title: Glycoengineering of pertuzumab and its impact on the pharmacokinetic/pharmacodynamic properties.
abstract: Pertuzumab is an antihuman HER2 antibody developed for HER2 positive breast cancer. Glycosylation profiles are always the important issue for antibody based therapy. Previous findings have suggested the impact of glycosylation profiles on the function of antibodies, like pharmacodynamics, antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). However, the roles of fucose and sialic acid in the function of therapeutic antibodies still need further investigation, especially the role of sialic acid in nonfucosylated antibodies. This study focused on the pharmacokinetic and pharmacodynamic properties of pertuzumab after glycoengineering. Herein, nonfucosylated pertuzumab was produced in CHOFUT8-/-cells, and desialylated pertuzumab was generated by enzymatic hydrolysis. Present data indicated that fucose was critical for ADCC activity by influencing the interaction between pertuzumab and FcγRIIIa, nevertheless removal of sialic acid increased the ADCC and CDC activity of pertuzumab. Meanwhile, regarding to sialic acid, sialidase hydrolysis directly resulted in asialoglycoprotein receptors (ASGPRs) dependent clearance in hepatic cells in vitro. The pharmacokinetic assay revealed that co-injection of asialofetuin can protect desialylated pertuzumab against ASGPRs-mediated clearance. Taken together, the present study elucidated the importance of fucose and sialic acid for pertuzumab, and also provided further understanding of the relationship of glycosylation/pharmacokinetics/pharmacodynamics of therapeutic antibody.
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China.
authors.forename: Cheng
authors.initials: C
authors.lastname: Luo
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China.
authors.forename: Song
authors.initials: S
authors.lastname: Chen
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China.
authors.forename: Na
authors.initials: N
authors.lastname: Xu
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China.
authors.forename: Chi
authors.initials: C
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China.
authors.forename: Wen Bo
authors.initials: WB
authors.lastname: Sai
authors.affiliation: Jiangsu Chia Tai Tianqing Pharmaceutical Co, Ltd, Nanjing, 210023 China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhao
authors.affiliation: Jiangsu Chia Tai Tianqing Pharmaceutical Co, Ltd, Nanjing, 210023 China.
authors.forename: Ying Chun
authors.initials: YC
authors.lastname: Li
authors.affiliation: Jiangsu Chia Tai Tianqing Pharmaceutical Co, Ltd, Nanjing, 210023 China.
authors.forename: Xiao Jing
authors.initials: XJ
authors.lastname: Hu
authors.affiliation: Jiangsu Chia Tai Tianqing Pharmaceutical Co, Ltd, Nanjing, 210023 China.
authors.forename: Hong
authors.initials: H
authors.lastname: Tian
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China.
authors.forename: Xiang Dong
authors.initials: XD
authors.lastname: Gao
authors.affiliation: Jiangsu Key Laboratory of Druggability of Biopharmaceuticals, School of Life Science and Technology, China Pharmaceutical University, Nanjing, 210009 China.
authors.forename: Wen Bing
authors.initials: WB
authors.lastname: Yao
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry* / Q000493:pharmacokinetics*; D000920:Antibody-Dependent Cell Cytotoxicity; D000074322:Antineoplastic Agents, Immunological / Q000737:chemistry* / Q000493:pharmacokinetics*; D001682:Biological Availability; D016466:CHO Cells; D045744:Cell Line, Tumor; D003412:Cricetulus; D006031:Glycosylation; D006801:Humans; D051379:Mice; D011485:Protein Binding; D015202:Protein Engineering; D011499:Protein Processing, Post-Translational; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D011994:Recombinant Proteins
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D018719:Erb-b2 Receptor Tyrosine Kinases; D011994:Recombinant Proteins; C485206:pertuzumab