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

• 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
• 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

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消除潜伏感染的细胞，导致复发 停止抗逆转录病毒治疗后出现病毒血症。我们建议利用我们对精确性的不断加深的理解 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 蛋白质，称为 synTacs。这些生物制剂通过 MHC 介导的定义的表达来模拟 APC 功能。 通过传递共刺激和/或细胞因子信号将肽转化为TCR。 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 完全激活 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。我们有 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，与共刺激 α-CD28 或 4-1BBL 分子连接，特异性激活和扩展初级 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 确定最佳共刺激和/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 发达。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， 传递最佳的共刺激和/或细胞因子信号，以放大 HIV 特异性 CAR-T 细胞的体内功能。