NDLI: Significance of Unfolding Thermodynamics for Predicting Aggregation Kinetics: A Case Study on High Concentration Solutions of a Multi-Domain Protein

Content Provider	Springer Nature Link
Author	Saluja, Atul Sadineni, Vikram Mungikar, Amol Nashine, Vishal Kroetsch, Andrew Dahlheim, Charles Rao, Venkatramana M.
Copyright Year	2014
Abstract	To enable aggregation rate prediction over a broad temperature range for complex multi-domain proteins at high concentrations.Thermal unfolding, non-isothermal kinetics and storage stability studies were conducted on a model multi-domain protein (MDP) at moderate to high concentrations (25–125 mg/mL) over a broad temperature range (4–40°C).Storage stability studies indicated the aggregation of MDP in solution to be a second order process. Application of Arrhenius kinetics to accelerated stability data resulted in underestimation of the aggregation rate under refrigerated conditions. Additional studies undertaken to understand the mechanism of the aggregation process highlighted the association of the monomer (or the aggregation competent species) to be the rate-limiting step for aggregation over the temperature range studied. Thermal unfolding studies in the presence of urea were used to calculate the heat capacity change upon unfolding (Δc$_{p,un}$). The resulting value of Δc$_{p,un}$ when used in the extended Lumry-Eyring model resulted in a more accurate and a conservative estimate of the aggregation rate under refrigerated condition. Some complicating factors for the aggregation rate prediction for multi-domain proteins at high concentration are discussed.The work highlights (i) the significance of incorporating unfolding thermodynamics in protein aggregation rate prediction, (ii) the advantages and challenges associated with the use of the extended Lumry-Eyring (ELE) model for rate prediction and (iii) the utility of using the Arrhenius and the ELE models in tandem during product development.
Starting Page	1575
Ending Page	1587
Page Count	13
File Format	PDF
ISSN	07248741
Journal	Pharmaceutical Research
Volume Number	31
Issue Number	6
e-ISSN	1573904X
Language	English
Publisher	Springer US
Publisher Date	2014-01-08
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Pharmacology/Toxicology Pharmacy Biochemistry Medical Law Biomedical Engineering
Content Type	Text
Resource Type	Article
Subject	Organic Chemistry Pharmacology Molecular Medicine Pharmacology (medical) Biotechnology Pharmaceutical Science

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