In Vivo Glycan Engineering via the Mannosidase I Inhibitor (Kifunensine) Improves Efficacy of Rituximab Manufactured in Nicotiana benthamiana Plants
| Autor: | Somen Nandi, Jasmine Deng, Sylvain Marcel, Armando Tejeda, Sreenath R. Palle, Matthew J. Markert, Karen A. McDonald, Vally Kommineni, Barry R. Holtz, Berenice Carrillo, Zhongjie Ren |
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| Rok vydání: | 2019 |
| Předmět: |
0106 biological sciences
0301 basic medicine Glycosylation Nicotiana benthamiana kifunensine 01 natural sciences lcsh:Chemistry chemistry.chemical_compound lcsh:QH301-705.5 Spectroscopy Cancer Antibody-dependent cell-mediated cytotoxicity biology Chemistry Effector General Medicine Hematology Computer Science Applications Cell biology Kifunensine Metabolic Engineering Rituximab ADCC Biotechnology Glycan glycosylation medicine.drug_class Monoclonal antibody Article Catalysis Inorganic Chemistry 03 medical and health sciences Alkaloids In vivo Polysaccharides Tobacco Mannosidases medicine Genetics biochemistry CD20 Physical and Theoretical Chemistry Antigens Molecular Biology Fucose Chemical Physics plant made pharmaceuticals Organic Chemistry Antibody-Dependent Cell Cytotoxicity Antigens CD20 biology.organism_classification Fragment crystallizable region 030104 developmental biology lcsh:Biology (General) lcsh:QD1-999 monoclonal antibody biology.protein Other Biological Sciences Other Chemical Sciences Mannose 010606 plant biology & botany |
| Zdroj: | International journal of molecular sciences, vol 20, iss 1 International Journal of Molecular Sciences, Vol 20, Iss 1, p 194 (2019) International Journal of Molecular Sciences Volume 20 Issue 1 |
| Popis: | N-glycosylation has been shown to affect the pharmacokinetic properties of several classes of biologics, including monoclonal antibodies, blood factors, and lysosomal enzymes. In the last two decades, N-glycan engineering has been employed to achieve a N-glycosylation profile that is either more consistent or aligned with a specific improved activity (i.e., effector function or serum half-life). In particular, attention has focused on engineering processes in vivo or in vitro to alter the structure of the N-glycosylation of the Fc region of anti-cancer monoclonal antibodies in order to increase antibody-dependent cell-mediated cytotoxicity (ADCC). Here, we applied the mannosidase I inhibitor kifunensine to the Nicotiana benthamiana transient expression platform to produce an afucosylated anti-CD20 antibody (rituximab). We determined the optimal concentration of kifunensine used in the infiltration solution, 0.375 µ M, which was sufficient to produce exclusively oligomannose glycoforms, at a concentration 14 times lower than previously published levels. The resulting afucosylated rituximab revealed a 14-fold increase in ADCC activity targeting the lymphoma cell line Wil2-S when compared with rituximab produced in the absence of kifunensine. When applied to the cost-effective and scalable N. benthamiana transient expression platform, the use of kifunensine allows simple in-process glycan engineering without the need for transgenic hosts. |
| Databáze: | OpenAIRE |
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