High-mannose glycans on the Fc region of therapeutic IgG antibodies increase serum clearance in humans

Glycobiology. 2011 Jul;21(7):949-59. doi: 10.1093/glycob/cwr027. Epub 2011 Mar 18.


Glycan structures attached to the C(H)2 domain of the Fc region of immunoglobulin G (IgG) are essential for specific effector functions but their role in modulating clearance is less clear. Clearance is of obvious importance for therapeutic monoclonal antibodies (Mabs) as it directly impacts efficacy. Here, we study the impact of Fc glycan structure on the clearance of four therapeutic human IgGs (one IgG1 and three IgG2s) in humans. The therapeutic IgGs were affinity purified from serum samples from human pharmacokinetic studies, and changes to the glycan profile over time were determined by peptide mapping employing high-resolution mass spectrometry. Relative levels of high-mannose 5 (M5) glycan decreased as a function of circulation time, whereas other glycans remained constant. These results demonstrate that therapeutic IgGs containing Fc high-mannose glycans are cleared more rapidly in humans than other glycan forms. The quantitative effect of this on pharmacokinetic area under the curve was calculated and shown to be relatively minor for three of the four molecules studied, but, depending on the dosing regimen and the relative level of the high-mannose glycan, this can also have significant impact. High-mannose content of therapeutic Mabs should be considered an important product quality attribute which may affect pharmacokinetic properties of therapeutic antibodies.

MeSH terms

  • Adult
  • Antibodies, Monoclonal / chemistry
  • Antibodies, Monoclonal / metabolism*
  • Antibodies, Monoclonal / therapeutic use
  • Chromatography, Liquid
  • Clinical Trials, Phase I as Topic
  • Glycopeptides / metabolism
  • Glycoproteins / metabolism
  • Humans
  • Immunoglobulin Fc Fragments / chemistry
  • Immunoglobulin Fc Fragments / metabolism*
  • Immunoglobulin G / chemistry
  • Immunoglobulin G / metabolism*
  • Mannose / chemistry*
  • Mannose / metabolism
  • Metabolic Clearance Rate
  • Polysaccharides / chemistry*
  • Polysaccharides / metabolism*
  • Serum / chemistry*
  • Serum / metabolism
  • Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization


  • Antibodies, Monoclonal
  • Glycopeptides
  • Glycoproteins
  • Immunoglobulin Fc Fragments
  • Immunoglobulin G
  • Polysaccharides
  • Mannose