The primary safety concern for biosimilar agents is their potential immunogenicity. Using biopharmaceuticals to replace endogenous proteins that may be present at insufficient concentrations carries the serious risk of stimulating the immune system to develop anti-product antibodies (Abs), which may cross-react with endogenous protein.
Factors that may influence the immunogenicity of proteins include variation in amino acid sequence or glycosylation patterns, denaturation or aggregation caused by oxidation due to storage conditions, the presence of contaminants or impurities in the preparation, dose, route of administration, treatment duration and the genetic characteristics of patients.
The patient may develop binding Abs that do not significantly affect the activity of the biopharmaceutical or endogenous protein. On the other hand, anti-product Abs can bind to, and attenuate the activity of, a biopharmaceutical. General effects include allergy, anaphylaxis or serum sickness. Major clinical impact can occur if the endogenous protein with essential biological activity is neutralised. For example, neutralising naturally occurring erythropoietin (EPO) can result in a usually rare condition known as Ab-mediated pure red cell aplasia (PRCA).
Such Ab-mediated PRCA occurred a lot between 1998 and 2003 in patients with chronic kidney disease (CKD)-associated anaemia treated with subcutaneously administered Eprex (epoetin alfa, manufactured by Ortho Biologicals LLC and marketed by Johnson & Johnson), resulting in neutralising Ab formation against both recombinant and endogenous EPO.
The apparent increase in immunogenicity coincided with a relatively minor formulation change for Eprex – the replacement of human serum albumin as a stabiliser with glycine and polysorbate 80 in 1998 – and was possibly caused by micelle formation from polysorbate 80 and epoetin alfa or leachates from rubber stoppers breaking B-cell tolerance. A contraindication for subcutaneous administration led to a subsequent decrease in the incidence of PRCA. This illustrates how a difference in the manufacturing process can alter product characteristics with a drastic impact on clinical outcome.
Regulatory approved biosimilars may also have different immunogenic profiles versus their similar biological medicinal products (SBMPs). For example, the biosimilar epoetin zeta product Retacrit (SB309, from Hospira) showed a marked difference in immunogenicity in dogs compared with epoetin alfa (its SBMP), although the Abs were non-neutralising and were not associated with any deterioration. Only longer-term clinical data can fully address this issue.
Source: Huub Schellekens, NDT Plus. 2009;2(Suppl 1):i27-i36.
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