The Formidable Challenge of Controlling High Mannose-Type N-Glycans in Therapeutic mAbs

• Published in: Trends in biotechnology (Regular ed.) 2020-10, Vol.38 (10), p.1154-1168
• Main Authors: Mastrangeli, Renato, Audino, Maria Concetta, Palinsky, Wolf, Broly, Hervé, Bierau, Horst
• Format: Article
• Language: English
• Subjects: Antibodies; Batch processes; Batch processing; Biological products; biopharmaceuticals; C-type lectin receptors; Cell culture; Cytotoxicity; Endoplasmic reticulum; Enzymes; glycoengineering; Glycosylation; high mannose glycans; Lectins; Mannose; Manufacturing; Manufacturing industry; Metabolism; Monoclonal antibodies; monoclonal antibody; N-glycans; N-glycosylation; Pharmacokinetics; Polysaccharides; Process intensification; Productivity; Toxicity
• ISSN: 0167-7799; 1879-3096
• DOI: 10.1016/j.tibtech.2020.05.009

The clinical efficacy and safety of therapeutic monoclonal antibodies (mAbs) are significantly affected by their Fc-glycosylation profile. High mannose-type N-glycans (HM) affect efficacy (in terms of antibody-dependent cell cytotoxicity), pharmacokinetics, and stability. While in endogenous IgGs the HM levels are very low, they are significantly higher in marketed therapeutic mAbs. In order to meet the demands for late-phase clinical trial and market supply, process intensification is required. Since glycosylation profiles are sensitive to process variations and changes, controlling HM levels in robust manufacturing processes presents a formidable challenge and requires a thorough understanding of the cellular processes as well as the biotechnical aspects that govern the production of HM glycans. mAbs are currently the prime focus in biopharmaceutical drug development.Glycosylation is a critical quality attribute for mAbs because their clinical efficacy and safety are significantly affected by their glycosylation profile, which is generally heterogeneous, profoundly dependent on the manufacturing process, and thus prone to variations depending on cell culture conditions.As opposed to endogenous IgGs, marketed therapeutic mAbs contain higher levels of high mannose glycans, which can affect efficacy, pharmacokinetics, and stability.Current trends in biopharmaceutical manufacturing, such as process intensification and the rise of biosimilars, emphasize the need for a thorough understanding of the cellular processes, as well as the biotechnical process aspects that govern the production of high mannose-type N-glycans, in order to establish robust manufacturing processes.