mAbs：自身免疫性疾病的潜在治疗抗体

耐药结核病菌株正在增多,尽管有几十年抗生素研究，治疗方案选择还是受到了限制。2010年, 至少有650000例结核病患者对两种最有效的一线抗生素产生耐药, 在2012年,广泛耐药,无法有效治愈的结核分枝杆菌菌株-泛耐药肺结核病-在印度被发现。现在, 数以百计的结核分枝杆菌样本的基因组测序完成后，两个小组的科学家发表了广泛的基因突变被确认产生耐药。他们的研究,发表在《自然遗传学》杂志上,大大增加我们的理解，长期有力的避免潜在的耐药。

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Infectious disease: TB's revenge Resistance to backup tuberculosis drugs increases TB drugs chalk up rare win More related stories ―The biggest bottleneck to managing drug-resistant tuberculosis is the delay between suspecting it and confirming it,‖ says epidemiologist Megan Murray at the Harvard School of Public Health in Boston, Massachusetts, who co-led one of the studies. With a more complete list of resistance mutations, physicians could avoid giving patients drugs that will not help them, while quickly prescribing more appropriate treatments.

哈佛大学公共卫生学院的流行病学家梅根·默里在波士顿,马萨诸塞州,共同领导的这项研究时说“怀疑与确认之间的延迟是管理耐药结核病最大的瓶颈,“。发现更完整的一系列的抵抗突变, 医生可以避免给病人那些毫无帮助的药物, 快速找到更合适的治疗处方。

Resistance map

Murray‘s team sequenced 123 strains from a worldwide collection and mapped the sequences on to an evolutionary tree. They then searched for mutations that were independently linked to resistance across different branches. They

identified every part of the M. tuberculosis genome that was already linked to resistance, along with 39 new mutations.

The second team, led by Lijun Bi from the Institute of Biophysics in Beijing, part of the Chinese Academy of Sciences, sequenced 161 samples from

Chinese patients and analysed them using a similar method. They identified 84 genes and 32 other regions that were strongly associated with drug resistance.

The two lists have few overlaps, probably because the teams used slightly

different methods and studied strains that had evolved resistance from different genetic starting points. ―However, the overall message is similar,‖ says Murray. ―A lot more genes are implicated in the development of resistance than we thought, and we don‘t really know what they do. There are a lot of ways for the organism to become resistant.‖

In the classical view of resistance, M. tuberculosis picks up mutations in

enzymes that either activate drugs or are targeted by them. ―We‘ve been stuck in this mould for too long,‖ says Robin Warren, a TB specialist from

Stellenbosch University in South Africa and a co-author on Murray‘s paper. ―These new studies show that there‘s much greater complexity to resistance than we dreamed of.‖

耐药图谱

Murray‘s团队对全世界收集的123株结核菌株进行了测序并把序列一一画在进化树上。

然后寻找突变, 耐药则被独立地指向不同的分支。他们发现了结核分枝杆菌基因组的每一部分,已经与耐药有关联了, 还是发现了39个新的突变。第二个团队, 由北京中国科学院研究所的生物生理学研究所的Lijun Bi

领导，使用类似Murray‘s团队的方法, 分析来自中

国的161个病人的测序样本。他们发现了84个基因和其他的32个区域与耐药密切相关。 两个队列的研究几乎没有重叠, 可能是因为两个团队之间使用稍微不同的研究方法，研究的耐药菌株有不同遗传的起点。然而, 总体的信息是相似的,” Murray‘s说，“许多的基因发展成耐药超出了我们的想象, 而我们真的不知道耐药基因是怎么运转的。有很多途径可以导致菌体产生耐药。”

经典视图中的阻力,结核分枝杆菌拿起突变酶激活药物或者是他们的目标。“我们被困在这个模具太久,”罗宾·沃伦说, 南非Stellenbosch大学的结核病专家和穆雷的报告的合著者。“这些新的研究表明,有更大的复杂性比我们梦想的阻力。”

Drug barriers

Many of the resistance regions identified in both studies affect the waxy cell wall that surrounds M. tuberculosis cells. Some change its structure, or alter its permeability. Others influence the production of molecular pumps that evict drugs that get into the cells. And others boost the rate at which M. tuberculosis mutates, allowing it to pick up beneficial mutations more quickly.

The teams also identified mutations that are likely to influence other resistance genes, either boosting their activity or compensating for their detrimental

effects, allowing the bacteria to carry them without being outcompeted by drug-sensitive strains.

But many of the regions that the teams identified have unclear roles. ―For

around half the genes in our list, we have a name but we don‘t know what they do,‖ says Murray. For example, her list includes 16 genes from the PE/PPE family, which are unique to M. tuberculosis and its kin, and whose roles are largely unknown.

William Jacobs, Jr., a tuberculosis specialist at the Albert Einstein College of Medicine in New York, says that the teams now need to validate their lists. ―You‘ve got to be able to move the mutation, and show it causes what you think it causes,‖ he says.

Murray‘s group made a start by introducing a mutation in the ponA1 gene into M. tuberculosis, and showing that the microbes could then withstand double the dose of rifampicin. ―That‘ll need to happen on a much larger scale for all of these genes,‖ she says.

These latest studies show that M. tuberculosis evolves resistance through several gradual steps with subtle effects. ―It probably takes a bunch of these smaller steps to get to high-level resistance,‖ says Murray. David Alland of Rutgers University in Newark, New Jersey, supports this view through a third study, also published in Nature Genetics3. His team sequenced 63 clinical samples of M. tuberculosis that had been exposed to the frontline drug ethambutol. They found mutations in at least four genes that interacted to improve the bacterium‘s ability to resist the drug, allowing some strains to shrug off 16-fold higher doses than others.

Understanding these step-wise pathways could help clinicians to monitor

strains that are on the verge of evolving high-level resistance, or develop drugs that interfere with that evolution before it really gets going.

\drugs for specific targets. It's rather more hit and miss,\epidemiologist at the non-governmental organization Médecins Sans Frontières (also known as Doctors Without Borders), headquartered in Geneva,

Switzerland. But, she adds, \much more complex than the simple dichotomous 'resistant versus susceptible' understanding.\

基因组揭示结核病耐药性的根源

肺结核菌株发展逐步获得微妙的突变

随着抵抗抗生素的增加，治疗结核病的过程变得越来越少没有效 对肺结核来说，这从来都不是一个好消息, 近年来的前景变得更糟

Journal name: Nature DOI:

doi:10.1038/nature.2013.13645

References 1.

Farhat, M. R. et al. Nature Genet. http://dx.doi.org/10.1038/ng.2747 (2013).

2. 3.

Show context

Zhang, H. et al. Nature Genet. http://dx.doi.org/10.1038/ng.2735 (2013). 4. 5.

Show context

Safi, H. et al. Nature Genet. http://dx.doi.org/10.1038/ng.2743 (2013). 6.

Show context

mAbs：自身免疫性疾病的潜在治疗抗体

2014年10月28日讯 /生物谷BIOON/ --通过天然免疫选择和靶向蛋白技术的组合，A * STAR研究者已经制造出一种抗体，能够在人类细胞和小鼠实验模型中有效地阻断与疾病相关的炎症通路。

感染或受伤事件发生后，信号蛋白白细胞介素1β（IL-1β）帮助免疫系统进行快速免疫反击。然而，过量的IL-1β活性可导致有害的炎症，促进疾病状态如各种自身免疫性疾病。IL-1β抑制剂是药物研发的活跃区域，Cheng-I Wang和同事最近生成IL-1β特异性抗体，这可能是解决炎症性疾病的关键。

哺乳动物免疫系统已经进化能产生抗体，能结合外来分子，并且具有显著的亲和性和特异性。Wang和同事们利用蛋白质工程，获得一个有前途的抗体，被证明能够结合并抑制人类和小鼠的IL-1β。

研究人员集中在抗体的一小部分氨基酸，即可能有助于抗体结合IL-1β的氨基酸，随机置换这些氨基酸位点并产生抗体变体的一个库。通过筛选该抗体变体库，Wang和同事获得性能显着提高的抗体，得到了20?50倍更好亲和力的抗体变体。

这些抗体的最好变体是P2D7，其在抑制IL-1β上比康纳单抗（市售消炎药）更有效。康纳单抗和P2D7绑定相同的蛋白质，但识别相同分子上不同位点。

此外，P2D7结合至小鼠和猴子版本的IL-1β蛋白，并具有高亲和力的，而康纳单抗却没有此功效。研究人员利用小鼠模型显示，P2D7能对抗关节炎和腹膜炎症状，甚至延长了已经注射了人骨髓瘤细胞动物的存活。（生物谷Bioon.com）

本文系生物谷原创编译整理，欢迎转载！转载请注明来源并附原文链接。谢谢！

doi:10.4161/mabs.28614 PMC: PMID:

A novel human anti-interleukin-1β neutralizing monoclonal antibody showing in vivo efficacy

Goh, A. X. H., Bertin-Maghit, S., Yeo, S. P., Ho, A., Derks, H. et al.

The pro-inflammatory cytokine interleukin (IL)-1β is a clinical target in many conditions involving dysregulation of the immune system; therapeutics that block IL-1β have been approved to treat diseases such

as rheumatoid arthritis (RA), neonatal onset multisystem inflammatory diseases, cryopyrin-associated periodic syndromes, active systemic juvenile idiopathic arthritis. Here, we report the generation and engineering of a new fully human antibody that binds tightly to IL-1β with a neutralization potency more than 10 times higher than that of the marketed antibody canakinumab. After affinity maturation, the derived antibody shows a >30-fold increased affinity to human IL-1β compared with its parent antibody. This anti-human IL-1β IgG also cross-reacts with mouse and monkey IL-1β, hence facilitating preclinical

development. In a number of mouse models, this antibody efficiently reduced or abolished signs of disease associated with IL-1β pathology. Due to its high affinity for the cytokine and its potency both in vitro and in vivo, we propose that this novel fully human anti-IL-1β monoclonal antibody is a promising therapeutic candidate and a potential alternative to the current therapeutic arsenal.

Cancer Cell：癌症外染色体微小分子新功能

来源：生物谷 2014-10-28 18:09

2014年10月28日 讯 /生物谷BIOON/ --近日研究发现，通过癌细胞释放的外染色体、微小的病毒型颗粒可以表达导致肿瘤生长的微RNA分子。通过Dicer蛋白质的帮助他们进行了该研究，研究人员表明，Dicer也可以作为一种生物标志物对诊断和治疗乳腺癌开辟新的途径。调查结果发表在《癌症细胞》上。

“当Dicer和其他蛋白质与微RNA的存在发展相关时，来自乳腺癌患者细胞和血清的外染色体已被证明在非肿瘤细胞形成时启动肿瘤细胞生长。”Raghu Kalluri医学博士说，“这些发现为以外来染色体为基础的生物标记的发展提供机会并解释了癌症扩散的机制。”

外染色体是由DNA，RNA和蛋白质组成的小囊泡，它们附着在两个脂质层膜之间。这些外染色体拥有特殊功能如凝固、细胞间信号传导和细胞“垃圾管理”。“它们脱落进入到体液中形成核酸和蛋白质特异疾病的来源。越来越多的外染色体因其作为潜在疾病的指标而被研究，这将成为一种潜在的治疗方法。

所有Dicer含有更小的成分包括蛋白质，信使核糖核酸(mRNA)和小RNA。Kalluri的研究小组报告说，与乳腺癌关联的外染色体含有特定的小RNA与多重

World Health Organization Global Tuberculosis Control 2011 WHO/HTM/TB/2011.16

http://whqlibdoc.who.int/publications/2011/9789241564380_eng.pdf (World Health Organization, 2011).

8.

Show context Stop TB Partnership The Global Plan to Stop TB 2011–2015 http://stoptb.org/assets/documents/global/plan/TB_GlobalPlanToStopTB2011-2015.pdf (World Health Organization, 2011). 6. 7.

Show context

World Health Organization Global Tuberculosis Control 2011 WHO/HTM/TB/2011.16

http://whqlibdoc.who.int/publications/2011/9789241564380_eng.pdf (World Health Organization, 2011).

8.

Show context. 'Hidden' tuberculosis raises drug-resistance fears

New study doubles known rate of infection at a South African hospital. Amy Maxmen

Researchers found high rates of TB and

HIV, seen here in scanning electron microscope images.Janice Haney Carr-CDC / CDC

Huge and hidden levels of tuberculosis discovered in a South African province devastated by HIV are increasing concerns about the prevalence of drug-resistant tuberculosis in Africa.

As reported in PLoS Medicine1, when researchers examined newly deceased patients at Edendale hospital in the province of KwaZulu-Natal, they discovered that 50% were infected with the bacterium M. tuberculosis, the causal agent of tuberculosis, with 17% of the infected individuals carrying a multi-drug resistant (MDR) strain.

Among those with TB, only 58% had been diagnosed and started on treatment before their death. A previous study had found that only 28% of patients admitted to the same hospital were diagnosed with active tuberculosis.

In the new study, 96% of those positive for M. tuberculosis were also HIV positive, and the alarming prevalence of tuberculosis may reflect the situation in other low-income countries

plagued by HIV. With weakened immunity, HIV-positive individuals are extremely vulnerable to other infections.

\

Department in Geneva, Switzerland. \tuberculosis has become rampant in people living with HIV [in Africa]\

According to the World Health Organization, South Africa ranks fifth among countries with the highest tuberculosis burden. Infection rates in KwaZulu-Natal may be especially high as 39% of adults are HIV-positive, according to a 2008 UNAIDS report2.

Douglas Wilson, head of medicine at Edendale and an author on the PLoS Medicine paper, hadn't expected such staggering rates of tuberculosis. \of funeral parlours along the road,\The new study looked at 240 adults aged between 20 and 45 who died from any cause excluding trauma or childbirth. Many of these patients might have survived had their tuberculosis been detected earlier, as 42% of them were not being treated for it.

Tuberculosis slips under the radar because many patients admitted to hospitals never get tested. Even if they do, the cheapest and most commonly used diagnostic tests, which involve examining sputum under a microscope, often miss cases. In particular, HIV-positive people typically suffer from forms of tuberculosis that sputum tests don't detect.

By culturing samples drawn from organs and the respiratory tract, this team diagnosed the presence of MDR M. tuberculosis with greater accuracy than less invasive tests can. Drug-resistant danger

Although too little information exists to tell if MDR tuberculosis is on the rise globally, Peter Cegielski, at the US Center for Disease Control's Division of Tuberculosis Elimination in Atlanta, Georgia, predicts that the epidemic will worsen because of inadequate capability for diagnosis and treatment.

\sun will rise tomorrow,\selective pressure on those bacteria, the drug-resistant mutants are going to survive.\Poor-quality drugs or incomplete drug regimens also give resistant TB bacteria time to arise, multiply, and infect others.

On June 15, the non-profit Center for Global Development in Washington DC warned that drug quality must be more carefully monitored and diagnostic capabilities improved so that drug-resistant tuberculosis can be stopped before it spreads further. ADVERTISEMENT

Rachel Nugent, deputy director of global health at the organization, says long-term savings from such moves will vastly exceed up-front costs, as standard tuberculosis treatments cost US$20 whereas those for the drug-resistant form of the disease start at $3,500.

Yet Wilson says Edendale lacks the expertise and resources required to run faster, more accurate tests on a large scale.

In the meantime he's turned to HIV prevention as a means to slow the tuberculosis epidemic. \can chose to have safe sex,\

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References

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1. Cohen, T. et al. PLoS Med. 7, e1000296 (2010). | Article 2. 2008 Report on the Global AIDS Epidemic (UNAIDS, 2008

Genomes reveal roots of TB drug resistance

Tuberculosis strains evolve by gradually acquiring subtle mutations.

基因组揭示结核病耐药性的根源

肺结核菌株发展逐步获得微妙的突变

随着抵抗抗生素的增加，治疗结核病的过程变得越来越少没有效 对肺结核来说，这从来都不是一个好消息, 近年来的前景变得更糟

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Ed Yong 01 September 2013

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Courses of treatment against TB are becoming less and less effective as resistance to antibiotics increases.

It is never a good time to come down with tuberculosis, but in recent years the outlook has become worse.

Resistant strains of tuberculosis are on the rise, limiting treatment options despite decades of antibiotic research. In 2010, at least 650,000 cases of the disease were resistant to the two most effective frontline antibiotics, and in 2012, totally resistant and effectively untreatable strains of Mycobacterium tuberculosis — the bacterium behind the disease — were detected in India. Now, two teams of scientists have published large catalogues of the mutations that confer resistance on M. tuberculosis after sequencing the complete genomes of hundreds of samples. Their studies, both published in Nature Genetics, greatly increase our understanding of the ways in which this long-term nemesis evades our most potent drugs1, 2.

These phase I trials will assess the vaccines‘ safety and whether they elicit levels of immune response that have been shown to confer protection in non-human primates. The trials will also assess the dose needed to generate sufficient immune response, which in turn helps to determine how quickly manufacturers can produce doses. A third candidate is a two-vaccine regimen: one developed by US pharmaceutical company Johnson and Johnson and the US National Institute of Allergy and

Infectious Diseases, and another by Bavarian Nordic, a biotechnology company based in Denmark. It will begin phase I testing in the United States and Europe in January. Johnson and Johnson announced on 22 October that it would spend up to US$200 million to fast track the vaccine‘s development; it plans to produce more than 1 million doses in 2015, with 250,000 available by May. Advanced testing

The first phase II and III trials, to test efficacy as well as safety, are set to start in Liberia in December and in Sierra Leone in January. The current plan is to test both the GSK and NewLink vaccines simultaneously, but that could change depending on the results of the ongoing phase I trials. Data from the phase II and III tests are expected by April, Kieny says.

The ?three-arm‘ Liberia trial would test and compare the safety and effectiveness of the two vaccines against each other and a placebo. Each vaccine would be tested on 10,000 subjects, with an equal number of subjects given placebo. This allows researchers to obtain quick, reliable data on how well the vaccines work.

A ?stepped-wedge‘ randomized trial in Sierra Leone would give subjects vaccine

sequentially, with no group given a placebo. This is useful for testing products that are expected to benefit patients, and products that are in short supply.

No trial design has yet been fixed for Guinea, where a lack of infrastructure has precluded early testing. If the Liberia and Sierra Leone trials show that the vaccines works and is safe, subsequent trials in Guinea would be used to answer follow-up questions.

Ethical and practical considerations

The Sierra Leone trial will enrol at least 8,000 health-care workers, and other frontline responders, such as ambulance drivers and burial workers. The Liberia trial might include health-care workers, but these would not be the primary study population, Kieny says.

Any decision to give a placebo to health-care and other frontline workers will be controversial; many consider it to be unethical, given these individuals‘ work caring for Ebola patients, and the risks that they face in doing so.

Mass vaccinations are usually only carried out after years of trials to accumulate full safety and efficacy data. The proposed timeline for Ebola vaccine development is therefore unprecedented.

If existing public-health interventions to control Ebola outbreaks begin to slow the epidemic, the need for mass vaccination will lessen, Kieny says. But if the epidemic continues to expand, the WHO could consider expanding vaccination programmes. In the meantime, the WHO and its partners are considering how best to engage with communities to prepare for vaccination programmes. Another issue is simply

determining how to keep vaccine at –80 degrees Celsius, the temperature needed to maintain its efficacy. This will require specialized refrigerators and the establishment of cold supply chains to affected areas.

Also to be determined is who will pay for mass vaccination. Kieny says simply that ―money will not be an issue‖. Aid groups and governments have begun to pledge support for such efforts. Médecins Sans Frontières (MSF, also known as Doctors Without Borders) has said that it will create a fund for Ebola vaccination, and the European Union has committed

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