Formation, Distribution, and Elimination of Infliximab and Anti-Infliximab Immune Complexes in Cynomolgus Monkeys

Abstract

Infliximab (IFX) is a chimeric IgG1 monoclonal antibody specific for human tumor necrosis factor-␣ that is approved in the United States and Europe for the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). Approximately 10% of RA and CD patients receiving maintenance treatment with IFX will develop antibodies to IFX. The objective of this study was to develop a model to assess the in vivo formation, distribution, and elimination of immune complexes resulting from a low-level immune response in the presence of the excess concentration of a therapeutic antigen. In this model, cynomolgus monkeys were treated with a single intravenous injection of IFX, followed by injection of either radiolabeled, purified monkey anti-IFX IgG antibody (n ϭ 3, test group) or radiolabeled monkey, nonimmune IgG (n ϭ 3, control group). High-performance liquid chromatography analysis of collected sera revealed a rapid formation of immune complexes comprised of IFX and radiolabeled anti-IFX IgG antibody immune complexes. The terminal half-life of the anti-IFX IgG antibody immune complex was approximately 38 h compared with 86 h for the nonimmune antibody. However, the pharmacokinetic profile of IFX, although slightly lower in concentration over time for the test group, was not notably different relative to the control group. There were no macroscopic or microscopic histological findings in either treatment group. These data confirm that immune complexes between IFX and anti-IFX IgG antibodies can form in vivo and that these immune complexes are eliminated more rapidly than nonimmune antibodies in the presence of excess IFX.

Predicting durable response or resistance to antitumor necrosis factor therapy in inflammatory bowel disease

“…While it is still unclear which epitopes induce antibody production that is clinically relevant, it was demonstrated that the antibodies bind to the Fab segment [Ben-Horin et al 2011]. Antimonoclonal antibodies interfere with their biologic activity by inhibiting the binding of TNFα inhibitors to both serum and membranebound TNFα molecules, and by the generating of immune complexes that are eliminated by the reticuloendothelial system [Rojas et al 2005;Yamada et al 2010]. In a recent large retrospective study from Israel, antibodies to IFX were detected in 47% of patients with secondary LOR, and to ADA in 23% [Yanai et al 2015].…”

Application of Quantitative Pharmacology in Development of Therapeutic Monoclonal Antibodies

“…Robust immunoassays are critical for evaluation of antibody immunogenicity (IM) during both preclinical and clinical phases (40)(41)(42)(43)(44). Various methodologies have been used for IM testing; however, these methodologies differ with respect to sensitivity for measuring both low-and high-affinity antibody responses (45,46).…”

Therapeutic Drug Monitoring in Inflammatory Bowel Disease

“…ATI interfere with the biologic activity by inhibiting the binding of the TNF-α inhibitors to both serum and membrane-bound [28,29]. Formation of ATIs has been demonstrated to be correlated with decreased levels of anti-TNFs and diminished clinical response, although not all studies support that [13][14][15][16]30].…”