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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.

项目总结/文摘