Using X-Ray Crystallography to Simplify and Accelerate Biologics Drug Development

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• 作者：Mark L. Brader¹ ; ^{mbra988@aucklanduni.ac.nz} ; Edward N. Baker¹ ; Michael F. Dunn² ; Thomas M. Laue³ ; John F. Carpenter⁴
• 关键词：biopharmaceuticals characterization ; biotechnology ; crystal structure ; crystallization ; crystallography ; crystals ; protein formulation ; protein structure
• 刊名：Journal of Pharmaceutical Sciences
• 出版年：2017
• 出版时间：February 2017
• 年：2017
• 卷：106
• 期：2
• 页码：477-494
• 全文大小：3171 K
• 卷排序：106

文摘

Every major biopharmaceutical company incorporates a protein crystallography unit that is central to its structure-based drug discovery efforts. Yet these capabilities are rarely leveraged toward the formal higher order structural characterization that is so challenging but integral to large-scale biologics manufacturing. Although the biotech industry laments the shortcomings of its favored biophysical techniques, x-ray crystallography is not even considered for drug development. Why not? We suggest that this is due, at least in part, to outdated thinking (for a recent industry-wide survey, see Gabrielson JP, Weiss IV WF. Technical decision-making with higher order structure data: starting a new dialogue. J Pharm Sci. 2015;104(4):1240-1245). We examine some myths surrounding protein crystallography and highlight the inherent properties of protein crystals (molecular identity, biochemical purity, conformational uniformity, and macromolecular crowding) as having practicable commonalities with today's patient-focused liquid drug products. In the new millennium, protein crystallography has become essentially a routine analytical test. Its application may aid the identification of better candidate molecules that are more amenable to high-concentration processing, formulation, and analysis thereby helping to make biologics drug development quicker, simpler, and cheaper.