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：
9752177
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/9752177
关键词：
Adoptive Transfer Antigen-Presenting Cells Antigens Architecture Back Binding Biological 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 design dimer humanized mouse in vivo in vivo Model 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，以支持开发具有免疫调节作用的下一代生物制剂，可能会导致艾滋病毒的长期缓解。 HIV感染者免疫系统的无力阻碍了HIV感染的功能性治愈个体在重新激活后有效地消除潜伏的感染细胞，导致复发我们建议利用我们对精确病毒血症的日益了解。调动有效 T 细胞反应和复杂蛋白质设计和工程的信号和分子构建由高度稳定的二聚体 IgG Fc 融合体组成的新型免疫刺激生物制剂的原理这些生物制剂通过 MHC 介导的特定表达来模拟 APC 功能。通过传递共刺激和/或细胞因子信号将肽转化为 TCRs synTac 的关键要素。结构是使用单链 MHC 分子，与定义的 HIV 衍生肽共价连接作为触发主要 TCR 激活信号的靶向模块同时，synTac 共价传递。将共刺激配体或细胞因子与靶向的 HIV 特异性 CD8+ T 细胞连接起来，以提供共刺激我们有充分激活 T 细胞的信号或驱动 T 细胞增殖和/或分化的细胞因子信号。通过构建针对 HLA-A*0201 限制性 HIV Gag 表位的 synTacs 验证了该方法， SL9，与特异性激活和初级扩增的共刺激 α-CD28 或 4-1BBL 分子相连来自 HIV 感染者的 SL9 特异性 CD8+ T 细胞我们建议开发 HIV 特异性 synTacs 和确定成本最优的刺激和/或细胞因子信号，使它们能够作为靶向生物制剂能够选择性地刺激、扩增和分化患者来源的 HIV 特异性 CD8+ T 细胞消除 HIV 感染 T 细胞的最有效能力我们将确定 synTac 的体内能力。激活、扩增和分化 HIV 特异性 CD8+ T 细胞的生物制剂，能够预防复发通过使用我们的新型人源化小鼠模型消除重新激活的潜伏感染细胞来消除病毒血症作为一种替代方法，我们还建议利用 HIV 特异性 CAR-的潜在效力。 T 细胞，通过重组免疫受体（例如 scFv）而不是 MHC 限制的抗原来识别抗原 TCR，通过开发一种替代生物、synTac 样分子，与 CAR-T 免疫受体结合，传递成本最优的刺激和/或细胞因子信号，以放大 HIV 特异性 CAR-T 细胞的体内功能。