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: 9908044
• 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/9908044
• 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; 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

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.

该应用对RFA（AI-18-017）的主要目标高度响应，以支持开发 具有免疫调节作用的下一代生物制剂可能导致持久的HIV缓解。 HIV感染的功能治愈已被HIV感染的免疫系统所阻碍 重新激活后，个体有效地消除了有效的潜在感染细胞，导致 停止抗逆转录病毒疗法后的病毒血症。我们建议利用我们对精度的日益理解 动员有效的T细胞反应以及复杂蛋白质设计和工程的信号和分子 构建新型免疫刺激生物制剂的原理，由高度稳定的二聚体IgG FC融合组成 蛋白质，称为Santacs。这些生物制剂通过MHC介导的定义表现来模拟APC功能 通过递送共刺激和/或细胞因子信号的TCR肽。 Santac的关键要素 结构是单链MHC分子的使用，共价链接到定义的HIV衍生肽作为一个 针对触发主要TCR激活信号的模块。同时，Santac共价提供 连接的共刺激配体或细胞因子与靶向的HIV特异性CD8+ T细胞可提供共刺激性 信号完全激活T细胞或细胞因子信号以驱动T细胞增殖和/或分化。我们有 通过构建针对HLA-A*0201限制的HIV GAG表位的语法来验证了这种方法， SL9，与专门激活和扩展的主要基本的共刺激性-CD28或4-1BBL分子相关 来自HIV感染的个体的SL9特异性CD8+ T细胞。我们建议开发艾滋病毒特异性的义务和 确定最佳的共刺激和/或细胞因子信号，使其能够充当靶向生物制剂 能够刺激，扩展和区分有选择性的患者衍生的HIV特异性CD8+ T细胞 消除感染HIV的T细胞的最有效能力。我们将确定Santac的体内能力 生物制剂激活，扩展和区分HIV特异性CD8+ T细胞，能够预防复发 通过使用新型的人源性小鼠模型消除重新激活的潜在感染细胞，病毒血症我们有 发达。作为另一种方法，我们还建议利用HIV特异性汽车的潜在效力 T细胞，识别具有重组免疫感受器（如SCFV）而不是MHC限制性的抗原 TCR，通过开发一种与CAR-T免疫受体结合的替代生物学，类似于Syntac的分子 传递最佳的共刺激和/或细胞因子信号，以在体内功能扩增HIV特异性CAR-T细胞。