title: Protein instability and immunogenicity: roadblocks to clinical application of injectable protein delivery systems for sustained release.
abstract: Protein instability and immunogenicity are two main roadblocks to the clinical success of novel protein drug delivery systems. In this commentary, we discuss the need for more extensive analytical characterization in relation to concerns about protein instability in injectable drug delivery systems for sustained release. We then will briefly address immunogenicity concerns and outline current best practices for using state-of-the-art analytical assays to monitor protein stability for both conventional and novel therapeutic protein dosage forms. Next, we provide a summary of the stresses on proteins arising during preparation of drug delivery systems and subsequent in vivo release. We note the challenges and difficulties in achieving the absolute requirement of quantitatively assessing the degradation of protein molecules in a drug delivery system. We describe the potential roles for academic research in further improving protein stability and developing new analytical technologies to detect protein degradation byproducts in novel drug delivery systems. Finally, we provide recommendations for the appropriate approaches to formulation design and assay development to ensure that stable, minimally immunogenic formulations of therapeutic proteins are created. These approaches should help to increase the probability that novel drug delivery systems for sustained protein release will become more readily available as effective therapeutic agents to treat and benefit patients.
authors.affiliation: Division of Drug Delivery Technology, Leiden/Amsterdam Center for Drug Research, Leiden University, Leiden 2300 RA, the Netherlands. w.jiskoot@lacdr.leidenuniv.nl
authors.forename: Wim
authors.initials: W
authors.lastname: Jiskoot
authors.forename: Theodore W
authors.initials: TW
authors.lastname: Randolph
authors.forename: David B
authors.initials: DB
authors.lastname: Volkin
authors.forename: C Russell
authors.initials: CR
authors.lastname: Middaugh
authors.forename: Christian
authors.initials: C
authors.lastname: Schöneich
authors.forename: Gerhard
authors.initials: G
authors.lastname: Winter
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Friess
authors.forename: Daan J A
authors.initials: DJ
authors.lastname: Crommelin
authors.forename: John F
authors.initials: JF
authors.lastname: Carpenter
mesh_terms: D003692:Delayed-Action Preparations / Q000737:chemistry; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D007267:Injections; D019344:Lactic Acid / Q000737:chemistry; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D055550:Protein Stability; D011506:Proteins / Q000008:administration & dosage* / Q000737:chemistry / Q000276:immunology / Q000627:therapeutic use
chemical_list: D003692:Delayed-Action Preparations; D011506:Proteins; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid