Abstract
The development of recombinant therapeutic proteins has been a major revolution in modern medicine. Therapeutic-based monoclonal antibodies (mAbs) are growing rapidly, providing a potential class of human pharmaceuticals that can improve the management of cancer, autoimmune diseases, and other conditions. Most mAbs are typically of the immunoglobulin G (IgG) subclass, and they are glycosylated at the conserved asparagine position 297 (Asn-297) in the CH2 domain of the Fc region. Post-translational modifications here account for the observed high heterogeneity of glycoforms that may or not impact the stability, pharmacokinetics (PK), efficacy, and immunogenicity of mAbs. These modifications are also critical for the Fc receptor binding, and consequently, key antibody effector functions including antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Moreover, mAbs produced in non-human cells express oligosaccharides that are not normally found in serum IgGs might lead to immunogenicity issues when administered to patients. This review summarizes our understanding of the terminal sugar residues, such as mannose, sialic acids, fucose, or galactose, which influence therapeutic mAbs either positively or negatively in this regard. This review also discusses mannosylation, which has significant undesirable effects on the PK of glycoproteins, causing a decreased mAbs’ half-life. Moreover, terminal galactose residues can enhance CDC activities and Fc–C1q interactions, and core fucose can decrease ADCC and Fc–FcγRs binding. To optimize the therapeutic use of mAbs, glycoengineering strategies are used to reduce glyco-heterogeneity of mAbs, increase their safety profile, and improve the therapeutic efficacy of these important reagents.
Highlights
Monoclonal antibody-based therapeutics have been increasingly studied and utilized as therapeutic agents for the past 20 years [1]
There are more than 60 products of therapeutic monoclonal antibodies that are approved in the US for human use, about 240 in clinical testing, and around 40 entering clinical trials each year [5,6]
Another study afucosylation of monoclonal antibodies (mAbs) leads the greatest influence on antibody-dependent cell-mediated cytotoxicity (ADCC) enhancement, which mediates the efficacy has shown that higher binding affinity of afucosylated immunoglobulin G (IgG) to Fcγ RIIIa apply for all IgG subclasses of potential therapeutic recombinant antibodies
Summary
Monoclonal antibody (mAb)-based therapeutics have been increasingly studied and utilized as therapeutic agents for the past 20 years [1]. Therapeutic antibodies are generally IgGs. An IgG is a glycoprotein that contains four polypeptide chains: Two identical heavy chains (H) and two identical light chains (L). Therapeutic antibodies are generally IgGs. An IgG is a glycoprotein that contains four polypeptide. Each antibody molecule is made three globular chain is connected to one light by one bond. IgG molecules bear N-glycosylation at (FcγRs) on leukocytes and the C1 component of complement [6]. IgG strategy to enhance functionality and efficacy of therapeutic IgG antibodies. In theoffollowing sections we willwhich discuss aspects glycosylation variations which relate glycosylation variations relate tothose the PK and of pharmacodynamic (PD) parameters of to currently approved antibody-based therapeutics. Reproduced from Bakhtiar, 2012 [4]
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