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.
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Authors | Ruijiang Song, Deena A Oren, David Franco, Michael S Seaman, David D Ho |
Journal | Nature biotechnology
(Nat Biotechnol)
Vol. 31
Issue 11
Pg. 1047-52
(Nov 2013)
ISSN: 1546-1696 [Electronic] United States |
PMID | 24097413
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Monoclonal
- Antibodies, Neutralizing
- CD4 Antigens
- HIV Fusion Inhibitors
- Polysaccharides
- ibalizumab
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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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