of RF provides PD-1 antibodies with the ability to induce complement-dependent cytotoxicity (CDC) of a PD-1⁺ target cell line in the presence of human complement. Although RF provided avelumab with the ability to induce CDC in assays using rabbit complement, no CDC was observed in the presence of human complement. The presence of RF did not modulate the level of Fc receptor-triggered cellular cytotoxicity or neutrophil activation that was induced by PD-1/PD-L1 antibodies alone. This study demonstrates that RF has the potential to modulate the Fc-associated signals generated following binding of PD-1/PD-L1 antibodies. The impact of RF on their efficacy therefore merits further investigation.