Immunogenicity of therapeutic proteins. Part 1: Impact of product handling

A Protein’s Conformational Stability Is an Immunologically Dominant Factor: Evidence That Free-Energy Barriers for Protein Unfolding Limit the Immunogenicity of Foreign Proteins

“…Recombinant human proteins have been reported to induce Ab production (12,41,42), and the therapeutic administration of humanized or chimeric Abs, in which the murine constant regions are replaced with human ones, has led to an anti-Ab response (43). In addition, there is extensive overlap between the induction of Abs to therapeutic mAbs between anti-humanized and anti-chimera Abs, making the advantage of humanization less obvious (43).…”

“…These results indicate that the antigenicity of a protein is not always determined by the primary sequence of the protein Ag. In contrast, the data from the literature suggest that immune responses to therapeutic proteins vary within a population and even between different manufacturers of the same protein (12). Although IFN-a2a and -b2b have minimal sequence differences, IFN-a2a was more immunogenic than IFN-b2b, suggesting that there was minimal structural difference between them (6).…”

“…However, the use of therapeutic proteins is associated with the risk for Ab formation (5-7). Protein degradation by proteases occurs via the unfolded state of a protein (8)(9)(10)(11), and an understanding of the relationship between protein conformational stability and immunogenicity is important for the development of biopharmaceutical therapeutics (12).…”

Refolding of scFv mini-antibodies using size-exclusion chromatography via arginine solution layer

“…Such a transformation did not result in altering of molecular secondary structure, as it could be seen from CD spectra, but affected the compactness of the molecule and led to the increase of its electrophoretic mobility. Very important biotechnological and pharmacological feature of recombinant therapeutic preparation is the stability of its functional and physical-chemical characteristics in storage [48]. To evaluate this feature antibody storage stability was examined.…”

Biosimilar epoetins and other “follow‐on” biologics: Update on the European experiences

“…The immunogenicity of a biopharmaceutical cannot be deduced from the molecular structure of its active substance or from preclinical laboratory and animal studies [37,38]. Both productspecific (amino acid sequence alteration, posttranslational modification, aggregation, impurity) and patient-specific (application route and frequency, duration of treatment, comedication, underlying disease) factors impact on the incidence and degree of Abs formation [39][40][41]. In general, the administration via the s.c. route induces a much stronger immunogenic response than i.v.…”