Evaluation of Heavy-Chain C-Terminal Deletion on Product Quality and Pharmacokinetics of Monoclonal Antibodies
| Autor: | Sheila Ulufatu, Reed J. Harris, Zhilan Hu, Roxanne Vega, Jia Chen, Mark Iverson, Cecilia Leddy, Eileen T. Duenas, Xanthe M. Lam, Helen Davis, Christopher Yu, Daniela Bumbaca Yadav, Amy Shen, Dongwei Li, Y. John Wang, Pin Y. Wong, Guoying Jiang, Kai Zheng, Annamarie Amurao, Marc Wong |
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| Rok vydání: | 2016 |
| Předmět: |
Male
0301 basic medicine medicine.drug_class Injections Subcutaneous Lysine Mutant Glycine Biological Availability Pharmaceutical Science Monoclonal antibody 01 natural sciences Fragment antigen-binding Rats Sprague-Dawley 03 medical and health sciences Drug Stability In vivo medicine Animals Chromatography High Pressure Liquid biology Chemistry 010401 analytical chemistry Antibodies Monoclonal Chromatography Ion Exchange Complement-dependent cytotoxicity In vitro Rats 0104 chemical sciences 030104 developmental biology Biochemistry Mutation Chromatography Gel biology.protein Isoelectric Focusing Antibody |
| Zdroj: | Journal of Pharmaceutical Sciences. 105:2066-2072 |
| ISSN: | 0022-3549 |
| Popis: | Due to their potential influence on stability, pharmacokinetics, and product consistency, antibody charge variants have attracted considerable attention in the biotechnology industry. Subtle to significant differences in the level of charge variants and new charge variants under various cell culture conditions are often observed during routine manufacturing or process changes and pose a challenge when demonstrating product comparability. To explore potential solutions to control charge heterogeneity, monoclonal antibodies (mAbs) with native, wild-type C-termini, and mutants with C-terminal deletions of either lysine or lysine and glycine were constructed, expressed, purified, and characterized in vitro and in vivo. Analytical and physiological characterization demonstrated that the mAb mutants had greatly reduced levels of basic variants without decreasing antibody biologic activity, structural stability, pharmacokinetics, or subcutaneous bioavailability in rats. This study provides a possible solution to mitigate mAb heterogeneity in C-terminal processing, improve batch-to-batch consistency, and facilitate the comparability study during process changes. |
| Databáze: | OpenAIRE |
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