Antibody Based Therapeuticcs for Chikungunya Virus

基孔肯雅病毒抗体疗法

• 批准号: 8279166
• 负责人: Michael S Diamond
• 金额: $ 94.48万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-06-05 至 2015-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8279166
• 关键词: Aedes; Affinity; Alphavirus; Antibodies; Antiviral Agents; Area; Binding; Categories; Cell Culture Techniques; Cell Line; Chikungunya virus; Clinical; Clinical Trials; Collaborations; Culicidae; Development; Diamond; Disease Outbreaks; E protein; Encephalopathies; Engineering; Enzyme-Linked Immunosorbent Assay; Epidemic; Epitope Mapping; Family; Fever; Fostering; Foundations; Generations; Goals; Human; IFNAR1 gene; Immunotherapeutic agent; Immunotherapy; In Vitro; India; Industry; Infection; Infection prevention; Interferons; Laboratories; Mediating; Molecular; Monoclonal Antibodies; Mus; National Institute of Allergy and Infectious Disease; Pathogenesis; Phase; Phase II Clinical Trials; Prevention; RNA; RNA Viruses; Research; Resistance; Screening procedure; Staging; Surface; Surface Plasmon Resonance; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Effect; Togaviridae; Travel; Vaccines; Variant; Viral Hemorrhagic Fevers; Virulence; Virulent; Virus Diseases; West Nile virus; Yeasts; base; env Gene Products; experience; humanized antibody; humanized monoclonal antibodies; immunoprophylaxis; in vivo; mouse model; neutralizing monoclonal antibodies; pathogen; pre-clinical; prophylactic; protective efficacy; receptor; research study; resistant strain; skills; vector; vector mosquito; virus development; virus pathogenesis

DESCRIPTION (provided by applicant): Chikungunya virus (CHIKV) is a mosquito-transmitted, single-stranded RNA alphavirus of the Togaviridae family that causes explosive epidemics of a severe febrile illness characterized by debilitating polyarthalgias in humans. CHIKV (NIAID Category C pathogen) caused an estimated 1.4 million new cases in India alone in 2006, and has the potential to spread globally because of the distribution and abundance of its primary mosquito vector, Aedes aegypti. During recent outbreaks, more severe forms of CHIKV infection were observed including encephalopathy and hemorrhagic fever, suggesting the emergence of more virulent strains. Currently, no specific treatment or vaccine is available. Given its global burden, the increased travel into CHIKV-endemic areas, and the worldwide spread of its vector, there is a pressing need for the development of prophylactic and therapeutic agents against CHIKV. In preliminary experiments, we have generated strongly neutralizing monoclonal antibodies (MAbs) against CHIKV that prevent infection in mice. Here, an established academic-industry collaborative partnership between the Diamond laboratory and MacroGenics will develop humanized antibody therapeutics that protect against virtually all strains of CHIKV. In Aim 1, panels of mouse MAbs against the E1 and E2 envelope proteins of CHIKV will be generated and screened functionally. The most potent neutralizing MAbs that recognize an array of genetically diverse CHIKV strains will be evaluated for protection in mice. In Aim 2, mechanistic correlates of antibody protection will be defined by characterizing the cellular stages of antibody blockade. Additionally, we will identify CHIKV recognition determinants using high-throughput yeast surface display epitope-mapping technology. In Aim 3, we will engineer humanized MAbs that block infection of CHIKV. These will be tested for neutralizing activity in cell culture and in mice. Humanized MAbs will be tested for protective efficacy, durability, and therapeutic effect in vivo. High-expressing cell lines producing the best candidates will be established. Overall, the generation of strongly protective humanized MAbs against CHIKV will foster the clinical development of immunotherapeutic agents against CHIKV infection.

描述（由申请人提供）：Chikungunya病毒（Chikv）是Togaviridae家族的一种蚊子传播的单链RNAαα，导致严重的发热性流行病，是一种严重的发热性疾病，其特征是人类衰弱的人。 CHIKV（NIAID类别C病原体）估计在2006年在印度造成了大约140万例新病例，并且由于其主要蚊子载体的分布和丰度而有可能在全球范围内传播。在最近的暴发期间，观察到更严重的Chikv感染形式，包括脑病和出血热，表明出现了更多毒性菌株。目前，没有特定的治疗方法或疫苗可用。鉴于其全球负担，增加了进入Chikv流行地区的旅行以及其向量的全球传播，因此迫切需要开发针对Chikv的预防性和治疗剂。在初步实验中，我们已经对CHIKV产生了强烈中和单克隆抗体（mAb），以防止小鼠感染。在这里，钻石实验室和宏源学之间建立的学术行业合作伙伴关系将开发人性化的抗体疗法，以防止几乎所有CHIKV菌株。在AIM 1中，将在功能上生成并筛选Chikv的E1和E2包膜蛋白的小鼠mAB面板。识别一系列遗传多样的CHIKV菌株的最有效的中和MAB将被评估以在小鼠中进行保护。在AIM 2中，将通过表征抗体阻滞的细胞阶段来定义抗体保护的机械相关性。此外，我们将使用高通量酵母表面显示表位图技术确定CHIKV识别决定因素。在AIM 3中，我们将设计封闭Chikv感染的人源化mAB。这些将测试在细胞培养和小鼠中中和活性。人源化的mAb将在体内测试保护性功效，耐用性和治疗效应。将建立产生最佳候选者的高表达细胞系。总体而言，对CHIKV的强烈保护性人性化的mAb产生将促进免疫治疗剂抗Chikv感染的临床发展。