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Why Should We Pay Attention to Glycan Antibodies?

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What are the glyconegineering and glycosylation?

Glycoengineering, as well as protein engineering and gene engineering, belongs to the category of biotechnology, and its basic research is also called glycobiology. The research of glycoengineering is still in the stage of basic and applied basic research. glycoengineering, which was born in 1990s, is a discipline to study the structure, function, metabolic regulation and application of glycoconjugates.With the research and elucidation of the biological functions of sugar chains, a variety of glycan antibodies are being developed, some of which have gone into clinical practice.

Among many post-translational modifications of proteins, glycosylation modification is one of the most important and complex modifications, and also one of the key quality attributes for evaluating antibodies. The function of monoclonal antibodies is closely related to glycosylation modification. Glycosylation modification can affect the properties of proteins, such as conformation, stability, solubility, pharmacokinetics, activity and immunogenicity.

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Figure1.Types of glycosylation

Different glycosylation modifications have different effects on the stability, half-life, safety and biological activity of the antagonists, which are described below.

Stability and half-life

The most obvious effect of glycosylation modification is that it can increase the stability and solubility of protein. Studies have shown that glycosylation protects proteins by hiding binding sites between proteins and proteases. Rudd et al found that the steric protection of N-glycosylation on adjacent polypeptides was due to the formation of hydrogen bonds between glycosylation and hydrophilic amino acids. Glycosylation modification can also hinder the binding of protease and antibody, thereby increasing the stability of antibody.

Sialic acid glycosylation can prolong the existence time of glycoprotein in serum. When the glycoprotein chains are terminated by galactose modification or desalicitated, they can be recognized by the sialic glycoprotein receptor (ASGPR), resulting in a significant reduction in half-life. The ASGPR located on the surface of hepatocytes can not recognize the glycoprotein of total sialic acid, but it will be desalibrated by the non-specific sialidase in the blood as the blood circulates. The galactose glycosyl group of bare can be recognized by ASGPR, and the glycoprotein is degraded. Other studies suggest that high levels of mannose reduce the half-life of antibodies in serum.

In general, the more stable the drug is in the body and the longer its half-life, the more effective it will be. As for antineoplastic drugs, if the stability of drugs is high and the half-life is long, the dosage can be reduced appropriately and the interval between doses can be designed longer, and the effect is the same. However, with the increase of drug stability and half-life in human body, drug safety will become one of the factors to be considered because of potential miss-target.

Safety

The key quality attributes of antibodies (CQAs) are the criteria to judge whether they are qualified or not. CQAs must be within an appropriate range to ensure the effectiveness of drugs and, more importantly, the safety of drugs. By influencing the effect function of Fc terminal, glycosylation modification of Fc terminal can affect the safety of antibodies in the form of immunogenicity, PK/PD.

The development of antibodies has experienced the development of murine primordial antibody, chimeric antibody, humanized antibody, and finally the whole human antibody. The immunogenicity of antibodies has been continuously decreasing.Antibodies have developed into human antibodies, and the immunogenicity caused by different glycosylation modifications should not be considered. However, in order to increase the efficacy of antibodies or prolong their half-life, some amino acid mutations and glycosylation modifications are often introduced artificially, and their potential immunogenicity should be considered when making such modifications. Moreover, immunogenicity is not only caused by internal factors, but also by external factors such as materials, formation of polymers and introduction of surfactants.

The main consideration of PK/PD is the minimum dose and time of drug action in vivo. It is particularly important to minimize the immunogenicity of antibodies that can not completely eliminate the immunogenicity. Glycosylation affects PK mainly by affecting the stability and half-life of antibodies. The effect of glycosylation on the activity of antibodies acts on PD, which will be discussed in the following sections. The clearance of antibodies that bind strongly to Fc receptor is low, and glycosylation can affect the binding strength of antibodies to Fc receptor or C1q complement. If the clearance rate of antibody is low, antibodies bound to Fc receptor or C1q complement may cause the immune system to attack normal cells, resulting in serious miss-target effect.

Biological activity

Antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) are two important pathways for the efficacy of antibodies in cancer therapy. The glycosylation modification sites of Fc end of antibody are usually the binding sites of Fc receptor (ADCC mechanism) and C1q (CDC mechanism). By adjusting glycosylation, the binding of Fc receptor and C1q with antibody can be increased, thus the activity of antibody ADCC and CDC can be increased.It has been reported in many studies that glycosylation of sialic acid can affect the binding of antibody to FcγRIIa, thus reducing the activity of ADCC.

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Figure2.Mechanisms of action of ADCC and CDC

Conformation determines performance. The effects of glycosylation modification on the stability, half-life, safety and biological activity of antibiotics are cross-cutting. It is the best choice to control the glycosylation modification of antibodies within an appropriate range so as to balance the three.

Expectation

Drug glycosylation is a unique post-translational modification. Their synthesis is not a mode-driven process, so it is a difficult task to obtain a consistent glycosylation. Sugar forms are known to regulate a range of complex functions, and it is pertinent to invent strategies that are easy to monitor sugars in real time. In addition to significant progress in process analysis, glycosylation level control remains an unrealized goal. Biopharmaceutical industry and academic researchers have made great efforts to bridge this gap, and have made great progress in understanding the complexity of post-translational modification. They have also understood the effects of process variables on sugar types and the effects of polysaccharide types on the efficacy of biopharmaceuticals. This also clearly implies that in the development of bio-analogue drugs, similar drug manufacturers can not obtain information about the original research and development of drugs.


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