TY - JOUR
T1 - Machine learning prediction of antibody aggregation and viscosity for high concentration formulation development of protein therapeutics
AU - Lai, Pin Kuang
AU - Gallegos, Austin
AU - Mody, Neil
AU - Sathish, Hasige A.
AU - Trout, Bernhardt L.
N1 - Publisher Copyright:
© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.
PY - 2022
Y1 - 2022
N2 - Machine learning has been recently used to predict therapeutic antibody aggregation rates and viscosity at high concentrations (150 mg/ml). These works focused on commercially available antibodies, which may have been optimized for stability. In this study, we measured accelerated aggregation rates at 45°C and viscosity at 150 mg/ml for 20 preclinical and clinical-stage antibodies. Features obtained from molecular dynamics simulations of the full-length antibody and sequences were used for machine learning model construction. We found a k-nearest neighbors regression model with two features, spatial positive charge map on the CDRH2 and solvent-accessible surface area of hydrophobic residues on the variable fragment, gives the best performance for predicting antibody aggregation rates (r = 0.89). For the viscosity classification model, the model with the highest accuracy is a logistic regression model with two features, spatial negative charge map on the heavy chain variable region and spatial negative charge map on the light chain variable region. The accuracy and the area under precision recall curve of the classification model from validation tests are 0.86 and 0.70, respectively. In addition, we combined data from another 27 commercial mAbs to develop a viscosity predictive model. The best model is a logistic regression model with two features, number of hydrophobic residues on the light chain variable region and net charges on the light chain variable region. The accuracy and the area under precision recall curve of the classification model are 0.85 and 0.6, respectively. The aggregation rates and viscosity models can be used to predict antibody stability to facilitate pharmaceutical development.
AB - Machine learning has been recently used to predict therapeutic antibody aggregation rates and viscosity at high concentrations (150 mg/ml). These works focused on commercially available antibodies, which may have been optimized for stability. In this study, we measured accelerated aggregation rates at 45°C and viscosity at 150 mg/ml for 20 preclinical and clinical-stage antibodies. Features obtained from molecular dynamics simulations of the full-length antibody and sequences were used for machine learning model construction. We found a k-nearest neighbors regression model with two features, spatial positive charge map on the CDRH2 and solvent-accessible surface area of hydrophobic residues on the variable fragment, gives the best performance for predicting antibody aggregation rates (r = 0.89). For the viscosity classification model, the model with the highest accuracy is a logistic regression model with two features, spatial negative charge map on the heavy chain variable region and spatial negative charge map on the light chain variable region. The accuracy and the area under precision recall curve of the classification model from validation tests are 0.86 and 0.70, respectively. In addition, we combined data from another 27 commercial mAbs to develop a viscosity predictive model. The best model is a logistic regression model with two features, number of hydrophobic residues on the light chain variable region and net charges on the light chain variable region. The accuracy and the area under precision recall curve of the classification model are 0.85 and 0.6, respectively. The aggregation rates and viscosity models can be used to predict antibody stability to facilitate pharmaceutical development.
KW - Machine learning
KW - antibody aggregation
KW - antibody viscosity
KW - developability
KW - molecular dynamics simulations
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U2 - 10.1080/19420862.2022.2026208
DO - 10.1080/19420862.2022.2026208
M3 - Article
C2 - 35075980
AN - SCOPUS:85123681797
SN - 1942-0862
VL - 14
JO - mAbs
JF - mAbs
IS - 1
M1 - 2026208
ER -