TY - JOUR
T1 - Calculation of therapeutic antibody viscosity with coarse-grained models, hydrodynamic calculations and machine learning-based parameters
AU - Lai, Pin Kuang
AU - Swan, James W.
AU - Trout, Bernhardt L.
N1 - Publisher Copyright:
© 2021 The Author(s). Published with license by Taylor & Francis Group, LLC.
PY - 2021
Y1 - 2021
N2 - High viscosity presents a challenge for manufacturing and drug delivery of therapeutic antibodies. The viscosity is determined by protein–protein interactions among many antibodies. Molecular simulation is a promising method to study protein–protein interactions; however, all-atom models do not allow the simulation of multiple molecules, which is necessary to compute viscosity directly. Coarse-grained models, on the other hand can do this. In this work, a 12-bead coarse-grained model based on Swan and coworkers (J. Phys. Chem. B 2018, 122, 2867–2880) was applied to study antibody interactions. Two adjustable parameters related to the short-range interactions on the variable and constant regions were determined by fitting experimental data of 20 IgG1 monoclonal antibodies at 150 mg/mL. The root-mean-square deviation improved from 1 to 0.68, and the correlation coefficient improved from 0.63 to 0.87 compared to that of a previous model that assumed the short-range interactions were the same for all the beads. Our model is also able to calculate the viscosity over a wide range of concentrations without additional parameters. A tabulated viscosity based on our model is provided to facilitate antibody screening in early-stage design.
AB - High viscosity presents a challenge for manufacturing and drug delivery of therapeutic antibodies. The viscosity is determined by protein–protein interactions among many antibodies. Molecular simulation is a promising method to study protein–protein interactions; however, all-atom models do not allow the simulation of multiple molecules, which is necessary to compute viscosity directly. Coarse-grained models, on the other hand can do this. In this work, a 12-bead coarse-grained model based on Swan and coworkers (J. Phys. Chem. B 2018, 122, 2867–2880) was applied to study antibody interactions. Two adjustable parameters related to the short-range interactions on the variable and constant regions were determined by fitting experimental data of 20 IgG1 monoclonal antibodies at 150 mg/mL. The root-mean-square deviation improved from 1 to 0.68, and the correlation coefficient improved from 0.63 to 0.87 compared to that of a previous model that assumed the short-range interactions were the same for all the beads. Our model is also able to calculate the viscosity over a wide range of concentrations without additional parameters. A tabulated viscosity based on our model is provided to facilitate antibody screening in early-stage design.
KW - Antibody viscosity
KW - coarse-grained models
KW - hydrodynamic calculations
KW - molecular dynamics simulations
UR - http://www.scopus.com/inward/record.url?scp=85104209652&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85104209652&partnerID=8YFLogxK
U2 - 10.1080/19420862.2021.1907882
DO - 10.1080/19420862.2021.1907882
M3 - Article
C2 - 33834944
AN - SCOPUS:85104209652
SN - 1942-0862
VL - 13
JO - mAbs
JF - mAbs
IS - 1
M1 - 1907882
ER -