Song Ruijiang, Oren Deena A, Franco David, Seaman Michael S, Ho David D
Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, USA.
Nat Biotechnol. 2013 Nov;31(11):1047-52. doi: 10.1038/nbt.2677. Epub 2013 Oct 6.
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.
依巴利珠单抗是一种人源化单克隆抗体，可与人CD4（HIV的关键受体）结合并阻断HIV-1感染。然而，包膜糖蛋白gp120的V5环发生突变导致N-连接聚糖缺失的HIV-1毒株对依巴利珠单抗具有抗性。先前的结构分析表明，这种聚糖填补了gp120 V5环与依巴利珠单抗轻链之间的空隙，可能造成空间位阻从而破坏病毒进入。如果这个空隙导致HIV-1对依巴利珠单抗产生抗性，我们推测通过在依巴利珠单抗轻链上与gp120 V5在空间上接近的位置工程化引入一个N-连接聚糖来“重新填充”该空隙，可能会恢复对依巴利珠单抗的敏感性。事实上，一种这样的依巴利珠单抗变体在体外中和了所测试的118种不同HIV-1毒株中的100%，包括10株对亲本依巴利珠单抗耐药的毒株。这些发现表明，在单克隆抗体可变区中聚糖的策略性定位可显著增强其活性。
