NMR Spectroscopy for Protein Higher Order Structure Similarity Assessment in Formulated Drug Products

化学 异核单量子相干光谱 马氏距离 生物仿制药 主成分分析 计算生物学 二维核磁共振波谱 生物系统 计算机科学 立体化学 医学 人工智能 生物 内科学
作者
Deyun Wang,You Zhuo,Mike Karfunkle,Sharadrao M. Patil,Cameron J. Smith,David A. Keire,Kang Chen
出处
期刊:Molecules [MDPI AG]
卷期号:26 (14): 4251-4251 被引量:13
标识
DOI:10.3390/molecules26144251
摘要

Peptide and protein drug molecules fold into higher order structures (HOS) in formulation and these folded structures are often critical for drug efficacy and safety. Generic or biosimilar drug products (DPs) need to show similar HOS to the reference product. The solution NMR spectroscopy is a non-invasive, chemically and structurally specific analytical method that is ideal for characterizing protein therapeutics in formulation. However, only limited NMR studies have been performed directly on marketed DPs and questions remain on how to quantitively define similarity. Here, NMR spectra were collected on marketed peptide and protein DPs, including calcitonin-salmon, liraglutide, teriparatide, exenatide, insulin glargine and rituximab. The 1D 1H spectral pattern readily revealed protein HOS heterogeneity, exchange and oligomerization in the different formulations. Principal component analysis (PCA) applied to two rituximab DPs showed consistent results with the previously demonstrated similarity metrics of Mahalanobis distance (DM) of 3.3. The 2D 1H-13C HSQC spectral comparison of insulin glargine DPs provided similarity metrics for chemical shift difference (Δδ) and methyl peak profile, i.e., 4 ppb for 1H, 15 ppb for 13C and 98% peaks with equivalent peak height. Finally, 2D 1H-15N sofast HMQC was demonstrated as a sensitive method for comparison of small protein HOS. The application of NMR procedures and chemometric analysis on therapeutic proteins offer quantitative similarity assessments of DPs with practically achievable similarity metrics.
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