Understanding Anti-TNF Treatment Failure: Pre-Existing Antidrug Antibodies Are Common but Do Not Neutralize Drug Activity In Vitro or Influence Clinical Response to Infliximab or Adalimumab in Patients with Crohn Disease

Background We sought to determine the prevalence, clinical impact, neutralizing capacity, and cross-reactivity of pre-existing antibodies to infliximab and adalimumab in antitumor necrosis factor (TNF) treatment-naïve patients with active luminal crohn disease. Methods The prevalence of antibodies to infliximab and adalimumab at entry to the “Personalised Anti-TNF Therapy in Crohn's Disease Study” (PANTS) were measured using the drug-tolerant IDKmonitor Total antidrug antibody ELISAs. Neutralizing capacity in positive cases was determined using iLite™ cell-based assays. Results Pre-existing antibodies to infliximab were more common (6.3%, 96/1525 vs 2.4%, 36/1525, P < 0.01) and detectable at higher concentrations [median (IQR) 23.9 (14.2–55.2) AU/mL vs 7.2 (6.3–10.4) AU/mL, P < 0.0001] to infliximab than adalimumab. A few patients [1.3% (95% CI 0.6–1.8) 20/1525] had antidrug antibody reactivity to both drugs. None of the detected antidrug antibodies had demonstrable anti-TNF neutralizing capacity. No associations were seen between pre-existing antibody positivity, adverse drug reactions, drug levels, or response status at weeks 14 or 54 or subsequent immunogenicity. Cross-reactivity with rheumatoid factor and antimouse antibodies was detected (>10 IU/mL) in 6.6% (95% CI 3.2–13.0) (7/106) and 17.0% (95% CI 10.5–25.2) (19/112) of patients with pre-existing antibodies. Conclusions Pre-existing antidrug antibodies are common but do not neutralize anti-TNF drug activity in vitro, promote drug clearance, or influence clinical response to anti-TNF drugs. Further work is required to understand this cross-reactivity and to determine the exact nature of the antibodies detected in drug-naïve individuals.