Next Generation Broadly Neutralizing Antibodies to Clear HIV-1 Reservoir

项目摘要 HIV-1治疗是艾滋病干预措施的最高优先事项之一。最近隔离的许多有效的 抗HIV包膜糖蛋白（Env）的广泛中和抗体（bNAb）提供了 探索其作为被动给药药物治疗的潜力的巨大机会 建立感染。bNAb的保护功效主要是由它们的极强的免疫原性介导的。 抑制病毒感染性和细胞-细胞病毒传播（中和）的高能力，以及它们的 促进杀死在细胞上表达同源Env抗原的感染细胞的能力 通过抗体依赖性细胞介导的细胞毒性（ADCC）表面，并形成抗体-病毒 免疫复合物导致病毒清除。不幸的是，最近的结果 用bNAb作为治疗剂的临床试验表明， 持续进化的HIV-1 Env可以迅速获得突变，从而逃避作为药物给药的bNAb。 单一代理同时通过物理作用靶向不同的同源表位， 结合多种bNAb可以导致几乎100%的病毒覆盖率，使用“单一”试剂 由这些多功能结合部分组成的结合部分优选用于调节和 生产目的，除了由本发明产生的增强效力的潜力之外， 通过二价或多价Env结合增加的亲合力以及 bNAb。此外，最近的一项研究表明，在非人类灵长类动物模型中， 用bNAb治疗，CD 8+细胞溶解性T细胞可以有效地控制停药后的病毒反弹 抗病毒治疗。因此，及时设计治疗剂， 感染的细胞和细胞溶解性T细胞介导感染细胞的杀伤。此外，委员会认为， 先前的研究确定，抗体Fc区中增加它们的免疫原性的修饰， 介导细胞毒性并延长其半衰期的能力。然而，这种修改并没有 已经很好地应用于bNAb用于HIV治疗。这项研究旨在填补巨大的知识， 1）产生HIV Env bNAb 多个表位结合部分具有改善的效力、亲合力和宽度， 2）工程化bNAb，其将有效地募集CD 8+溶细胞性T细胞， 潜伏感染的CD 4 + T细胞并杀死感染的细胞;和3）提高Fc区效应子 函数（ADCC）。这项研究的总体结果将促进我们对以下问题的基本认识： 保护性免疫力对抗持续的病毒感染，并有助于开发安全的 和有效的干预策略来缓解和根除艾滋病毒。

Project summary HIV-1 curing is one of the top priorities for AIDS interventions. The recent isolation of many potent and broadly neutralizing antibodies (bNAbs) against HIV envelope glycoproteins (Env) offers great opportunities for exploring their potential as passively administered agents to treat established infections. The protective efficacy of bNAbs is primarily mediated by their extremely high capacity to inhibit virus infectivity and cell-cell virus spread (neutralization), as well as their ability to facilitate the killing of infected cells that express the cognate Env antigens on the cell surface through antibody-dependent cell-mediated cytotoxicity (ADCC) and to form antibody-virus immune complexes leading to viral clearance. Unfortunately, the outcome of the most recent clinical trials with bNAb as therapeutic agent demonstrated that the antigenically diverse and persistently evolving HIV-1 Env can rapidly acquire mutations that evade bNAbs administered as single agents. While simultaneously targeting distinct cognate epitopes by physically combining multiple bNAbs can result in virtually 100% virus coverage, the use of a “single” agent consisting of these multiple functional binding moieties is preferred for both regulatory and manufacturing purposes, in addition to the potential of augmented potency resulting from the increased avidity through bi- or multi- valence Env binding and possible synergistic effect between bNAbs. In addition, a recent study demonstrated in non-human primate model that in conjunction with bNAb therapy, CD8+ cytolytic T cells can effectively control virus rebound after the cessation of anti-viral therapy. Therefore, it is timely to engineer therapeutic agent that can effectively bridge the infected cells and the cytolytic T cells to mediate the killing of infected cells. Furthermore, previous studies established that modifications in the antibody Fc regions that increase their abilities to mediate cytotoxicity and extend their half-lives. However, such modifications have not been well applied to bNAbs for HIV treatment. This study aims to fill in the tremendous knowledge gap in the field by investigations with the following specific aims: 1) To generate HIV Env bNAbs with multiple epitope binding moieties possessing improved potency, avidity and breadth by structure-based design; 2) To engineer bNAbs that will efficiently recruit CD8+ cytolytic T cells to latently infected CD4+ T cells and kill the infected cells; and 3) To improve Fc region effector function (ADCC). The overall outcome of this study will advance our basic understanding of protective immunity against persistent virus infection and contribute to the development of safe and effective intervention strategies for HIV remission and eradication.