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.

项目摘要/摘要潜在的HIV储藏，主要由CD4+休息的HIV感染和长期寿命的亚群组成记忆T细胞是在最早的感染阶段建立的。虽然目前可用的抗逆转录病毒疗法（ART）可以将血液中的艾滋病毒水平降低到无法检测到的水平，它们无法消除潜伏水库，从而施加了治愈感染的主要障碍。许多延迟反转代理（LRA）在体外显示了活性，但迄今为止，在临床试验中，所有这些都对潜在储层几乎没有影响。因为增加LRA的剂量在其当前形式上是由于增加的潜力全身毒性，潜在的HIV水库的特定靶向和激活的替代策略是需要。因此，我们建议利用单克隆抗体（mAb）的精致特异性和通过构建双特异性抗体来进一步提高其特异性水库。我们将设计一个双特异性抗体，能够靶向CD4+的狭窄子集静止的记忆T细胞已被表征为血液和组织中可能的HIV储存细胞。我们然后，将与每种有希望的双特异性抗体结合一组LRA，以递送此类药物优先地对潜在感染的细胞。评估我们所有工程双特异性抗体的活性和抗体 - 药物结合物（ADC），我们将采用一种迭代方法来评估结合亲和力和亲和力， LRA递送的选择性，从体外或离体中从潜在储层中激活HIV。 ADC与最有前途的体外或体内特性将进一步评估其对潜在储层的影响使用人源化的HIV感染和治疗的人源化小鼠模型的体内。基本假设拟议的研究是使用双特异性抗体将LRA浓缩在携带的细胞群体中潜在的艾滋病毒，同时最大程度地降低了无病毒细胞的暴露，可能会显着增加治疗性 LRA的指数通过几个数量级。我们相信我们的建议提供了有希望的新颖高度特异性和有效激活HIV储藏细胞的策略，我们相信一个或几个我们工程化的抗体药物缀合物可能会成为多方面方法的关键组成部分消除潜在储层和治愈HIV-1感染。