Strategic addition of an N-linked glycan to a monoclonal antibody improves its HIV-1-neutralizing activity
Oren, Deena A.
Ho, David D.
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CitationSong, Ruijiang, Deena A. Oren, David Franco, Michael S. Seaman, and David D. Ho. 2013. “Strategic addition of an N-linked glycan to a monoclonal antibody improves its HIV-1-neutralizing activity.” Nature biotechnology 31 (11): 10.1038/nbt.2677. doi:10.1038/nbt.2677. http://dx.doi.org/10.1038/nbt.2677.
AbstractIbalizumab 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 protein gp120 are resistant to ibalizumab. Previous structural analysis suggests that this glycan fills a void between the gp120 V5 loop and the ibalizumab L 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 L chain at a position spatially proximal to gp120 V5 may restore susceptibility to ibalizumab. Indeed, one such ibalizumab variant neutralized 100% of 118 tested diverse HIV-1 strains in vitro, including ten 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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