Bispecific and Trispecific Anti-Env Antibodies for Eliminating HIV Reservoir Cells

用于消除 HIV 储存细胞的双特异性和三特异性抗 Env 抗体

• 批准号: 10224769
• 负责人: DAVID D HO
• 金额: $ 71.39万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-10 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10224769
• 关键词: Acute; Adult; Affinity; Antibodies; Antibody Therapy; Antiviral Agents; Berlin; Binding; Biological Models; Bispecific Antibodies; Bone Marrow Transplantation; CCR5 gene; Cell surface; Cells; Chronic; Clinical; Collection; Diagnosis; Drug Kinetics; Early treatment; Engineering; Epitopes; France; Goals; HIV; HIV-1; Hour; IgG1; Infection; Investigation; Knowledge; Libraries; Measures; Mediating; Mississippi; Mutation; Pathway interactions; Patients; Population; Population Heterogeneity; Prevention; Property; Proviruses; Research Personnel; Series; Sleep; Time; Ursidae Family; Viral; Virion; Virus; Virus Diseases; Virus Latency; Whole-Body Irradiation; acute infection; antibody engineering; antibody-dependent cell cytotoxicity; antigen binding; antiretroviral therapy; arm; cell killing; chemotherapy; clinical candidate; clinical development; cohort; design; efficacy evaluation; experience; experimental study; fighting; humanized mouse; improved; in vitro activity; in vivo; latent HIV reservoir; lead candidate; mouse model; neutralizing antibody; novel therapeutics; prevent; purge; screening; spatial relationship; stem cells; viral rebound; weapons

PROJECT SUMMARY/ABSTRACT Antibodies constitute a powerful weapon to fight viral infections. They could neutralize the infectivity of virus particles as well as mediate killing of productively infected cells via mechanisms such as antibody-dependent cell-mediated cytotoxicity (ADCC). In the past five years, our group has utilized the advances made in the antibody engineering field, as well as the growing lists of broadly neutralization antibodies (bNAbs) identified by other investigators, to construct new bispecific antibodies that have exquisite antiviral breadth and potency for the purpose of HIV-1 prevention. Now, with this proposal, we wish to expand our antibody engineering effort to generate a collection of bispecific and trispecific antibodies that are optimized for killing of Env-expressing cells, and for important properties such as pharmacokinetics. Instead of screening for virus-neutralization activity as we have previously done, we will now engineer and screen a library of Env-targeting multi-specific antibodies for cell-binding and cell-killing activities in vitro. The best performing antibody constructs will then be evaluated systematically in vivo in a humanized mouse model for the effect on their cell-killing capacity, their ability to restrict or eliminate latent reservoir cells after activation, and their ability to prevent or limit the establishment of the HIV-1 latent reservoir. Along with our knowledge of HIV-1 bNAbs and antibody engineering, our deep understanding of viral dynamics and our prior experience studying the HIV-1 latent reservoir will be brought to bear on the design, conduct, and interpretation of experiments to evaluate and quantify the antiviral effects of our top antibody constructs in humanized mice. Our group has successfully engineered two bispecific antibodies with exquisite HIV-1-neutralizing activity, and we have since extended our know-how in antibody engineering to the construction of bispecific or trispecific antibodies that target Env for the purpose of facilitating the elimination of infected cells. In the end, we hope to offer to the field one or two multi-specific antibodies that could be applied toward the elimination of latent reservoir cells as one critical component of a multi-pronged approach to HIV-1 eradication.

项目总结/摘要 抗体是对抗病毒感染的有力武器。它们可以中和病毒的传染性 颗粒以及介导通过抗体依赖性的机制， 细胞介导的细胞毒性（ADCC）。在过去的五年里，我们的团队利用了在 抗体工程领域，以及越来越多的广泛中和抗体（bNAb）的名单确定， 其他研究人员，以构建新的双特异性抗体，具有精致的抗病毒广度和效力， 预防HIV-1的目的。现在，有了这个建议，我们希望扩大我们的抗体工程努力， 产生双特异性和三特异性抗体的集合，所述抗体被优化用于杀死表达Env的 细胞，以及重要的性质，如药代动力学。而不是筛选病毒中和 正如我们以前所做的那样，我们现在将设计和筛选一个Env靶向多特异性 用于体外细胞结合和细胞杀伤活性的抗体。然后，表现最好的抗体构建体将 在人源化小鼠模型中系统地评价其对细胞杀伤能力的影响， 它们在激活后限制或消除潜伏储库细胞的能力，以及它们防止或限制 建立HIV-1潜伏库。沿着我们对HIV-1 bNAb和抗体的了解 工程，我们对病毒动力学的深刻理解和我们之前研究HIV-1潜伏的经验， 储层将承担的设计，进行，和解释的实验，以评估和 量化我们的顶级抗体构建体在人源化小鼠中的抗病毒效果。 我们的团队已经成功地设计了两种具有精致的HIV-1中和活性的双特异性抗体， 从那时起，我们已经将我们在抗体工程方面的专业知识扩展到双特异性或三特异性抗体的构建。 靶向Env的抗体，目的是促进受感染细胞的消除。最后，我们希望 为该领域提供一种或两种多特异性抗体，其可用于消除潜在的 作为根除HIV-1的多管齐下方法的一个关键组成部分。