Rational design and characterization of the novel, broad and potent bispecific HIV-1 neutralizing antibody iMabm36.
Rational design and characterization of the novel, broad and potent bispecific HIV-1 neutralizing antibody iMabm36.
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DOI：
10.1097/qai.0000000000000218
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发表时间：
2014-08-15
期刊：
影响因子：
--
通讯作者：
Ho DD
中科院分区：
文献类型：
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作者：
Sun M;Pace CS;Yao X;Yu F;Padte NN;Huang Y;Seaman MS;Li Q;Ho DD
虽然广泛中和的单克隆抗体（bNAb）一直被认为是预防和治疗HIV感染的潜在治疗选择，但它们缺乏针对所有HIV变体的广度一直是限制因素之一。为了提供足够的中和广度和针对不同病毒（包括中和逃逸变体）的效力，最近已经探索了联合收割机组合不同bNAb的策略。我们合理地设计和工程化了一种新的双特异性HIV-1中和抗体（bibNAb），iMabm 36，用于对抗HIV的高效力和广度。iMabm 36由抗CD 4 Ab ibalizumab（iMab）与两个拷贝的单结构域Ab m36（靶向高度保守的CD 4诱导表位）连接组成。iMabm 36在IC 50浓度小于10 μg/mL时可中和大多数大型多进化枝假病毒（96%，n=118），在IC 50浓度小于0.1μg/mL时可中和83%。此外，在基于PBMC的中和试验中，iMabm 36在低于0.1μg/ml的浓度下可中和6种具有复制能力的传播创始者病毒至100%抑制。从机制上讲，iMabm 36的抗病毒活性的改善依赖于iMab组分的CD 4结合活性和m36组分的CD 4 i结合活性。在表征病毒对iMabm 36中和的抗性是由于存在于gp 120的桥接片层中的突变之后，工程化优化的m36变体，其当与iMab融合时显著改善抗病毒活性。这种双重作用机制的相互依赖性使iMabm 36能够有效抑制HIV-1进入。这些结果表明，bibNAb的基于机制的设计可以产生潜在的预防和治疗HIV/AIDS的候选药物。
While broadly neutralizing monoclonal antibodies (bNAbs) have always been considered potential therapeutic options for the prophylactic and treatment of HIV infection, their lack of breadth against all HIV variants has been one of the limiting factors. To provide sufficient neutralization breadth and potency against diverse viruses, including neutralization escape variants, strategies to combine different bNAbs have been explored recently. We rationally designed and engineered a novel bispecific HIV-1 neutralizing antibody (bibNAb), iMabm36, for high potency and breadth against HIV. iMabm36 is composed of the anti-CD4 Ab ibalizumab (iMab) linked to two copies of the single-domain Ab m36 which targets a highly conserved CD4-induced epitope. iMabm36 neutralizes a majority of a large, multi-clade panel of pseudoviruses (96%, n=118) at an IC50 concentration of less than 10 μg/mL, with 83% neutralized at an IC50 concentration of less than 0.1μg/ml. In addition, iMabm36 neutralizes six replication-competent transmitted-founder viruses to 100% inhibition at a concentration of less than 0.1μg/ml in a PBMC-based neutralizing assay. Mechanistically, improved antiviral activity of iMabm36 is dependent on both CD4 binding activity of iMab component and CD4i binding activity of the m36 component. After characterizing viral resistance to iMabm36 neutralization was due to mutations residing in the bridging sheet of gp120, an optimized m36 variant was engineered that, when fused to iMab, improved antiviral activity significantly. Together inter-dependency of this dual mechanism of action enables iMabm36 to potently inhibit HIV-1 entry. These results demonstrate that mechanistic-based design of bibNAbs could generate potential preventive and therapeutic candidates for HIV/AIDS.