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Characterization of Glycoproteins with the Immunoglobulin Fold by X-Ray Crystallography and Biophysical Techniques
Published on: July 5, 2018
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Crystallizable Fragment Glycoengineering for Therapeutic Antibodies Development
Wei Li1, Zhongyu Zhu1, Weizao Chen1
1Protein Interactions Section, Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Frederick, MD, United States.
Frontiers in Immunology
|November 29, 2017
Summary
Fc glycoengineering enhances therapeutic monoclonal antibodies (mAbs). Removing fucose from immunoglobulin G (IgG) Fc regions boosts antibody-dependent cell-mediated cytotoxicity (ADCC) for more effective treatments.
Area of Science:
- Biochemistry
- Immunology
- Biotechnology
Background:
- Monoclonal antibody (mAb) therapeutics, primarily IgG1, possess N-glycans on their Fc region.
- Fc glycoforms critically influence mAb pharmacokinetics, stability, safety, and effector functions.
- Glycosylation impacts antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).
Purpose of the Study:
- To review advancements in IgG-Fc glycoengineering.
- To highlight the impact of Fc glycoforms on antibody effector functions.
- To discuss strategies for producing homogeneous glycoforms, particularly defucosylated mAbs.
Main Methods:
- Review of IgG N-glycan structures and biosynthesis.
- Analysis of Fc glycoforms' effects on effector functions.
- Examination of cell and chemoenzymatic glycoengineering strategies.
- Discussion of aglycosylated mAbs and Fc glycan-specific antibody-drug conjugates (ADCs).
Main Results:
- Terminal galactose enhances CDC; fucose significantly reduces ADCC.
- Defucosylated IgGs demonstrate potent ADCC, enabling reduced therapeutic doses.
- Glycoengineering strategies yield homogeneous glycoforms, especially afucosyl variants.
- Chemoenzymatic remodeling allows for site-specific drug conjugation.
Conclusions:
- Understanding Fc glycobiology drives the development of improved therapeutic mAbs.
- Glycoengineering technologies facilitate the generation of mAbs with enhanced efficacy and homogeneity.
- Targeted glycoengineering, like Fc defucosylation, offers next-generation therapeutic potential.
