Factors influencing the immunogenicity of therapeutic proteins.

Several diseases and disorders are treatable with therapeutic proteins, but some of these products may induce an immune response, especially when administered as multiple doses over prolonged periods. Antibodies are created by classical immune reactions or by the breakdown of immune tolerance; the latter is characteristic of human homologue products. Many factors influence the immunogenicity of proteins, including structural features (sequence variation and glycosylation), storage conditions (denaturation, or aggregation caused by oxidation), contaminants or impurities in the preparation, dose and length of treatment, as well as the route of administration, appropriate formulation and the genetic characteristics of patients. The clinical manifestations of antibodies directed against a given protein may include loss of efficacy, neutralization of the natural counterpart and general immune system effects (including allergy, anaphylaxis or serum sickness). An upsurge in the incidence of antibody-mediated pure red cell aplasia (PRCA) among patients taking one particular formulation of recombinant human erythropoietin (epoetin-alpha, marketed as Eprex(R)/Erypo(R); Johnson & Johnson) in Europe caused widespread concern. The PRCA upsurge coincided with removal of human serum albumin from epoetin-alpha in 1998 and its replacement with glycine and polysorbate 80. Although the immunogenic potential of this particular product may have been enhanced by the way the product was stored, handled and administered, it should be noted that the subcutaneous route of administration does not confer immunogenicity per se. The possible role of micelle (polysorbate 80 plus epoetin-alpha) formation in the PRCA upsurge with Eprex is currently being investigated.