Evaluation of anti-drug antibodies against therapeutic monoclonal antibodies and related product in Japanese patients with rheumatoid arthritis and their clinical impact.

Biopharmaceuticals are widely used to treat rheumatoid arthritis (RA) due to their high therapeutic efficacy. However, these drugs may elicit immunogenicity and induce the production of anti-drug antibodies (ADA), potentially impacting their efficacy and safety. Therefore, the detection and characterization of ADA in patient samples during clinical development is crucial. However, data regarding biopharmaceutical immunogenicity and associated clinical factors in Japanese patients with RA remain limited. Here, we measured ADA levels in the sera of Japanese patients with RA treated with biopharmaceuticals (infliximab, adalimumab, golimumab, tocilizumab, and etanercept), investigated the clinical factors associated with ADA formation, and examined the effect of ADA on the pharmacological activity of each drug. Although the prevalence of ADA varied among biopharmaceuticals, no apparent neutralizing activity was observed. Among clinical factors, the use of concomitant methotrexate (MTX) influenced ADA prevalence in patients treated with adalimumab and the route of administration was a significant factor in patients treated with tocilizumab. Analyzing the relationship between ADA-positive/negative status and human leukocyte antigen (HLA) revealed that HLA-DRB1*04:01 allele frequency tended to be higher in the anti-etanercept ADA-positive group. The free drug concentration tended to be lower in ADA-positive samples, suggesting that the presence of ADA may have pharmacokinetic implications. Although experimental evaluation of the impact of ADA on drug pharmacological activity in patient samples is typically complex, we developed a method to measure residual drug bioactivity using cell-based assays as an alternative to evaluating the neutralization activity of ADA, and demonstrated the utility of this approach to assess the clinical impact of ADA.