Polysorbates, Peroxides, Protein Aggregation, and Immunogenicity – A growing Concern

  • Edward T. Maggio Aegis Therapeutics

Abstract

Aggregation underlies a number of deleterious effects for biotherapeutics including loss of efficacy, induction of unwanted immunogenicity, altered pharmacokinetics, and reduced shelf life. Aggregation is ameliorated by the inclusion of surfactants in biotherapeutics formulations -- typically non-ionic polymeric ether surfactants. The most commonly used examples are Tween 20 (Polysorbate 20) and Tween 80 (Polysorbate 80). Others include Triton X-100, Pluronic F-68, Pluronic F-88, Pluoronic F-127 (poloxamers), and Brij 35 (polyoxyethylene alkyl ether). The usefulness of polysorbates in particular in preventing protein aggregation in biotherapeutic formulations is well accepted. However, polysorbates contain ether linkages and unsaturated alkyl chains that have been shown to auto-oxidize in aqueous solution to protein-damaging peroxides and reactive aldehydes including formaldehyde and acetaldehyde. The peroxides principally affect methionine and tryptophan moieties. The aldehydes react with primary amino groups on proteins and are known to induce immunogenicity of proteins in the absence of aggregation or adjuvants. Detection of protein aggregation and prevention of aggregation using polysorbates is relatively straightforward using light scatter or size exclusion chromatography methods. Detection of oxidative damage to amino acyl moieties or increased immunogenicity resulting from reaction of biotherapeutic with the degradation products of polysorbates is considerably more difficult and has generally been ignored in the scientific literature. As an increasing number of biotherapeutic agents, come into use in common clinical practice, both innovator and biosimilar products, these latter issues will come under increased scrutiny. Substitution of non-ionic non-ether-based surfactants could offer significant improvements in stability, reduced immunogenicity, and shelf life and represents a significant unmet need in the field of biotherapeutics formulation.

Author Biography

Edward T. Maggio, Aegis Therapeutics
Edward T. Maggio, Ph.D., Chief Executive Officer and Director. Prior to co-founding Aegis, Dr. Maggio was founder and Chief Executive Officer of Structural Bioinformatics Inc., subsequently renamed Cengent Therapeutics. He was founder and Chief Executive Officer of ImmunoPharmaceutics, Inc. (IPI), which developed a number of endothelin antagonists, including Pfizer’s (formerly Encysive Pharmaceuticals') Thelin® (Sitaxsentan), approved in 2006 for sale in Europe for cardiovascular disease and currently in US clinical trials. Dr. Maggio has been a founder and board member of seven public and private life science companies in the San Diego area and one in Copenhagen, Denmark. He received his Ph.D. from the University of Michigan and was an NIH postdoctoral fellow at the University of California, San Francisco (UCSF) Department of Pharmaceutical Chemistry. He is a member of the Advisory Board of the Polytechnic Institute of New York University, Department of Chemical and Biological Sciences; and serves on the University of California, San Diego Dean's Board of Advisors for Biological Sciences; the California State University, San Marcos, Biotechnology Programs Advisory Board; and the Industry Council of the San Diego Consortium for Regenerative Medicine. Dr. Maggio has edited and coauthored a number of books and scientific articles in the biotechnology area and is an author of more than five-dozen issued and pending U.S. and foreign patents.
Published
2012-06-20
How to Cite
MAGGIO, Edward T.. Polysorbates, Peroxides, Protein Aggregation, and Immunogenicity A growing Concern. Journal of Excipients and Food Chemicals, [S.l.], v. 3, n. 2, p. 45-53, june 2012. ISSN 21502668. Available at: <https://ojs.abo.fi/ojs/index.php/jefc/article/view/157>. Date accessed: 28 oct. 2021.
Section
Reviews

Keywords

polysorbate, alkylsaccharide, peroxides, oxidation, immunogenicity, biotherapeutics, biosimilars