title: Using X-Ray Crystallography to Simplify and Accelerate Biologics Drug Development.
abstract: 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 We suggest that this is due, at least in part, to outdated thinking (for a recent industry-wide survey, see Gabrielson JP, Weiss IV WF.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.
authors.affiliation: School of Biological Sciences, University of Auckland, Auckland, New Zealand. Electronic address: mbra988@aucklanduni.ac.nz.
authors.forename: Mark L
authors.initials: ML
authors.lastname: Brader
authors.affiliation: School of Biological Sciences, University of Auckland, Auckland, New Zealand.
authors.forename: Edward N
authors.initials: EN
authors.lastname: Baker
authors.affiliation: Department of Biochemistry, University of California, Riverside, California 92521.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Dunn
authors.affiliation: Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, New Hampshire 03824.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Laue
authors.affiliation: Department of Pharmaceutical Sciences, Center for Pharmaceutical Biotechnology, University of Colorado Health Sciences Center, Denver, Colorado 80262.
authors.forename: John F
authors.initials: JF
authors.lastname: Carpenter
mesh_terms: D000818:Animals; D001688:Biological Products / Q000737:chemistry*; D059451:Biosimilar Pharmaceuticals / Q000737:chemistry; D003460:Crystallization / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods*; D006801:Humans; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*
chemical_list: D001688:Biological Products; D059451:Biosimilar Pharmaceuticals; D011506:Proteins
keywords: biopharmaceuticals characterization; biotechnology; crystal structure; crystallization; crystallography; crystals; protein formulation; protein structure