The Mechanistic Impact of N-Glycosylation on Stability, Pharmacokinetics, and Immunogenicity of Therapeutic Proteins.
N-glycosylation is one of major post-translational modifications in nature, and it is essential for protein structure and function. As hydrophilic moieties of glycoproteins, N-glycans play important roles in protein stability. They protect the proteins against proteolytic degradation, aggregation, and thermal denaturation through maintaining optimal conformations. There are extensive evidences showing the involvement of N-glycans in the pharmacodynamics and pharmacokinetics of recombinant therapeutic proteins and antibodies. Highly sialylated complex-type glycans enable the longer serum half-lives of proteins against uptake through hepatic asialoglycoprotein receptor and mannose receptor for degradation in lysosomes. Moreover, the presence of nonhuman glycans results in clearance through pre-existing antibodies from serum and induces IgE-mediated anaphylaxis. N-glycans also facilitate or reduce the adverse immune responses of the proteins through interacting with multiple glycan-binding proteins, including those specific for mannose or mannose 6-phosphate. Due to the glycan impacts, a few therapeutic proteins were glycoengineered to improve the pharmacokinetics and stability. Thus, N-glycosylation should be extensively investigated and optimized for each individual protein for better efficacy and safety.
['Zhou|Qun|Q|', 'Qiu|Huawei|H|']
D002616:Chemical Engineering D002626:Chemistry, Pharmaceutical D006031:Glycosylation D006207:Half-Life D006801:Humans D011134:Polysaccharides D011499:Protein Processing, Post-Translational D055550:Protein Stability D011994:Recombinant Proteins
stability pharmacokinetics immunogenicity protein structures glycoproteins clearance immune responses glycan-binding proteins glycosylation monoclonal antibodies