Harnessing the structural flexibility of bovine monoclonal antibodies for the treatment of emerging virus infections

利用牛单克隆抗体的结构灵活性来治疗新出现的病毒感染

• 批准号: MR/R010307/1
• 负责人: Jonathan Ball
• 金额: $ 65.35万
• 依托单位: University of Nottingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2018
• 资助国家: 英国
• 起止时间: 2018 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FR010307%2F1
• 关键词: Harnessing; structural; flexibility; bovine; monoclonal

Emerging virus infections such as Ebola and Lassa Fever virus are highly dangerous and result in significant illness and death. Outbreaks of these are set to increase in the future so it is crucial that we have effective and safe ways to treat infected individuals, for when outbreaks occur. Monoclonal antibodies have very potent antiviral activity but the virus can escape from their effects by mutating. This is particularly true for the majority of antibodies raised in mice and humans. This is because these antibodies predominately bind to highly exposed regions of the virus - regions that the virus can change without losing its ability to infect. However, some parts of the virus are more genetically conserved as they are directly involved in the infection pathway. These regions represent a vulnerability to the virus so it hides them away from antibody surveillance using the overall 'bulk' of the protein or by using sugars to hide them. Some animals, for example cattle, produce unusually large antibodies that are able to directly interact with these hidden regions so the virus cannot easily escape from them. We have developed a method to allow us to generate monoclonal antibodies from cattle and we will use this to develop a new class of therapies to target some of the most important emerging virus infections. We will use the surface proteins of Ebola, Lassa Fever, Nipah and Marburg virus to immunise cattle then use recombinant DNA techniques to produce antibodies, which we can screen for their ability to neutralise different strains of each virus. Ultimately, those antibodies showing the most potent and broad antiviral activity can be progressed into clinical development for use in human outbreaks.

新出现的病毒感染，如埃博拉病毒和拉沙热病毒是高度危险的，并导致重大疾病和死亡。这些疾病的爆发将在未来增加，因此当爆发发生时，我们必须有有效和安全的方法来治疗感染者。单克隆抗体具有非常有效的抗病毒活性，但病毒可以通过突变逃避其影响。这对于小鼠和人类中产生的大多数抗体尤其如此。这是因为这些抗体主要与病毒的高度暴露区域结合-病毒可以在不失去感染能力的情况下改变这些区域。然而，病毒的某些部分在遗传上更为保守，因为它们直接参与感染途径。这些区域代表了对病毒的脆弱性，因此它使用蛋白质的整体“体积”或使用糖来隐藏它们，使它们远离抗体监测。有些动物，如牛，产生异常大的抗体，能够直接与这些隐藏的区域相互作用，因此病毒无法轻易逃脱。我们已经开发出一种方法，使我们能够从牛中产生单克隆抗体，我们将利用这种方法开发一类新的疗法，以针对一些最重要的新兴病毒感染。我们将使用埃博拉病毒、拉沙热病毒、尼帕病毒和马尔堡病毒的表面蛋白来免疫牛，然后使用重组DNA技术来产生抗体，我们可以筛选它们中和每种病毒不同菌株的能力。最终，那些显示出最有效和最广泛的抗病毒活性的抗体可以进入临床开发，用于人类疾病爆发。

项目成果

Human parainfluenza 2 & 4: Clinical and genetic epidemiology in the UK, 2013-2017, reveals distinct disease features and co-circulating genomic subtypes.

• DOI: 10.1111/irv.13012
• 发表时间: 2022-11
• 期刊: INFLUENZA AND OTHER RESPIRATORY VIRUSES
• 影响因子: 4.4
• 作者: Chellapuri, Akhil;Smitheman, Matthew;Chappell, Joseph G.;Clark, Gemma;Howson-Wells, Hannah C.;Berry, Louise;Ball, Jonathan K.;Irving, William L.;Tarr, Alexander W.;McClure, C. Patrick
• 通讯作者: McClure, C. Patrick

The Impact of Real-Time Whole-Genome Sequencing in Controlling Healthcare-Associated SARS-CoV-2 Outbreaks.

• DOI: 10.1093/infdis/jiab483
• 发表时间: 2022-01-05
• 期刊: The Journal of infectious diseases
• 作者: Francis RV;Billam H;Clarke M;Yates C;Tsoleridis T;Berry L;Mahida N;Irving WL;Moore C;Holmes N;Ball JK;Loose M;McClure CP;COVID-19 Genomics UK (COG-UK) consortium
• 通讯作者: COVID-19 Genomics UK (COG-UK) consortium

Immunogenicity of a new gorilla adenovirus vaccine candidate for COVID-19.

• DOI: 10.1016/j.ymthe.2021.04.022
• 发表时间: 2021-08-04
• 期刊: Molecular therapy : the journal of the American Society of Gene Therapy
• 作者: Capone S;Raggioli A;Gentile M;Battella S;Lahm A;Sommella A;Contino AM;Urbanowicz RA;Scala R;Barra F;Leuzzi A;Lilli E;Miselli G;Noto A;Ferraiuolo M;Talotta F;Tsoleridis T;Castilletti C;Matusali G;Colavita F;Lapa D;Meschi S;Capobianchi M;Soriani M;Folgori A;Ball JK;Colloca S;Vitelli A
• 通讯作者: Vitelli A

Hepatitis C subtyping assay failure in UK patients born in sub-Saharan Africa: Implications for global treatment and elimination.

• DOI: 10.1002/jmv.28178
• 发表时间: 2023-01
• 期刊: JOURNAL OF MEDICAL VIROLOGY
• 影响因子: 12.7
• 作者: Adeboyejo, Kazeem;King, Barnabas J.;Tsoleridis, Theocharis;Tarr, Alexander W.;McLauchlan, John;Irving, William L.;Ball, Jonathan K.;McClure, C. Patrick
• 通讯作者: McClure, C. Patrick

Arbovirus circulation, epidemiology and spatiotemporal distribution in Uganda.

• DOI: 10.1016/j.ijregi.2023.01.013
• 发表时间: 2023-03
• 期刊: IJID REGIONS
• 作者: Byaruhanga, Timothy;Kayiwa, John T.;Nankya, Annet M.;Ataliba, Irene J.;McClure, C. Patrick;Ball, Jonathan K.;Lutwama, Julius J.
• 通讯作者: Lutwama, Julius J.