Protein drug stability: a formulation challenge

Abstract

Recombinantly expressed proteins are increasingly important in drug therapy. This makes it crucial to assess how their properties as proteins affect drug efficacy, targeting and side effects, as well as the ability to survive long-term storage. Amino-acid substitutions have led to therapeutically improved variants of, for example, insulin and interleukin-2, but modifications such as acylation and PEGylation can be just as effective, by causing a decrease in the clearing rate and reducing immunogenicity. Aggregation and misfolding is a fundamental issue in the long-term storage of protein therapeutics before administration. Although the mechanisms of aggregation are complex and can differ between even closely related proteins, methods have been developed to predict how amino-acid substitutions can affect this process. An easier approach might be to modify drug formulations. Simple additives, such as detergents, amino-acid pairs or cyclodextrins, can markedly reduce aggregation. Furthermore, judicious use of lyophilization can also provide a very reliable way to extend shelf-life.