Predicting multimodal chromatography of therapeutic antibodies using multiscale modeling

Multimodal chromatography has emerged as a powerful method for the purification of therapeutic antibodies. However, process development of this separation technique remains challenging because of an intricate and molecule-specific interaction towards multimodal ligands, leading to time-consuming and costly experimental optimization. This study presents a multiscale modeling approach to predict the multimodal chromatographic behavior of therapeutic antibodies based on their sequence information. Linear gradient elution (LGE) experiments were performed on an anionic multimodal resin for 59 full-length antibodies, including five different antibody formats at pH 5.0, 6.0, and 7.0 that were used for parameter determination of a linear adsorption model at low loading density conditions. Quantitative structure-property relationship (QSPR) modeling was utilized to correlate the adsorption parameters with up to 1374 global and local physicochemical descriptors calculated from antibody homology models. The final QSPR models employed less than eight descriptors per model and demonstrated high training accuracy (R² > 0.93) and reasonable test set prediction accuracy (Q² > 0.83) for the adsorption parameters. Model evaluation revealed the significance of electrostatic interaction and hydrophobicity in determining the chromatographic behavior of antibodies, as well as the importance of the HFR3 region in antibody binding to the multimodal resin. Chromatographic simulations using the predicted adsorption parameters showed good agreement with the experimental data for the vast majority of antibodies not employed during the model training. The results of this study demonstrate the potential of sequence-based prediction for determining chromatographic behavior in therapeutic antibody purification. This approach leads to more efficient and cost-effective process development, providing a valuable tool for the biopharmaceutical industry.