Prospects for engineering HIV-specific antibodies for enhanced effector function and half-life.
Prospects for engineering HIV-specific antibodies for enhanced effector function and half-life.
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DOI：
10.1097/coh.0000000000000149
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发表时间：
2015-05
影响因子：
4.1
通讯作者：
Ackerman ME
中科院分区：
文献类型：
--
作者：
Boesch AW;Alter G;Ackerman ME
最近大量的动物模型数据表明，随着抗体在被动免疫治疗策略中使用的令人兴奋的可能性不断发展，广泛考虑抗体如何在体内实现抗HIV-1作用将是重要的。除了中和广度和效力，来自自然感染、疫苗接种和动物模型研究的大量证据表明，抗体Fc受体（FcR）在降低感染风险、减少感染后病毒血症和延迟病毒反弹方面发挥着关键作用。支持HIV背景中的这些发现，重组抗体治疗剂的临床成熟已经加强了Fc驱动的体内活性在许多疾病背景中的重要性，并且适时地导致开发和探索了许多具有与FcR的差异结合的工程化Fc序列和糖基化变体。利用这些变体作为工具，现在正在探索抗体效应子功能的个体和协同效应，例如抗体依赖性细胞毒性、抗体依赖性细胞介导的病毒抑制、吞噬作用、补体依赖性细胞毒性、抗体半衰期和区室化。随着令人兴奋的分子疗法的发展，这些研究有望提供对最佳体内抗体活性谱的深入了解。仔细考虑最近在了解体内保护性抗体活性方面的进展，可以指出如何通过Fc结构域修饰来定制抗体活性，从而优化HIV预防和根除策略。
A wealth of recent animal model data suggests that as exciting possibilities for the use of antibodies in passive immunotherapy strategies continue to develop, it will be important to broadly consider how antibodies achieve anti-HIV-1 effect in vivo. Beyond neutralization breadth and potency, substantial evidence from natural infection, vaccination, and studies in animal models points to a critical role for antibody Fc receptor (FcR) engagement in reducing risk of infection, decreasing postinfection viremia, and delaying viral rebound. Supporting these findings in the setting of HIV, the clinical maturation of recombinant antibody therapeutics has reinforced the importance of Fc-driven activity in vivo across many disease settings, as well as opportunely resulted in the development and exploration of a number of engineered Fc sequence and glycosylation variants that possess differential binding to FcRs. Exploiting these variants as tools, the individual and concerted effects of antibody effector functions such as antibody-dependent cellular cytotoxicity, antibody-dependent cell-mediated virus inhibition, phagocytosis, complement-dependent cytotoxicity, antibody half-life, and compartmentalization are now being explored. As exciting molecular therapies are advanced, these studies promise to provide insight into optimal in-vivo antibody activity profiles. Careful consideration of recent progress in understanding protective antibody activities in vivo can point toward how tailoring antibody activity via Fc domain modification may enable optimization of HIV prevention and eradication strategies.