The effect of immunomodulators on the immunogenicity of TNF-blocking therapeutic monoclonal antibodies: a review

Therapeutic monoclonal antibodies (TmAbs) that block tumor necrosis factor are powerful modalities in the treatment of various inflammatory diseases, but both chimeric and human TmAbs can induce anti-TmAb antibodies. Immunogenicity can change the pharmacokinetics of biological therapeutics, resulting in suboptimal therapeutic levels of the drug in patient serum. The problem of immunogenicity against therapeutic antibodies has been described since TmAbs have been on the market for the treatment of various inflammatory diseases, and knowledge regarding anti-TmAb antibodies is increasing. Nevertheless, technical factors, standardization of the assays used to measure anti-TmAb antibodies, and the timing of the measurements make immunogenicity a complex subject to investigate. Several studies in various inflammatory diseases demonstrate the presence of anti-TmAb antibodies [1]. Table 1 gives an overview of the reported frequency of anti-TmAb antibodies in infliximab (antibodies to infliximab, or ATIs) and in adalimumab (anti-adalimumab antibodies, or AAAs) [2-22]. The large variation in the percentages of anti-TmAb antibodies measured could be related to the differences in assays, duration of treatment, and the use of concomitant immunosuppressive treatment.In studies in which trough serum adalimumab or infliximab concentrations were measured, the presence of anti-TmAb antibodies was associated with decreased serum drug levels and a diminished response [2,5-7,10,11,13,14]. Furthermore, anti-TmAb antibodies in the presence of TmAb concentrations in patients serum lead to the formation of immune complexes [23]. The continuous presence of immune complexes in the serum could lead to adverse events. Little is known about the safety of TmAb and anti-TmAb antibody immune complexes. The presence of ATIs and of immune complexes of various sizes might be associated with infusion- related hypersensitivity reactions [2,6,10,23,24]. In one study, higher concentrations of ATIs predict