Strategic addition of an N-linked glycan to a monoclonal antibody improves its HIV-1-neutralizing activity.
Strategic addition of an N-linked glycan to a monoclonal antibody improves its HIV-1-neutralizing activity.
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DOI：
10.1038/nbt.2677
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发表时间：
2013-11
影响因子：
46.9
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Ibalizumab是一种人源化单克隆抗体，可结合人CD 4（HIV的关键受体）并阻断HIV-1感染。然而，具有导致包膜蛋白gp 120的V5环的N-连接聚糖丢失的突变的HIV-1菌株对ibalizumab具有抗性。先前的结构分析表明，这种聚糖填充了gp 120 V5环和ibalizumab L链之间的空隙，可能导致空间位阻，破坏病毒进入。如果该空隙有助于HIV-1对ibalizumab的耐药性，我们推断，通过在空间上接近gp 120 V5的位置将N-连接聚糖工程化到ibalizumab L链中来“重新填充”它可能会恢复对ibalizumab的敏感性。事实上，一种这样的ibalizumab变体在体外100%中和了118种测试的不同HIV-1菌株，包括10种对亲本ibalizumab耐药的菌株。这些发现表明，单克隆抗体可变区中聚糖的策略性放置可以显著增强其活性。
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 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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影响因子：
64.8
作者：
Huang J;Ofek G;Laub L;Louder MK;Doria-Rose NA;Longo NS;Imamichi H;Bailer RT;Chakrabarti B;Sharma SK;Alam SM;Wang T;Yang Y;Zhang B;Migueles SA;Wyatt R;Haynes BF;Kwong PD;Mascola JR;Connors M
通讯作者：
Connors M
影响因子：
56.9
作者：
Haynes, BF;Fleming, J;Alam, SM
通讯作者：
Alam, SM
影响因子：
64.8
作者：
Balazs, Alejandro B.;Chen, Joyce;Hong, Christin M.;Rao, Dinesh S.;Yang, Lili;Baltimore, David
通讯作者：
Baltimore, David
DOI：
10.1126/science.1213782
发表时间：
2011-12-02
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Diskin R;Scheid JF;Marcovecchio PM;West AP Jr;Klein F;Gao H;Gnanapragasam PN;Abadir A;Seaman MS;Nussenzweig MC;Bjorkman PJ
通讯作者：
Bjorkman PJ
影响因子：
158.5
作者：
Thigpen, Michael C.;Kebaabetswe, Poloko M.;Brooks, John T.
通讯作者：
Brooks, John T.