Influence of Immunogenicity on the Long-Term Efficacy of Infliximab in Crohn's Disease
Filip Baert, M.D., Maja Noman, M.D., Severine Vermeire, M.D., Ph.D., Gert Van Assche, M.D., Ph.D., Geert D' Haens, M.D., Ph.D., An Carbonez, Ph.D., and Paul Rutgeerts, M.D., Ph.D.
ABSTRACT
Background Treatment with infliximab, a chimeric monoclonal IgG1 antibody against tumor necrosis factor, can result in the formation of antibodies against infliximab. We evaluated the clinical significance of these antibodies in patients with Crohn's disease.
Methods In a cohort of 125 consecutive patients with Crohn's disease who were treated with infliximab infusions, we evaluated the concentrations of infliximab and of antibodies against infliximab, clinical data, side effects (including infusion reactions), and the use of concomitant medications before and 4, 8, and 12 weeks after each infusion.
Results A mean of 3.9 infusions (range, 1 to 17) per patient were administered over a mean period of 10 months. Antibodies against infliximab were detected in 61 percent of patients. The presence of concentrations of 8.0 µg per milliliter or greater before an infusion predicted a shorter duration of response (35 days, as compared with 71 days among patients with concentrations of less than 8.0 µg per milliliter; P<0.001) and a higher risk of infusion reactions (relative risk, 2.40; 95 percent confidence interval, 1.65 to 3.66; P<0.001). Infliximab concentrations were significantly lower at four weeks among patients who had had an infusion reaction than among patients who had never had an infusion reaction (median, 1.2 vs. 14.1 µg per milliliter; P<0.001). Patients who had infusion reactions had a median duration of clinical response of 38.5 days, as compared with 65 days among patients who did not have an infusion reaction (P<0.001). Concomitant immunosuppressive therapy was predictive of low titers of antibodies against infliximab (P<0.001) and high concentrations of infliximab four weeks after an infusion (P<0.001).
Conclusions The development of antibodies against infliximab is associated with an increased risk of infusion reactions and a reduced duration of response to treatment. Concomitant immunosuppressive therapy reduces the magnitude of the immunogenic response.
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Some comments: I am surprised to see such a strong HAMA response. And it seems to be relevant from a clinical standpoint too. Although the response can be suppressed, I guess that is not something one would like to do if it is avoidable.
Will this leave the field open for companies developing fully human monoclonal antibodies to come forward with their versions?
As far as I know, J&J already have a potential Remicade replacement in the clinics.
Erik |
