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Bispecific-Antibody-Drug Conjugates for Selective Targeting and Activation of the HIV Latent Reservoir

用于选择性靶向和激活 HIV 潜伏库的双特异性抗体药物偶联物

基本信息

批准号：
10222490
负责人：
DAVID D HO
金额：
$ 49.62万
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：
2017-07-25 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10222490
关键词：
Affinity Agonist Antibody-drug conjugates Avidity Belief Binding Biological Assay Bispecific Antibodies Blood Bromodomain Cell Fraction Cell Line Cells Clinical Clinical Trials Dose Engineering Exposure to Fluorescein HIV HIV Infections HIV-1 Histone Deacetylase Histone Deacetylase Inhibitor IL2RB gene In Vitro Individual Infection Laboratories Measures Memory Monoclonal Antibodies Outcome PTEN gene Pathway interactions Patients Peripheral Blood Mononuclear Cell Population Property Protein Kinase C Proviruses Reporting Rest Sleep Specificity Surface T memory cell T-Lymphocyte Subsets TNFRSF6 gene Therapeutic Index Tissues Toxic effect Variant Viral Viremia Virus antibody engineering antiretroviral therapy cell type cellular targeting clinically relevant experience falls humanized mouse in vitro activity in vivo inhibitor/antagonist interest latent HIV reservoir mouse model novel strategies programmed cell death protein 1 purge stem cells systemic toxicity viral rebound

项目摘要

PROJECT SUMMARY/ABSTRACT Latent HIV reservoirs, primarily comprised of HIV-infected and long-lived subpopulations of CD4+ resting memory T cells are established during the earliest stage of infection. While currently available antiretroviral therapies (ART) can reduce the level of HIV in blood to an undetectable level, they cannot eliminate the latent reservoir, thereby imposing a major obstacle to curing the infection. A number of latency reversal agents (LRAs) has shown activity in vitro, but all have little or no impact on the latent reservoir in clinical trials to date. Because increasing the doses of LRAs is prohibitive in their current forms due to the potential for increased systemic toxicity, alternative strategies for the specific targeting and activation of the latent HIV reservoir are needed. We therefore propose to harness the exquisite specificity of monoclonal antibodies (mAbs) and to further increase their specificity through the construction of bispecific antibodies for targeting the HIV latent reservoir. We will engineer a panel of bispecific antibodies capable of targeting the narrow subsets of CD4+ resting memory T cells that have been characterized as the likely HIV reservoir cells in blood and tissues. We will then conjugate a panel of LRAs to each of the promising bispecific antibodies to deliver such agents preferentially to the latently infected cells. To evaluate the activity of all of our engineered bispecific antibodies and antibody-drug conjugates (ADCs), we will take an iterative approach to assess binding affinity and avidity, selectivity of LRA delivery, and HIV activation from the latent reservoir in vitro or ex vivo. The ADCs with the most promising in vitro or ex vivo properties will be further evaluated for their impact on the latent reservoir in vivo using a humanized mouse model of HIV infection and treatment. The underlying hypothesis of the proposed studies is that the use of bispecific antibodies to concentrate LRAs in cell populations harboring latent HIV, while minimizing the exposure to cells that are virus free, could markedly increase the therapeutic index of LRAs by several orders of magnitude. We believe that our proposal offers a promising and novel strategy for highly specific and potent activation of HIV reservoir cells, and it is our belief that one or several of our engineered antibody drug conjugates could become a key component in a multi-pronged approach to eliminating the latent reservoir and curing HIV-1 infection.

项目概要/摘要潜伏 HIV 储存库，主要由 HIV 感染者和长寿命 CD4+ 静息亚群组成记忆 T 细胞是在感染的最早阶段建立的。虽然目前可用的抗逆转录病毒药物治疗（ART）可以将血液中的艾滋病毒水平降低到不可检测的水平，但不能消除潜伏的艾滋病毒水库，从而对治愈感染造成重大障碍。一些延迟逆转剂（LRA）已在体外显示出活性，但迄今为止在临床试验中对潜在储存库的影响很小或没有影响。因为以目前的形式增加 LRA 的剂量是禁止的，因为可能会增加系统毒性，特异性靶向和激活潜伏 HIV 储存库的替代策略是需要。因此，我们建议利用单克隆抗体 (mAb) 的精致特异性并通过构建针对潜伏 HIV 的双特异性抗体，进一步提高其特异性水库。我们将设计一组能够靶向 CD4+ 狭窄子集的双特异性抗体静息记忆 T 细胞已被定性为血液和组织中可能的 HIV 储存细胞。我们然后将一组 LRA 与每种有前途的双特异性抗体结合以递送此类试剂优先于潜伏感染的细胞。评估我们所有工程双特异性抗体的活性和抗体药物偶联物（ADC），我们将采取迭代方法来评估结合亲和力和亲合力， LRA 递送的选择性，以及体外或离体潜伏病毒库的 HIV 激活。 ADC 具有最有希望的体外或离体特性将进一步评估其对潜在储存库的影响体内使用HIV感染和治疗的人源化小鼠模型。其基本假设是拟议的研究是使用双特异性抗体将 LRA 集中在含有 LRA 的细胞群中潜伏的艾滋病毒，同时最大限度地减少与无病毒细胞的接触，可以显着提高治疗效果 LRA 的指数提高了几个数量级。我们相信我们的建议提供了一个有前途且新颖的一种高度特异性和有效激活 HIV 储存细胞的策略，我们相信，其中一种或多种我们的工程抗体药物偶联物可能成为多管齐下的方法的关键组成部分消除潜伏病毒库并治愈 HIV-1 感染。