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.

项目摘要/摘要抗体构成了抵抗病毒感染的强大武器。他们可以中和病毒的感染力颗粒以及通过抗体依赖性的机制介导了有效感染的细胞的杀伤细胞介导的细胞毒性（ADCC）。在过去的五年中，我们的小组利用了抗体工程领域以及越来越多的广泛中和抗体（BNAB）的清单其他研究人员，建造具有精美抗病毒药广度和效力的新的双特异性抗体 HIV-1预防的目的。现在，通过此建议，我们希望将我们的抗体工程工作扩展到生成用于杀死ENV表达的双特异性和特异性抗体的集合细胞，以及重要特性，例如药代动力学。而不是筛查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针对性的多特异性库体外细胞结合和细胞杀伤活性的抗体。那么，性能最好的抗体构建体将在人源化小鼠模型中系统地对体内进行系统评估，以影响其细胞杀性能力，它们在激活后限制或消除潜在储层细胞的能力以及预防或限制的能力建立HIV-1潜在水库。以及我们对HIV-1 BNAB和抗体的了解工程学，我们对病毒动态的深刻理解以及我们先前研究HIV-1潜伏的经验水库将被带来对实验的设计，进行和解释，以评估和量化我们顶级抗体构建体在人源化小鼠中的抗病毒作用。我们的小组成功地设计了两种具有精致HIV-1中和活性的双特异性抗体，并且从那以后，我们将抗体工程方面的专业知识扩展到双特异性或三项特异性的构建靶向ENV的抗体，目的是促进消除感染细胞的抗体。最后，我们希望向场提供一种或两种多特异性抗体，可用于消除潜伏储层细胞是消除HIV-1的多管齐下方法的一个关键组成部分。