title: Protein aggregation and lyophilization: Protein structural descriptors as predictors of aggregation propensity.
abstract: Lyophilization can induce aggregation in therapeutic proteins, but the relative importance of protein structure, formulation and processing conditions are poorly understood. To evaluate the contribution of protein structure to lyophilization-induced aggregation, fifteen proteins were co-lyophilized with each of five excipients. Extent of aggregation following lyophilization, measured using size-exclusion chromatography, was correlated with computational and biophysical protein structural descriptors via multiple linear regression. Descriptor selection was performed using exhaustive search and forward selection. The results demonstrate that, for a given excipient, extent of aggregation is highly correlated by eight to twelve structural descriptors. Leave-one-out cross validation showed that the correlations were able to successfully predict the aggregation for a protein "left out" of the data set. Selected descriptors varied with excipient, indicating both protein structure and excipient type contribute to lyophilization-induced aggregation. The results show some descriptors used to predict protein aggregation in solution are useful in predicting lyophilized protein aggregation.
authors: Bioengineering Graduate Program, University of Kansas, Lawrence, KS, United States.
authors: Brock C
authors: BC
authors: Roughton
authors: Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, United States.
authors: Lavanya K
authors: LK
authors: Iyer
authors: Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, United States ; Department of Pharmaceutics and Analytical Chemistry, University of Copenhagen, Copenhagen, Denmark.
authors: Esben
authors: E
authors: Bertelsen
authors: Department of Industrial and Physical Pharmacy, Purdue University, West Lafayette, IN, United States.
authors: Elizabeth M
authors: EM
authors: Topp
authors: Department of Chemical and Petroleum Engineering, University of Kansas, Lawrence, KS, United States.
authors: Kyle V
authors: KV
authors: Camarda
keywords: Aggregation prediction; Biologics; Lyophilization; Multiple linear regression; Protein formulation; Structural descriptors