Nature：新型艾滋病抗体“3BNC117"首个临床试验效果明显

marine0425030

根据在HIV患者中对新一代的广泛中和抗体开展试验测试生成的初步结果，来自洛克菲勒大学的研究人员证实这种实验疗法可以显著地减少患者血液中的病毒数量。这项发布在本周《自然》（Nature）杂志上的研究工作，给HIV免疫治疗领域带来了新的乐观情绪，并提出了一些可对抗甚至是预防HIV感染的新策略。

在HIV感染者体内，病毒和机体免疫系统之间进行着一场持续的军备竞赛。当机体生成一些新抗体来靶向病毒之时，病毒也在不断地突变来逃避抗体，总是在设法领先几步。由Michel Nussenzweig分子免疫学实验室完成的这项新研究，发现给予一种叫做3BNC117的有效抗体，可以让HIV猝不及防，降低病毒载量。

以往在人体中测试HIV总是显示令人失望的结果。3BNC117属于新一代的广泛中和抗体，能够有力地对抗广泛的HIV病毒株。论文的共同第一作者、Nussenzweig实验室临床研究助理教授Marina Caskey说：“这些抗体的特别之处在于，它们有活力对抗80%以上的HIV病毒株，且非常有效。”3BN117最初是由Nussenzweig实验室的Johannes Scheid分离获得，它靶向的是HIV包膜上的CD4结合位点，CD4受体是HIV附着到宿主细胞上去的主要位点，3BNC117对237种HIV病毒株中的195种显示出对抗活力。

在大约10-30%的HIV感染者体内会自然生成广泛中和抗体，但都出现在感染数年后。那时他们体内的病毒通常都已进化至可以逃避这些强大的抗体。

通过分离然后克隆这些抗体，研究人员可以利用它们来作为治疗药物对抗少一些时间做好准备的HIV感染。在早先的研究工作中，Nussenzweig实验室证实这些有效地抗体可以阻止或抑制小鼠和非人类灵长类动物HIV模型中的感染。Caskey说，但这些动物模型与人类的感染粗略接近。必须要对小鼠进行遗传工程改造它才会易于感染HIV,因此缺乏完整的免疫系统，在HIV研究中利用的灵长类动物只会被一种猴版本的病毒感染。因此有待人类试验来获得原理证明。

在这项新研究中，研究人员通过静脉单次给予了HIV感染和未感染个体这一抗体，并在56天的时间内对他们进行了监测。研究中测试的最高剂量水平为每公斤体重30毫克，所有8名接受治疗的感染个体血液中测量的病毒数量显示下降了300倍，在治疗后一周大多数达到了他们的最低病毒载量。病毒载量的下降情况取决于个体起始病毒载量，以及他们的特定HIV病毒株对抗体的敏感度。

这是第一次在人体内测试这种新一代的HIV抗体。不仅单剂量的3BN117能够被很好地耐受，并可有效地暂时性降低病毒载量，在某些个体体内它可以在长时间内保持活性。在一半接受最高剂量的个体中，8周研究期结束时他们的病毒载量仍然低于起始水平，且没有发生3BNC117耐药。研究人员相信，这些抗体或许还能够增强患者对HIV的免疫反应，转而更好地控制感染。此外，3BNC117一类的抗体还有可能能够杀死隐藏在感染细胞中的病毒，这些病毒充当了病毒储藏库，当前的抗逆转录病毒药物无法触及它们。

最有可能的是，像其他的抗逆转录病毒药物一样，3BNC117将会与其他的抗体或抗逆转录病毒药物联合使用来控制感染。Caskey说：“就像单独的一种药物一样，由于将出现耐药单独一种抗体不足以长时间抑制病毒载量。一个重要的益处在于给药方案：一种HIV抗体治疗只需要每个几个月治疗一次，相比之下现在的HIV一线治疗要求每天服用抗逆转录病毒药物。”

“与传统的抗逆转录病毒治疗相比，抗体介导的治疗还可以让患者的免疫细胞参与进来，帮助更好地中和病毒，”论文共同第一作者、Nussenzweig实验室临床研究助理教授Florian Klein说。

除了有可能用于治疗，新研究还为HIV疫苗带来了希望。如果研究人员能够诱导未感染个体的免疫系统生成诸如3BNC117一类的有效抗体，或许就足以在HIV建立感染之前阻断它。

此外，Nussenzweig实验室和洛克菲勒大学医院正在开展另一项临床研究，目的在于阐明其他的广泛中和抗体单独或联合使用时对HIV感染患者病毒载量的影响。

原文检索：Antibody shows promise as treatment for HIV

Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117 (Nature)
HIV-1 immunotherapy with a combination of first generation monoclonal antibodies was largely ineffective in pre-clinical and clinical settings and was therefore abandoned1, 2, 3. However, recently developed single-cell-based antibody cloning methods have uncovered a new generation of far more potent broadly neutralizing antibodies to HIV-1 (refs 4, 5). These antibodies can prevent infection and suppress viraemia in humanized mice and nonhuman primates, but their potential for human HIV-1 immunotherapy has not been evaluated6, 7, 8,9, 10. Here we report the results of a first-in-man dose escalation phase 1 clinical trial of 3BNC117, a potent human CD4 binding site antibody11, in uninfected and HIV-1-infected individuals. 3BNC117 infusion was well tolerated and demonstrated favourable pharmacokinetics. A single 30 mg kg−1 infusion of 3BNC117 reduced the viral load in HIV-1-infected individuals by 0.8–2.5 log10 and viraemia remained significantly reduced for 28 days. Emergence of resistant viral strains was variable, with some individuals remaining sensitive to 3BNC117 for a period of 28 days. We conclude that, as a single agent, 3BNC117 is safe and effective in reducing HIV-1 viraemia, and that immunotherapy should be explored as a new modality for HIV-1 prevention, therapy and cure.

相关阅读：
1.Antibody shows promise as treatment for HIVhttp://www.nature.com/news/antib ... ent-for-hiv-1.17260

2.临床试验：https://clinicaltrials.gov/ct2/show/NCT02018510

3. In first human study, new antibody therapy shows promise in suppressing HIV infection

http://newswire.rockefeller.edu/2015/04/08/in-first-human-study-new-antibody-therapy-shows-promise-in-suppressing-hiv-infection/

rentianyixu

感谢分享。。。

ipsvirus

抗体治疗不是很常见，HIV以前没有过类似的报道吗？还是这次的抗体效果最好

marine0425030

3BNC117抗体的原始文献。

Sequence and Structural Convergence of Broad and Potent HIV Antibodies That Mimic CD4 Binding

摘要：Passive transfer of broadly neutralizing HIV antibodies can prevent infection, which suggests that vaccines that elicit such antibodies would be protective. Thus far, however, few broadly neutralizing HIV antibodies that occur naturally have been characterized. To determine whether these antibodies are part of a larger group of related molecules, we cloned 576 new HIV antibodies from four unrelated individuals. All four individuals produced expanded clones of potent broadly neutralizing CD4-binding-site antibodies that mimic binding to CD4. Despite extensive hypermutation, the new antibodies shared a consensus sequence of 68 immunoglobulin H (IgH) chain amino acids and arise independently from two related IgH genes. Comparison of the crystal structure of one of the antibodies to the broadly neutralizing antibody VRC01 revealed conservation of the contacts to the HIV spike.

marine0425030

ipsvirus 发表于 2015-4-11 10:35
抗体治疗不是很常见，HIV以前没有过类似的报道吗？还是这次的抗体效果最好 ...

是的，以前也有类似的报道，大部分的抗体效果实验都是在老鼠模型或者是在猴子身上完成的，而这个研究是第一次人体临床试验。
我把标题修改了下，还有重点内容和加颜色强调了下。

marine0425030

新增信息节选自 来源

http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2015/04/broadly-neutralizing-antibody-suppresses-hiv-in-clinical-trial.html

The study confirms that bNAbs are active against HIV in humans, consistent with humanized mice and macaqueexperiments. A number of pathways toward the therapeutic and preventive use of bNAbs can now be explored, but could still prove challenging to navigate. As the authors of the paper note, bNAbs will likely need to be used in combination to maximize activity and prevent resistance; they may also benefit from additional modifications to enhance their potency and persistence in the body.

On the therapeutic side, there is the potential to combine bNAbs with latency-reversing agents with the aim of promoting clearance of the viral reservoir via antibody-mediated cellular cytotoxicity (ADCC). Another approach is to test whether combination bNAbs could provide a long-acting alternative or supplement to daily ART. A trial involving the combination of the bNAb VRC01 plus ART is due to start later this year in individuals with acute HIV infection in Thailand (see Jintanat Ananworanich’s presentation at last year’s Forum for Collaborative HIV Research cure research meeting for background). Dan Barouch has plans to study the bNAb PGT121 in several different populations, as outlined in his talk at CROI 2015.

On the preventive side, there is interest in evaluating the efficacy of passive immunization (either intravenous or subcutaneous) with bNAbs in both high risk adults and infants exposed to HIV via breastfeeding (seethe webcast of Barney Graham’s presentation at the 2014 R4P conference for additional information).

While this research is likely to move forward, there are many lingering uncertainties regarding passive immunization: the need for repeated injections raises the concern of practicality (particularly in the prevention context), and another issue that has to be considered is the complexity and cost of bNAb manufacture (for an informative excursion into the industry of bNAb production, see Michael Dumiak’s 2014 IAVI Reportarticle, “Making it to Manufacturing”). As has been covered previously on the blog, there is at least one alternative, potentially simpler method of bNAb delivery: gene transfer with adeno-associated virus (AAV), which is being tested in an ongoing phase I trial in the UK. But it is not yet known if AAV can deliver bNAb levels high enough to be efficacious.  

To discuss the prospects for passive immunization against HIV, AVAC is hosting a webinar on Tuesday, April 21 at 11am EDT with Dr. Sarah Schlesinger from Rockefeller University (click here to register).