Protein heterogeneity and the immunogenicity of biotherapeutics

Abstract

High resolution analytical techniques reveal structural micro-heterogeneity within endogenous proteins, however; they are 'seen' as 'self' molecules by the immune system and immunological tolerance is established. In contrast the protein biotherapeutics are produced in non-human cells and multiple downstream protocols are employed in the isolation and purification of drug product; consequent micro-heterogeneities may 'seen' as 'non-self' and potentially immunogenic. In addition, extensive polymorphisms within and between outbred human populations suggests that any given protein biotherapeutic may be allogenic, and potentially immunogenic, when administered across different population groups. Further heterogeneity may result from differential intra-cellular processing and the addition of co-, trans-, and post-translational modifications. These processes are explored against reported incidences of immunogenicity for recombinant forms of human erythropoietin [EPO] and IgG.