Mechanisms of Protection of Universal Therapeutic Antibodies to Influenza A
甲型流感通用治疗抗体的保护机制
基本信息
- 批准号:10078587
- 负责人:
- 金额:$ 77.37万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AdamantaneAnimal ModelAnimalsAntibodiesAntibody Binding SitesAntibody TherapyAntiviral AgentsAvian Influenza A VirusB-LymphocytesBindingBinding SitesBiologicalCell LineCellsClinicalComplementComplement ActivationDataDevelopmentDiseaseDoseEffectivenessEpitopesEscape MutantExtracellular DomainFc ReceptorFerretsGoalsHealthHemagglutininHumanIgG1ImmuneImmune responseImmunoglobulin Class SwitchingImmunologic MemoryImmunologicsImmunologistIn VitroInbred BALB C MiceIndividualInfectionInfection preventionInfluenzaInfluenza A Virus, H1N1 SubtypeInfluenza A virusInfluenza vaccinationIon ChannelMediatingModelingMonoclonal AntibodiesMorbidity - disease rateMusMutant Strains MiceMutationNeuraminidaseOrthomyxoviridaePathogenicityPathologyPeptidesPhagocytosisProteinsScientistSerotypingSpecific qualifier valueSpleenTestingTherapeuticTherapeutic AgentsTherapeutic InterventionTherapeutic Monoclonal AntibodiesTherapeutic antibodiesTimeTreatment ProtocolsVaccinatedVaccinationVaccinesViralVirionVirusVirus DiseasesVirus ReplicationVirus SheddingZoonosesadaptive immune responseantibody-dependent cell cytotoxicitybasedosageextracellularhuman modelin vivoinfluenza infectioninfluenzavirusinhibitor/antagonistlead candidatemortalitymouse modelmutantnanoGoldneutralizing monoclonal antibodiesoverexpressionpandemic influenzapreventprophylacticrespiratoryresponseviral resistance
项目摘要
Influenza virus infection causes contagious respiratory illness in humans and animals, and significant morbidity
and mortality worldwide. Humans fail to make a universally protective memory immune response to influenza
A, as Hemagglutinin and Neuraminidase, the two immune-dominant influenza A virus-encoded epitopes,
undergo antigenic shift and drift, resulting in influenza A strains to which even previously infected humans are
susceptible to. In the absence of a universal influenza A vaccine, prophylactic or therapeutic agent, influenza A
will remain a significant threat to human health. To generate such agents, we developed a panel of Matrix
Protein 2 extracellular (M2e)-specific monoclonal antibodies (MAbs). The extracellular domain of the M2-ion
channel is an ideal antigenic target for a universal therapeutic agent: It is 99% conserved across influenza A
serotypes, has a low mutation rate, and is essential for viral entry and replication. However, less than 20% of
infected individuals generate M2e-specific antibodies in response to influenza A infection, perhaps due to
M2e's small size and rarity. Thus, we seek to accomplish our long-term goal, to develop a universal
prophylactic or therapeutic agent to prevent or treat influenza A infection and associated pathologies, by
provision of M2e-specific MAbs, an essential component of a protective influenza A-specific immune response
currently lacking in most humans. To achieve this goal, we generated seven monoclonal antibodies specific to
M2e, two of which completely protect, and three of which partially protect highly influenza A virus susceptible
Balb/c mice from lethal challenge. Based on these considerations, it is our central hypothesis that a cocktail of
M2e-specific MAbs can prevent or ameliorate influenza A infection and associated pathology. As antibodies
can mediate a variety of complementary effector functions that contribute to host protection, we hypothesize
that a combination of M2e-specific MAbs capable of interference with M2-ion channel activity, elicitation of
ADCC, phagocytosis and complement activation will be most effective at reducing influenza A virus replication
and associated pathology, while preventing immune escape. We expect to test our central hypothesis and to
achieve the objective of this application by pursuing the following three specific aims: Aim 1: to identify
biological effects of MAb binding on M2e-function and viral replication in vitro; Aim 2: to develop protective and
therapeutic MAb treatment regimens in vivo; and Aim 3: to dissect the individual contributions of M2e-specific
MAb-dependent cytotoxicity, phagocytosis and complement activation to host protection from influenza A virus
infection. To achieve our aims, we have assembled and expert team of collaborating scientists: Dr. Beeton, an
expert in the ion channel function; Dr. Tompkins, an expert in animal models of human and zoonotic influenza
infection, vaccination, and therapeutics, with specified M2 expertise; Dr. Ross, an expert in the ferret model of
influenza vaccination and infection; and, myself, Dr. Paust, an expert immunologist with a detailed
understanding of the innate and adaptive immune response to Influenza A infection.
流感病毒感染引起人和动物的传染性呼吸道疾病,
和死亡率。人类未能对流感做出普遍保护性记忆免疫反应
A,作为血凝素和神经氨酸酶,两种免疫显性的甲型流感病毒编码表位,
经历抗原性转变和漂移,导致甚至先前感染人类的甲型流感病毒株,
易受影响的在缺乏通用甲型流感疫苗、预防剂或治疗剂的情况下,
仍将对人类健康构成重大威胁。为了生成这样的代理,我们开发了一个矩阵面板,
蛋白2细胞外(M2 e)特异性单克隆抗体(MAb)。M2-离子的胞外结构域
通道是通用治疗剂的理想抗原靶点:它在甲型流感病毒中具有99%的保守性
血清型,具有低突变率,并且对于病毒进入和复制是必需的。然而,只有不到20%的
感染个体产生M2 e特异性抗体以响应甲型流感感染,这可能是由于
M2 E的体积小,稀有。因此,我们寻求实现我们的长期目标,发展一个普遍的
预防或治疗甲型流感感染和相关病理的预防剂或治疗剂,
提供M2 e特异性单克隆抗体,这是保护性甲型流感特异性免疫应答的重要组成部分
这是目前大多数人所缺乏的。为了实现这一目标,我们产生了七种特异性单克隆抗体,
M2 e,其中两种完全保护,其中三种部分保护高度易感的甲型流感病毒
致死攻毒的Balb/c小鼠。基于这些考虑,我们的中心假设是,
M2 e特异性MAb可以预防或改善甲型流感感染和相关病理。如抗体
可以介导多种互补效应子功能,有助于宿主保护,我们假设
能够干扰M2-离子通道活性、诱导M2-离子通道活性的M2 e-特异性单克隆抗体的组合,
ADCC、吞噬作用和补体激活将最有效地减少甲型流感病毒复制
和相关的病理学,同时防止免疫逃逸。我们希望测试我们的中心假设,
通过追求以下三个具体目标来实现本申请的目标:目标1:
MAb结合对体外M2 e功能和病毒复制的生物学效应;目的2:开发保护性和
目的3:分析M2 e特异性单克隆抗体治疗方案的个体贡献,
单克隆抗体依赖的细胞毒性、吞噬作用和补体激活对宿主免受甲型流感病毒的保护
感染为了实现我们的目标,我们组建了一个由合作科学家组成的专家团队:
离子通道功能专家;汤普金斯博士,人类和人畜共患流感动物模型专家
感染,疫苗接种和治疗,与指定的M2专业知识;罗斯博士,在雪貂模型的专家,
流感疫苗接种和感染;还有,我自己,Paust博士,一位免疫专家,
了解对甲型流感感染的先天性和适应性免疫反应。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Influenza A Virus Hemagglutinin and Other Pathogen Glycoprotein Interactions with NK Cell Natural Cytotoxicity Receptors NKp46, NKp44, and NKp30.
甲型流感病毒血凝素和其他病原体糖蛋白与 NK 细胞天然细胞毒性受体 NKp46、NKp44 和 NKp30 的相互作用。
- DOI:10.3390/v13020156
- 发表时间:2021-01-21
- 期刊:
- 影响因子:0
- 作者:Luczo JM;Ronzulli SL;Tompkins SM
- 通讯作者:Tompkins SM
Divergent Mast Cell Responses Modulate Antiviral Immunity During Influenza Virus Infection.
不同的肥大细胞反应调节流感病毒感染期间的抗病毒免疫力
- DOI:10.3389/fcimb.2021.580679
- 发表时间:2021
- 期刊:
- 影响因子:5.7
- 作者:Murphy-Schafer AR;Paust S
- 通讯作者:Paust S
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Silke Paust其他文献
Silke Paust的其他文献
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{{ truncateString('Silke Paust', 18)}}的其他基金
Novel mechanisms regulating immunity to respiratory virus infection
调节呼吸道病毒感染免疫力的新机制
- 批准号:
10753849 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
Novel mechanisms regulating immunity to respiratory virus infection
调节呼吸道病毒感染免疫力的新机制
- 批准号:
10931141 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
How antigen exposure shapes the subsequent NK cell response to HIV
抗原暴露如何影响随后的 NK 细胞对 HIV 的反应
- 批准号:
10924725 - 财政年份:2023
- 资助金额:
$ 77.37万 - 项目类别:
Control of HIV-induced MDSC expansion and immunosuppression by cytotoxic lymphocytes
细胞毒性淋巴细胞控制 HIV 诱导的 MDSC 扩增和免疫抑制
- 批准号:
10559918 - 财政年份:2022
- 资助金额:
$ 77.37万 - 项目类别:
Control of HIV-induced MDSC expansion and immunosuppression by cytotoxic lymphocytes
细胞毒性淋巴细胞控制 HIV 诱导的 MDSC 扩增和免疫抑制
- 批准号:
10674910 - 财政年份:2022
- 资助金额:
$ 77.37万 - 项目类别:
How antigen exposure shapes the subsequent NK cell response to HIV
抗原暴露如何影响随后的 NK 细胞对 HIV 的反应
- 批准号:
10561720 - 财政年份:2021
- 资助金额:
$ 77.37万 - 项目类别:
How antigen exposure shapes the subsequent NK cell response to HIV
抗原暴露如何影响随后的 NK 细胞对 HIV 的反应
- 批准号:
10374918 - 财政年份:2021
- 资助金额:
$ 77.37万 - 项目类别:
Harnessing NK Memory To Protect Against HIV Infection
利用 NK 记忆来预防 HIV 感染
- 批准号:
8996549 - 财政年份:2015
- 资助金额:
$ 77.37万 - 项目类别:
Harnessing NK Memory To Protect Against HIV Infection
利用 NK 记忆来预防 HIV 感染
- 批准号:
9204387 - 财政年份:2015
- 资助金额:
$ 77.37万 - 项目类别:
Harnessing NK Memory To Protect Against HIV Infection
利用 NK 记忆来预防 HIV 感染
- 批准号:
9430685 - 财政年份:2015
- 资助金额:
$ 77.37万 - 项目类别:
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