Formation and clearance of TNF-TNF inhibitor complexes during TNF inhibitor treatment

BACKGROUND AND PURPOSE: Millions of patients with inflammatory diseases are treated with TNF inhibitors (TNFi). Individual treatment response varies, in part related to variable drug clearance. The role of TNF-TNFi complexes in clearance of the different TNFi is controversial. Moreover, mechanistic insight into the structural aspects and biological significance of TNF-TNFi complexes is lacking. We hypothesized a role for Fc-mediated clearance of TNF-TNFi immune complexes. Therefore, we investigated circulating TNF-TNFi complexes upon treatment with certolizumab - lacking Fc tails - in comparison to adalimumab, golimumab, infliximab and etanercept. EXPERIMENTAL APPROACH: Drug-tolerant ELISAs were developed and used to quantify TNF during adalimumab (n=193), golimumab (n=26), etanercept (n=186), certolizumab (n=20) and infliximab (n=29) treatment in patients with inflammatory arthritis or ulcerative colitis for a maximum follow-up of one year. Effect on in vitro TNF production and Fc-mediated uptake of TNF-TNFi complexes were investigated for all five TNFi. KEY RESULTS: Circulating TNF concentrations were >20-fold higher during certolizumab treatment compared to adalimumab, reaching up to 23.1 ng/mL. Internalization of TNF-TNFi complexes by macrophages critically depended on Fc valency: efficient uptake for the full antibody TNFi (three Fc tails), but little or no uptake for etanercept and certolizumab (one and zero Fc tail, respectively). TNF production was not affected by TNFi. These findings also allowed estimation of total TNF load, which appears insufficient to significantly impact clearance rate of total TNFi. CONCLUSIONS AND IMPLICATIONS: Differences in TNFi structure profoundly impact the clearance of TNF, while it is unlikely that TNF itself significantly contributes to target-mediated drug disposition of TNFi.