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

Area of Science:

• Immunology
• Oncology
• Pharmacology

Background:

• The efficacy of immune checkpoint inhibitors like anti-PD-1/PD-L1 antibodies is influenced by Fc region signaling.
• Cell-bound antibodies can be recognized by autoantibodies, such as rheumatoid factor (RF).
• The interaction between RF and therapeutic PD-1/PD-L1 antibodies is not well understood.

Purpose of the Study:

• To investigate the interaction between RF and therapeutic PD-1/PD-L1 antibodies.
• To determine if RF influences the Fc-mediated functions of these antibodies.

Main Methods:

• Patient serum containing RF (IgM-RF and IgA-RF) was used to assess binding to PD-1 and PD-L1 antibodies.
• Complement-dependent cytotoxicity (CDC) assays were performed using target cell lines and human or rabbit complement.
• Fc receptor-triggered cellular cytotoxicity and neutrophil activation assays were conducted.

Main Results:

• PD-1 (pembrolizumab, nivolumab) and PD-L1 (avelumab) antibodies were recognized by both IgM-RF and IgA-RF from RF+ patient serum when bound to target cells.
• RF presence enabled PD-1 antibodies to induce CDC of PD-1+ target cells with human complement.
• RF enabled avelumab to induce CDC with rabbit complement, but not human complement.
• RF did not modulate Fc receptor-triggered cytotoxicity or neutrophil activation induced by PD-1/PD-L1 antibodies alone.

Conclusions:

• RF has the potential to modulate Fc-associated signals of PD-1/PD-L1 antibodies.
• The impact of RF on the clinical efficacy of these immunotherapies warrants further investigation.