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

Area of Science:

• Biopharmaceutical Manufacturing
• Glycobiology
• Protein Engineering

Background:

• Therapeutic monoclonal antibodies (mAbs) efficacy and safety are influenced by Fc-glycosylation.
• High mannose-type N-glycans (HM) negatively affect mAb efficacy, pharmacokinetics, and stability.
• Marketed therapeutic mAbs exhibit higher HM levels compared to endogenous immunoglobulins G (IgGs).

Purpose of the Study:

• To address the challenge of controlling high mannose (HM) glycan levels in therapeutic monoclonal antibodies (mAbs).
• To meet the increasing demand for mAbs in late-phase clinical trials and market supply through process intensification.
• To highlight the need for a comprehensive understanding of cellular and biotechnical factors governing HM glycan production.

Main Methods:

• Analysis of Fc-glycosylation profiles in therapeutic monoclonal antibodies.
• Investigation of factors influencing high mannose (HM) glycan formation during bioprocessing.
• Evaluation of process variations and their impact on glycosylation patterns.

Main Results:

• High mannose (HM) N-glycans significantly impact antibody-dependent cell cytotoxicity, pharmacokinetics, and stability.
• Therapeutic mAbs show elevated HM levels compared to endogenous IgGs.
• Process intensification is necessary for large-scale mAb production, but controlling HM levels remains a challenge.

Conclusions:

• Controlling high mannose (HM) glycan levels is critical for robust therapeutic monoclonal antibody (mAb) manufacturing.
• Understanding cellular and biotechnical aspects governing HM production is essential for process development.
• Addressing HM glycan challenges is vital for ensuring the consistent quality and efficacy of therapeutic mAbs.