Therapeutic monoclonal antibodies (mAbs), such as infliximab, constitute the fastest growing segment of the pharmaceutical industry. Use of these mAbs has provided substantial benefits, but can cause development of IgG anti-mAb antibodies and anaphylaxis. Mouse and human studies suggest that anaphylaxis caused by repeated infusion of these mAbs may be mediated by IgG rather than IgE;however, the existence of human IgG-mediated anaphylaxis has never been proven. We have developed novel peripheral blood assays that can distinguish murine IgE- from IgG-mediated anaphylaxis: murine IgE-, but not IgG-mediated anaphylaxis is associated with increases in serum soluble IL- 4R? concentration and T cell IL-4R? expression, while murine IgG-, but not IgE-mediated anaphylaxis is associated with decreased neutrophil Fc?RIII expression. Preliminary in vitro studies suggest that these same assays will be useful for differentiating human IgE- vs. IgG-mediated anaphylaxis. This proposal will evaluate whether the same assays may be used in vivo in humans to provide evidence for the existence of human IgG-mediated anaphylaxis. Specifically, we will use these assays, an established test for IgE- mediated anaphylaxis (serum tryptase concentration), an assay for IgG anti-infliximab antibodies and clinical evaluation to evaluate whether IgG-mediated anaphylaxis without evidence of IgE-mediated anaphylaxis develops more frequently in infliximab-treated Crohn's disease patients who have IgG antibodies to infliximab (our primary endpoint) and/or in patients who develop reactions to infliximab infusion (our secondary endpoint). A positive result would support the existence of human IgG-mediated anaphylaxis and could lead to improved diagnosis and prevention of this disorder by identifying patients who would benefit from changing therapy or pre-treatment with drugs that may prevent IgG-mediated anaphylaxis.
Proteins, including monoclonal antibodies, are the fastest growing category of therapeutic. Allergic reactions to protein therapeutics, including shock (anaphylaxis), are a considerable and growing problem with their use. Our proposed studies will determine whether anaphylaxis can be caused by IgG antibodies to protein therapeutics. This should improve the ability to prevent anaphylaxis by identifying individuals in whom the use of a specific protein therapeutic is likely to cause this disorder.
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