Abstract
Biologics Higher Order Structure (HOS) is important to its safety and efficacy but difficult to define. A novel technology called Protein Conformational Array (PCA) was developed using antibody arrays to analyze monoclonal antibody Higher Order Structure. Protein Conformational Array (PCA) technology was developed based on the immunology epitope scanning principle. This technology offers systematic coverage toward the full amino acid sequence of the biologics with high sensitivity and accuracy. For the high volume analytical assays such as cell line selection, bioprocess and formulation development, more accurate and relatively high throughput methods will be more desirable. By using 34 different antibodies covering the whole mAb molecule and measuring the mAb surface epitope exposure, the mAb HOS can be precisely and systematically described. PCA is in two different formats, the ELISA format and magnetic beads-based Luminex format. The first few sections of this chapter will focus on the applications and findings from the ELISA-based PCA and the last two sections will discuss the Luminex system in elucidating detains of mAbs HOS under different stress conditions. Results will be discussed related to mAb HOS stability polymorphism, the multifaceted nature of the PCA technology and its applications in bioprocess and formulation development and comparability studies.
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References
Abes R, Teillaud J. Impact of glycosylation on effector functions of therapeutic IgG. Pharmaceuticals. 2010;3:12.
Anfinsen CB. Principles that govern the folding of protein chains. Science. 1973;181(4096):8.
Anfinsen CB, Haber E. Studies on the reduction and re-formation of protein disulfide bonds. J Biol Chem. 1961;236:3.
Anfinsen CB, et al. The kinetics of formation of native ribonuclease during oxidation of the reduced polypeptide chain. PNAS. 1961;47(9):6.
Arosio P, et al. Aggregation stability of a monoclonal antibody during downstream processing. Pharm Res. 2011;28(8):11.
Arthur KK, Dinh N, Gabrielson JP. Technical decision making with higher order structure data: utilization of differential scanning calorimetry to elucidate critical protein structural changes resulting from oxidation. J Pharm Sci. 2015;104:6.
Beck A, et al. Characterization of therapeutic antibodies and related products. Anal Chem. 2014;85:715–36.
Berkowitz SA, et al. Analytical tools for characterizing biopharmaceuticals and the implications for biosimilars. Nat Rev Drug Discov. 2012;11:14.
Bessa J, et al. Immunogenicity of antibody aggregates in a novel transgenic mouse model. Pharm Res. 2015;32:16.
Buttel I, et al. Taking immunogenicity assessment of therapeutic proteins to the next level. Biologicals. 2011;39:10.
CBER/CDER. Guidance for industry on quality considerations in demonstrating biosimilarity to a reference protein product. Rockville: US Food and Drug Administration; 2015.
Chang J, Lu B, Li L. Conformational impurity of disulfide proteins: detection, quantification, and properties. Anal Biochem. 2005;342:8.
Chaudhari PS, Nath R, Gupta SK. Opportunities and challenges in biosimilar development. Bioprocess Int. 2017;15(5):10.
Davies M, et al. mAb higher order structure analysis with protein conformational array ELISA. Br J Pharma Res. 2015;7(6):12.
Davies M, et al. Biosimilar mAb in-process sample higher order structure analysis with protein conformational array ELISA. Br J Pharma Res. 2016;9(3):11.
DiPaola M. Analytical strategies in the development of biosimilars. BioPharm Int. 2017;30:10.
Gabrielson J, Weisis WF. Technical decision-making with higher order structure data: starting a new dialogue. J Pharm Sci. 2015;104:6.
Hermeling S, et al. Structure-immunogenicity relationships of therapeutic proteins. Pharm Res. 2004;21(6):7.
Hermeling S, et al. Structural characterization and immunogenicity in wild-type and immune tolerant mice of degraded recombinant human interferon alpha2b. Pharm Res. 2005;22(12):10.
Hermeling S, et al. Antibody response to aggregated human interferon alpha2b in wild-type and transgenic immune tolerant mice depends on type and level of aggregation. J Pharm Sci. 2006;95(5):13.
Jefferis R. Antibody therapeutics: isotype and glycoform selection. Exp Opin Biol Therap. 2007;7(9):13.
Jefferis R. Glycosylation as a strategy to improve antibody-based therapeutics. Nat Rev Drug Discov. 2009;8:9.
Jiang Y, et al. Technical decision making with higher order structure data: higher order structure characterization during protein therapeutic candidate screening. J Pharm Sci. 2015;104:6.
Jiskoot W, et al. Immunological risk of injectable drug delivery system. Pharm Res. 2009;26(6):12.
Jung S, et al. Physicochemical characterization of Remsima. MAbs. 2014;6(5):15.
Laat B, et al. Immune response against domain I beta2-glycoprotein I are driven by conformational changes. Arthritis Rheum. 2011;63(12):9.
Langer T, et al. Chaperonin-mediated protein folding: GroES binds to one end of the GroEL cylinder, which accommodates the protein substrate within its central cavity. EMBO J. 1992;11(13):9.
Maas C, et al. A role for protein misfolding in immunogenicity of biophmaceuticals. J Biol Chem. 2007;282:8.
Mason D, Schoneich C, Kerwin B. Effect of pH and light on aggregation and conformation of an IgG1 mAb. Mol Pharm. 2012;9(4):17.
Meager A, et al. An assessment of biological potency and molecular characterics of different innovator and noninnovator interferon-beta products. J Interf Cytokine Res. 2011;31(4):10.
Mok CC, et al. Immunogenicity of anti-TNF biologic agents in the treatment of rheumatoid arthritis. Exp Opin Biol Therap. 2016;16:11.
Ohkuri T, et al. A protein’s conformational stability is an immunologically dominant factor: evidence that free-energy barriers for protein unfolding limit the immunogenicity of foreign proteins. J Immunol. 2010;185:16.
Porter S. Human immune response to recombinant human proteins. J Pharm Sci. 2001;90(1):11.
Ratanji KD, et al. Immunogenicity of therapeutic proteins: influence of aggregation. J Immunotoxicol. 2014;11:11.
Reymond M, et al. Folding propensities of peptide fragments of myoglobin. Protein Sci. 1997;6:11.
Rosenberg A. Effects of protein aggregates: an immunologic perspective. AAPS J. 2006;8(3):8.
Schellekens H. Factors influencing the immunogenicity of therapeutic proteins. Nephrol Dial Translant. 2005;20:7.
Sharma B. Immunogenicity of therapeutic proteins. part 1: impact of product handling. Biotechnol Adv. 2007;25:8.
Thiagarajan G, et al. A comparison of biophysical characterization techniques in predicting monoclonal antibody stability. MAbs. 2016;8(6):10.
US FDA. Draft guidance for industry on quality condiserations in demonstrating biosimilarity to a reference protein product., in Fed. Regist. 2012.
Vermeer A, Norde W. The thermo stability of immunoglobulin: unfolding and aggregation of a multi-domain protein. Biophys J. 2000;78:11.
Wang X, Tabita FR. Interaction of inactivated and active ribulose 1,5-bisphosphate carboxylase/oxygenase of rhodobacter sphaeroides with nucleotides and the chaperonin 60 (GroEL) protein. J Bact. 1992;174(11):5.
Wang X, et al. Potential aggregation prone regions in biotherapeutics. MAbs. 2009;1:14.
Wang X, Li Q, Davies M. Development of antibody arrays for monoclonal antibody higher order structure analysis. Front Pharmacol. 2013;4:8.
Wang X, Li Q, Davies M. Higher order structure comparability: case studies of biosimilar monoclonal antibodies. Bioprocess Int. 2014;12:6.
Wang X, et al. Antibody higher order structure polymorphism revealed by protein conformational array. Bioprocess Int. 2017;15(10):8.
Wei Z, et al. The role of higher-order structure in defining biopharmaceutical quality. Bioprocess Int. 2011;9(4):9.
Weiss WF, Young TM, Roberts CJ. Principles, approaches and challenges for predicting protein aggregation rates and shelf life. J Pharm Sci. 2009;98:12.
Weiss WF, et al. Technical decision making with higher order structure data: perspectives on higher order structure characterization from the biopharmaceutical industry. J Pharm Sci. 2016;8:6.
Zheng K, Bantog C, Bayer R. The impact of glycosylation on monoclonal antibody conformation and stability. MAbs. 2011;3(6):9.
Zurdo J. Developability assessment as an early de-risking tool for biopharmaceutical development. Pharm Bioprocess. 2013;1:21.
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Wang, X., Lie, WR., Mistry, J. (2018). Protein Conformational Array Technology for Biosimilar Higher Order Structure Analysis. In: Gutka, H., Yang, H., Kakar, S. (eds) Biosimilars. AAPS Advances in the Pharmaceutical Sciences Series, vol 34. Springer, Cham. https://doi.org/10.1007/978-3-319-99680-6_14
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DOI: https://doi.org/10.1007/978-3-319-99680-6_14
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