Commentary: Current Perspectives on the Aggregation of Protein Drugs

Topp, Elizabeth M.

doi:10.1208/s12248-014-9580-0

Cited by 7 publications

(3 citation statements)

References 12 publications

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“…Subvisible particle, formed by the aggregation of protein monomers, has become a tough challenge for biopharmaceutical researchers. , Protein aggregation usually leads to lower biological potency, altered pharmacokinetic properties, reduced target binding affinity, and potentially life-threatening immunogenic responses. − To optimize the performance of therapeutic proteins, the manufacturing process, container quality, and storage conditions must be strictly controlled. ,, However, these measures alone cannot effectively inhibit protein aggregation since protein instability is intrinsic and comes from its structure or microconformation. , Because protein unfolding often initiates aggregation, improving the conformational stability is of paramount importance to retard or prevent the formation of aggregates. , The aromatic hydrophobic regions in protein molecules serve as binding sites for additives, and they contribute considerably to protein aggregation because they themselves are prone to aggregation. , Currently, there is growing interest in understanding the microconformational changes of proteins in the aggregation process.…”

Section: Introductionmentioning

confidence: 99%

Protein Aggregation and Performance Optimization Based on Microconformational Changes of Aromatic Hydrophobic Regions

et al. 2018

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Protein aggregation is a key concern in biopharmaceutical development and manufacturing. There is growing interest in understanding how the changes in protein microconformation affect the aggregation behavior. This study selected several representative proteins and first manipulated microconformational changes of the aromatic hydrophobic regions of proteins, especially tryptophan residues, by using amine or guanidine additives. The effects of the interactions between the additives and proteins on the aromatic hydrophobic regions could be grouped into three categories: exposure to solvent, burial into core, and no change. The microconformational parameters of the tryptophan residue, including fluorescence peak position (λ), degree of hydrolysis, solvent accessible surface area ( SAS), and packing density ( Den), were obtained by steady-state fluorescence spectroscopy, proteolysis coupled with electrophoresis, and molecular dynamics simulation. Furthermore, the aggregation degrees of globular proteins with distinct surface aromatic hydrophobilities under mechanical stress were investigated. A strong correlation was observed between protein aggregation and the microconformational changes of the aromatic hydrophobic regions incurred by amine or guanidine additives. Protein aggregation was enhanced when the aromatic hydrophobic regions were exposed to the solvent but suppressed when the additives led to burial of the aromatic hydrophobic regions with lower-polarity microenvironment. These findings shed light on the relationship between protein aggregation and molecular conformation and paved way for future preformulation studies of therapeutic proteins.

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Section: Introductionmentioning

confidence: 99%

Protein Aggregation and Performance Optimization Based on Microconformational Changes of Aromatic Hydrophobic Regions

et al. 2018

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“…Over the past few decades, peptide and protein drugs have been greatly developed because of their high curing effectiveness in metabolic disease, tumors, and infections . A number of protein and peptide drugs, including monoclonal antibodies and enzymes, have entered the marketplace after approval by the U.S. Food and Drug Administration and regulatory agencies in other countries.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, characterization, and cytotoxicity of star‐shaped polyester‐based elastomers as controlled release systems for proteins

Guo

Zhang

Pei

et al. 2016

J of Applied Polymer Sci

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With the growing number of therapeutic proteins on the market, effective delivery systems are receiving particular attention. In this study, biodegradable elastomers, intended for protein drug delivery and based on methacrylic tripoly(ε‐caprolactone‐co‐d,l‐lactide) cyclic ester with different ratios of ɛ‐caprolactone to d,l‐lactide and methacrylic bipoly[ɛ‐caprolactone‐b‐poly(ethylene glycol)‐b‐ɛ‐caprolactone], were synthesized and characterized. The degradation behavior, bovine serum albumin (BSA)‐releasing kinetics, and cytotoxicity of the elastomers in vitro were investigated. The elastomers were degraded by the hydrolysis of the ester bond; this resulted in pH changes, which further affected the degradation rate. The BSA‐releasing behavior was strongly dependent on the diffusion mechanism. In the diffusion‐controlled period, nearly sustained and stable BSA release was achieved. Furthermore, the elastomers displayed good biocompatibility, as demonstrated by a 3‐(4,5‐dimethyl thiazol‐2‐yl)−2,5‐diphenyl tetrazolium bromide assay and inflammation–induction experiments, and are considered promising candidates for the controllable delivery of protein drugs. © 2016 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2016, 133, 43393.

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“…Virtually, no rigorous assessment technique exists which would allow one to noninvasively (without opening the drug container) check aggregation level in biopharmaceutical products . Clearly, the pharmaceutical industry is in need of an inexpensive technique capable to quantify protein aggregation by measuring simple solution parameters with high‐throughput potential …”

Section: Introductionmentioning

confidence: 99%