Multimodal Chromatography in the Downstream Processing of mAb‐Based Products: Mechanisms, Strategies, and Applications

Multimodal chromatography has emerged as a powerful tool for the purification of monoclonal antibodies (mAbs) and their derivatives-including antibody fragments (Fabs), Fc-fusions, bispecific (BsAb), and antibody-drug conjugates (ADCs)-offering enhanced selectivity through the integration of ionic, hydrophobic, hydrogen-bonding, and π-π interactions. This review presents the first comprehensive comparison of all commercially available multimodal chromatography resins used in the purification of antibody-based (Ab-based) products, incorporating experimental data from peer-reviewed literature, supplier documentation, and technical reports. Beyond performance metrics such as binding capacity, recovery, host cell proteins (HCPs) and host cell DNA (hcDNA) clearance, this work synthesizes molecular-level insights into antibody-ligand interactions derived from NMR, DEPC labeling, molecular docking, and thermodynamic analyses. It also compiles data on resin orthogonality, aggregation removal, and the impact of mobile phase modifiers. Recent advances in quantitative structure-property relationship (QSPR) modeling, in silico partition coefficient prediction, and high-throughput screening are discussed as enablers of rational resin selection. This review presents a strategic framework that integrates molecular descriptors, mechanistic understanding, and empirical data to guide the selection and optimization of multimodal chromatography resins, positioning them as essential tools in next-generation biopharmaceutical purification platforms.