Alkylsaccharides: circumventing oxidative damage to biotherapeutics caused by polyoxyethylene-based surfactants.

Polysorbates and other polyoxyethylene-based surfactants are incorporated into most biotherapeutics to prevent protein aggregation in order to minimize loss of efficacy, induction of unwanted immunogenicity, altered pharmacokinetics and reduced shelf life. While they are effective in initially preventing protein aggregation, they contain ether linkages (within polyoxyethylene moieties) and in the case of polysorbate 80 unsaturated alkyl chains that spontaneously and rapidly auto-oxidize in aqueous solution to protein-damaging peroxides, epoxy acids and reactive aldehydes, including formaldehyde and acetaldehyde. Oxidative damage induces unwanted immunogenicity and in some instances promotes re-aggregation. Immunogenicity of biotherapeutics is a serious and growing concern for the US FDA and European Medicines Agency and will have significant and growing impact on the development and regulatory approval of both biosimilar and new innovator biotherapeutics.