Towards understanding polyol additive effects on the pH shift-induced aggregation of a monoclonal antibody using high throughput screening and quantitative structure-activity modeling.
pH shift-induced aggregation is frequently observed in downstream processing of monoclonal antibodies and has been shown to depend on solvent composition. To quantify the stabilizing effect of polyol additives against aggregation, we determined aggregation rate constants in the presence of a set of 14 compounds. Rate constants were then correlated with molecular descriptors in a quantitative structure activity relationship (QSAR) approach. The molecular size, volume, the charge, number of hydrogen acceptors, the stereochemistry and hydrophobicity of the compounds were identified as important descriptors. Generally larger compounds with a balanced surface polarity tend to inhibit aggregation better while hydrophobicity plays an important role at the nucleation phase, with hydrophobic compounds being more potent at inhibiting aggregation.
['Oyetayo|Olubukayo-Opeyemi|OO|', 'Méndez-Lucio|Oscar|O|', 'Bender|Andreas|A|', 'Kiefer|Hans|H|']
D000911:Antibodies, Monoclonal D006863:Hydrogen-Ion Concentration D057927:Hydrophobic and Hydrophilic Interactions D011108:Polymers D021281:Quantitative Structure-Activity Relationship D012997:Solvents
Monoclonal antibody High throughput screening QSAR D-(+)-Glucose (PubChem CID: 5793) D-(+)-Mannose (PubChem CID: 18950) D-Sorbitol (PubChem CID: 5780) Erythritol (PubChem CID: 222285) Glycerol (PubChem CID: 753) Lactulose (PubChem CID: 45039641) Myo-Inositol (PubChem CID: 892) Osmolytes Polyol solvent additives Protein aggregation Sucrose (PubChem CID: 5988) Trehalose (PubChem CID: 7427)