权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Novel Biologics Designed to Mobilize HIV-specific CTL for Sustained HIV Remission

旨在调动 HIV 特异性 CTL 以实现持续 HIV 缓解的新型生物制剂

基本信息

批准号：
10375382
负责人：
STEVEN C. ALMO
金额：
$ 82.92万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-05 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10375382
关键词：
Adoptive Transfer Antigen-Presenting Cells Antigens Architecture Back Binding Biological Biological Products Biological Response Modifiers CD28 gene CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell physiology Cells Cellular biology Chimeric Proteins Cytokine Signaling Cytomegalovirus Data Dendritic Cells Development Disease remission Elements Engineering Epitopes Equipment Generations Goals HIV HIV Infections HIV-1 HLA A*0201 antigen Histocompatibility Antigens Class I Human I-antigen Immune Immune response Immune system Immunoglobulin G Individual Intravenous Lead Ligands Link Mediating Modality Mus Pathway interactions Patients Peptide/MHC Complex Peptides Peripheral Blood Mononuclear Cell Population Pre-Clinical Model Production Protein Engineering Recombinants Recurrence Rest Signal Transduction Signaling Molecule Spleen Surface Antigens Synapses Systemic infection T cell response T-Cell Activation T-Cell Proliferation T-Lymphocyte TCR Activation Technical Expertise Viral Viremia Virus Diseases Withholding Treatment antigen-specific T cells antiretroviral therapy base chimeric antigen receptor T cells cytokine cytotoxic cytotoxic CD8 T cells design dimer humanized mouse in vivo in vivo Model latent HIV reservoir mouse model next generation novel prevent receptor scaffold treatment center

项目摘要

This application is highly responsive to the major goal of the RFA (AI-18-017) to support the development of next-generation biologics with immune-modulating effects that may lead to long-lasting HIV remission. Functional cure of HIV infection has been stymied by the inability of the immune system of HIV-infected individuals to eliminate effectively latently infected cells following reactivation, resulting in the recurrence of viremia after stopping antiretroviral therapy. We propose to exploit our increasing understanding of the precise signals and molecules that mobilize potent T cell responses and sophisticated protein design and engineering principles to construct novel immunostimulatory biologics consisting of highly stable dimeric IgG Fc-fusion proteins, termed synTacs. These biologics mimic APC functions by MHC-mediated presentation of defined peptides to TCRs with delivery of costimulatory and/or cytokine signals. The key element of the synTac architecture is the use of a single chain MHC molecule, covalently linked to a defined HIV-derived peptide as a targeting module that triggers the primary TCR activation signal. In parallel, the synTac delivers covalently linked costimulatory ligands or cytokines to the targeted HIV-specific CD8+ T cells to provide a costimulatory signal to activate fully the T cells or a cytokine signal to drive T cell proliferation and/or differentiation. We have validated this approach by constructing synTacs which target the HLA-A*0201-restricted HIV Gag epitope, SL9, linked to the costimulatory -CD28 or 4-1BBL molecules that specifically activated and expanded primary SL9-specific CD8+ T cells from HIV-infected individuals. We propose to develop HIV-specific synTacs and identify the optimal costimulatory and/or cytokine signals to enable them to function as targeted biologics capable of stimulating, expanding and differentiating selectively patient-derived HIV-specific CD8+ T cells with the most potent capacity to eliminate HIV-infected T cells. We will determine the in vivo capacity of synTac biologics to activate, expand and differentiate HIV-specific CD8+ T cells capable of preventing recurrent viremia by eliminating reactivated latently infected cells using a novel humanized mouse model we have developed. As an alternative approach, we also propose to harness the potential potency of HIV-specific CAR- T cells, which recognize antigen with recombinant immunoreceptors such as scFv rather than MHC-restricted TCRs, by developing an alternative biologic, synTac-like molecules that bind to the CAR-T immunoreceptor to deliver the optimal costimulatory and/or cytokine signals to amplify HIV-specific CAR-T cell in vivo function.

该应用程序高度响应RFA （AI-18-017）的主要目标，支持开发