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Strategic addition of an N-linked glycan to a monoclonal antibody improves its HIV-1-neutralizing activity.

Abstract
Ibalizumab is a humanized monoclonal antibody that binds human CD4--a key receptor for HIV--and blocks HIV-1 infection. However, HIV-1 strains with mutations resulting in loss of an N-linked glycan from the V5 loop of the envelope glycoprotein gp120 are resistant to ibalizumab. Previous structural analysis suggests that this glycan fills a void between the gp120 V5 loop and the ibalizumab light chain, perhaps causing steric hindrance that disrupts viral entry. If this void contributes to HIV-1 resistance to ibalizumab, we reasoned that 'refilling' it by engineering an N-linked glycan into the ibalizumab light chain at a position spatially proximal to gp120 V5 may restore susceptibility to ibalizumab. Indeed, one such ibalizumab variant neutralized 100% of 118 diverse HIV-1 strains tested in vitro, including 10 strains resistant to parental ibalizumab. These findings demonstrate that the strategic placement of a glycan in the variable region of a monoclonal antibody can substantially enhance its activity.
AuthorsRuijiang Song, Deena A Oren, David Franco, Michael S Seaman, David D Ho
JournalNature biotechnology (Nat Biotechnol) Vol. 31 Issue 11 Pg. 1047-52 (Nov 2013) ISSN: 1546-1696 [Electronic] United States
PMID24097413 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antibodies, Monoclonal
  • Antibodies, Neutralizing
  • CD4 Antigens
  • HIV Fusion Inhibitors
  • Polysaccharides
  • ibalizumab
Topics
  • Antibodies, Monoclonal (chemistry, pharmacology)
  • Antibodies, Neutralizing (chemistry, pharmacology)
  • CD4 Antigens (metabolism)
  • Cross Reactions
  • Drug Resistance, Viral (drug effects)
  • HEK293 Cells
  • HIV Fusion Inhibitors (chemistry, pharmacology)
  • HIV Infections (drug therapy, virology)
  • HIV-1 (drug effects, isolation & purification)
  • Humans
  • Models, Molecular
  • Polysaccharides (chemistry, pharmacology)
  • Structure-Activity Relationship

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