Diversity selection, screening and quantitative structure-activity relationships of osmolyte-like additive effects on the thermal stability of a monoclonal antibody

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• 作者：Olubukayo-Opeyemi Oyetayo^a ; ^{oyetayophdhbc@gmail.com} ; Oscar Mé ; ndez-Lucio^b ; Andreas Bender^b ; Hans Kiefer^a
• 关键词：mAb ; Monoclonal antibody ; MOE ; Molecular Operating Environment ; MDS ; Multi-dimensional scaling ; QSAR ; Quantitative structure&ndash ; activity relationship ; DSC ; Differential scanning calorimetry ; DSF ; Differential scanning fluorimetry ; DMSO ; Dimethyl sulfoxide ; NaOH ; Sodium hydroxide ; HCl ; Hydrochloric acid ; LOO-CV ; Leave-one-out cross-validation ; PCA ; Principal components analysis ; PLS ; Partial least squares ; TMAO ; Trimethylamine N-oxide ; Tm ; Melting temperature ; TS potency ; Thermal stabilization
• 刊名：European Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：15 January 2017
• 年：2017
• 卷：97
• 期：Complete
• 页码：151-157
• 全文大小：844 K
• 卷排序：97

文摘

Solvents used for therapeutic proteins in downstream processing and in formulations often contain stabilizing additives that inhibit denaturation and aggregation. Such additives are mostly selected based on their positive effect on thermal stability of the protein, and are often derived from naturally occuring osmolytes. To better understand the structural basis underlying the effect of additives, we selected a diverse library of compounds comprising 79 compounds of the polyol, amino acid and methylamine chemical classes and determined the effect of each compound on thermal stability of a monoclonal antibody as a function of compound concentration. Thermal stabilization of the antibody was influenced by solution pH. Quantitative structure–activity relationships (QSAR) were derived by partial least squares regression for individual compound classes and globally. The global model suggests that ligands with a phenyl ring will decrease the Tm, while highly soluble, polar compounds with at least two hydrogen bond donors will increase the Tm. This approach may be beneficial for further studies on the influence of other solution conditions like ionic strength and buffer species on additive-mediated protein stabilization.