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Nat Biotechnol. 2013 Nov;31(11):1047-52. doi: 10.1038/nbt.2677. Epub 2013 Oct 6.

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

Author information

1
Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, USA.

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.

PMID:
24097413
PMCID:
PMC3825789
DOI:
10.1038/nbt.2677
[Indexed for MEDLINE]
Free PMC Article

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