Calculation of therapeutic antibody viscosity with coarse-grained models, hydrodynamic calculations and machine learning-based parameters

Abstract

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.

Keywords: Antibody viscosity; coarse-grained models; hydrodynamic calculations; molecular dynamics simulations.

Figure 1.

A viscosity heatmap as a function of the charges on the heavy chain variable region (VH) and the Hamaker constants on the Fv region (${\mathrm{A}}_{\mathrm{H}}^{\mathrm{v}}$). The Hamaker constant on the constant region is 0.4 kcal/mol. mAb4 at 150 mg/mL is used for analysis

Figure 2.

Viscosity as a function of the Hamaker constants on the constant region (${\mathrm{A}}_{\mathrm{H}}^{\mathrm{c}}$) for small and large ${\mathrm{A}}_{\mathrm{H}}^{\mathrm{v}}$ values at 150 mg/mL. The error bars indicate standard deviation. mAb4 is used as a template

Figure 3.

Viscosity as a function of ${\mathrm{A}}_{\mathrm{H}}^{\mathrm{v}}$ for different numbers of molecules in the system at 150 mg/mL. The error bars indicate standard deviation. mAb4 is used as a template. The ${\mathrm{A}}_{\mathrm{H}}^{\mathrm{c}}$ is equal to 0.4 kcal/mol

Figure 4.

Comparison of the viscosity model with the experimental data at 150 mg/mL for (a) the original model where ${\mathrm{A}}_{\mathrm{H}}^{\mathrm{v}}$ = ${\mathrm{A}}_{\mathrm{H}}^{\mathrm{c}}$ = 0.4 kcal/mol and (b) the new model where ${\mathrm{A}}_{\mathrm{H}}^{\mathrm{v}}$ = 0.04 × HVI (kcal/mol) and ${\mathrm{A}}_{\mathrm{H}}^{\mathrm{c}}$= 0.2 kcal/mol

Figure 5.

The 12-bead CG model of antibodies. The cartoon representation shows the all-atom model. In the CG model, each antibody domain is represented by one sphere. The orange spheres represent the variable region, and the gray spheres represent the constant region

Figure 6.

Concentration dependence of the relative viscosity with the experimental data for the original model where ${\mathrm{A}}_{\mathrm{H}}^{\mathrm{v}}$ = ${\mathrm{A}}_{\mathrm{H}}^{\mathrm{c}}$ = 0.4 kcal/mol and the new model where ${\mathrm{A}}_{\mathrm{H}}^{\mathrm{v}}$ = 0.04 × HVI (kcal/mol) and ${\mathrm{A}}_{\mathrm{H}}^{\mathrm{c}}$ = 0.2 kcal/mol. Black circles indicate experimental measurement. Blue squares indicate results from the original model. Red triangles indicate results from the new model