A "Trojan Horse" bispecific antibody strategy for broad filovirus therapeutics

用于广泛丝状病毒治疗的“特洛伊木马”双特异性抗体策略

• 批准号: 10192496
• 负责人: Kartik Chandran
• 金额: $ 108.42万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-14 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10192496
• 关键词: ART protein; Address; African; Antibodies; Antibody Therapy; Architecture; Binding; Binding Sites; Biological Response Modifier Therapy; Bispecific Antibodies; Bundibugyo virus; Case Fatality Rates; Category A pathogen; Cavia; Chimeric Proteins; Clinical Trials; Complex; Democratic Republic of the Congo; Development; Disease; Disease Outbreaks; Ebola; Ebola Hemorrhagic Fever; Ebola virus; Elements; Endosomes; Engineering; Epidemic; Epitopes; Equus caballus; FDA approved; Family; Ferrets; Filoviridae Infections; Filovirus; Glycoproteins; Goals; Government; Half-Life; Human; Immunotherapy; In Vitro; Industrialization; Infection; Institution; Lead; Marburgvirus; Membrane Fusion; Modality; Modeling; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; NPC1 gene; Pathogenesis; Pathway interactions; Peptide Hydrolases; Performance; Pharmacology; Prevention; Property; Protein Engineering; Proteins; Rodent; Science; Specificity; Sudan Ebola virus; Techniques; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Tissues; Uganda; Viral; Virion; Virulent; Virus; Virus Receptors; Western Africa; Widespread Disease; Work; antibody engineering; antibody test; cross reactivity; design; efficacy testing; emerging pathogen; improved; innovative technologies; lead candidate; nonhuman primate; novel; novel strategies; particle; public health relevance; receptor; receptor binding; single molecule; therapeutic candidate

Filoviruses are Category A pathogens which cause a severe and rapidly fatal disease with human case fatality rates of 30-90%. The 2013-2016 epidemic in Western Africa, with over 28,000 cases, was caused by one of these agents, Ebola virus (Zaire species, EBOV), and highlights the urgent need for new countermeasures targeting all virulent filoviruses. Monoclonal antibodies (mAbs) have emerged as the most promising therapeutic platform for treatment and prevention of Ebola virus disease. However, most mAbs and mAb cocktails are narrowly specific for a single filovirus, and are thus of limited use in outbreaks caused by other filoviruses with epidemic potential, including Bundibugyo virus (BDBV), Sudan virus (SUDV), and Marburg virus (MARV). A major gap in the filovirus mAb therapeutic pipeline is the lack of broad- spectrum therapies that are active against multiple disease-causing filoviruses. This proposal leverages an innovative technology platform, bispecific antibody engineering, along with proprietary mAbs from academic (Einstein), government (USAMRIID/Geneva), and commercial (Integrated Biotherapeutics; Mapp Biophamaceutical) partners to develop bispecific antibodies (bis-mAbs) as cross-protective filovirus antibody therapies. We build on a new approach recently developed by our team—a `Trojan Horse' bis-mAb that can coöpt virus particles themselves to `hitch a ride' into cellular endosomes, where it targets crucial and highly conserved viral epitopes that are normally hidden from antibodies. This bis-mAb shows potent, broad neutralization of all ebolaviruses in vitro and provides cross-protection against EBOV and SUDV in mice, thus providing proof-of-concept that bis-mAbs engineered to localize to endosome with viral particles can effectively target sequestered epitopes (Wec et al., Science 2016). Furthermore, this bis-mAb is broadly protective as a single component, thus avoiding the manufacturing and development hurdles of cocktails of mAbs that have been previously shown to be required for broad filovirus protection. To further develop this therapeutic bis-mAb modality, we will expand the range of highly conserved external and endosomal epitopes that are targeted. The goal of this proposal is to optimize and advance bis-mAbs as single component, pan-ebolavirus or pan-filovirus immunotherapies.

丝状病毒是一种病原体类别，引起严重且快速致命的疾病， 人类病例死亡率为30-90％。 2013-2016在西非的流行病， 28,000例，是由这些药物之一，埃博拉病毒（Zaire Tops，Ebov）和 强调迫切需要针对所有有毒丝病毒的新对策。单克隆 抗体（mAb）已成为治疗和 预防埃博拉病毒疾病。但是，大多数mab和mab鸡尾酒都是狭窄的 针对单个丝状病毒的特异 具有流行潜力，包括Bundibugyo病毒（BDBV），苏丹病毒（SUDV）和Marburg 病毒（MARV）。 FILOVIRUS MAB治疗管道中的主要差距是缺乏广泛的 针对多种引起疾病病毒的活性的光谱疗法。这个建议 利用创新技术平台，双特异性抗体工程，以及 来自学术（爱因斯坦），政府（USAMRIID/日内瓦）和商业的专有mABS （集成的生物治疗剂； MAPP生物学）伴侣开发双特异性抗体 （BIS-MAB）作为跨保护病毒抗体疗法。我们以新方法为基础 最近由我们的团队开发的 - 一个可以加以coöpt病毒颗粒的“特洛伊木马” bis-mab 自己要“骑车”进入细胞内体，它针对至关重要且高度 通常隐藏在抗体中的保守病毒表位。这个bis-mab显示了潜力， 在体外所有埃博氏病毒的广泛神经化，并对EBOV和 小鼠中的sudv，因此提供了概念概念，即bis-mabs设计为本地化 带有病毒颗粒的内体可以有效靶向隔离的表位（Wec等，科学， 2016）。此外，该bis-mab被广泛保护为单个成分，从而避免了 以前已显示的mab鸡尾酒的制造和开发障碍 要进行广泛的丝状病毒保护所必需的。进一步开发这种治疗性bis-mab 方式，我们将扩大高度保守的外部和内体表位的范围 是针对性的。该提案的目的是优化和推进bis-mab作为单个 成分，泛弹病毒或泛 - 细胞病毒免疫疗法。