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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/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通过抗体依赖性等机制介导有效感染细胞的杀伤细胞介导的细胞毒性（ADCC）。在过去的五年里，我们集团充分利用了在抗体工程领域，以及不断增加的广泛中和抗体 (bNAb) 列表其他研究人员构建了新的双特异性抗体，这些抗体具有出色的抗病毒广度和效力预防 HIV-1 的目的。现在，通过这项提案，我们希望将我们的抗体工程工作扩展到生成一系列双特异性和三特异性抗体，这些抗体针对杀死表达 Env 的细胞进行了优化细胞，以及药代动力学等重要特性。而不是病毒中和筛选正如我们之前所做的那样，我们现在将设计和筛选环境靶向多特异性库体外细胞结合和细胞杀伤活性的抗体。然后，性能最佳的抗体构建体将在人源化小鼠模型中系统地体内评估对其细胞杀伤能力的影响，它们在激活后限制或消除潜伏储存细胞的能力，以及它们防止或限制潜在储存细胞的能力 HIV-1潜伏病毒库的建立。连同我们对 HIV-1 bNAb 和抗体的了解工程、我们对病毒动力学的深刻理解以及我们之前研究 HIV-1 潜伏病毒的经验水库将参与实验的设计、实施和解释，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作用。我们的团队已成功设计出两种具有出色的 HIV-1 中和活性的双特异性抗体，并且此后，我们将抗体工程技术扩展到双特异性或三特异性抗体的构建靶向 Env 的抗体，目的是促进消除受感染的细胞。最后，我们希望向该领域提供一种或两种多特异性抗体，可用于消除潜在的储存细胞是多管齐下根除 HIV-1 方法的关键组成部分。