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.

此应用程序高度响应RFA(AI-18-017)的主要目标，即支持开发 具有免疫调节作用的下一代生物制品可能导致艾滋病毒的长期缓解。 HIV感染的功能性治疗因HIV感染者的免疫系统无力而受阻 个体在重新激活后有效地消除潜伏感染的细胞，导致复发 停止抗逆转录病毒治疗后的病毒血症。我们建议利用我们日益增长的对准确 动员强大T细胞反应的信号和分子以及复杂的蛋白质设计和工程 构建高稳定二聚体免疫球蛋白Fc融合新型免疫刺激生物制品的原理 蛋白质，称为SynTacs。这些生物制剂通过MHC介导的已定义的递呈来模拟APC功能 通过传递共刺激和/或细胞因子信号，将多肽转化为TCR。SynTac的关键要素 结构是使用单链MHC分子，共价连接到定义的HIV衍生多肽作为 触发主TCR激活信号的目标模块。同时，SynTac以共价方式提供 将共刺激配体或细胞因子连接到靶向HIV特异性CD8+T细胞以提供共刺激 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来验证该方法， SL9，与协同刺激的-CD28或4-1BBL4-1BBL分子相连，这些分子特异性地激活和扩大初级 HIV感染者的SL9特异性CD8+T细胞。我们建议开发HIV特异的SynTacs和 确定最佳的共刺激和/或细胞因子信号，使其能够作为靶向生物制剂发挥作用 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 最有效的清除感染艾滋病毒的T细胞的能力。我们将测定SynTac的体内容量 激活、扩增和分化HIV特异性CD8+T细胞的生物制剂，能够防止复发 通过使用一种新的人源化小鼠模型消除再次激活的潜伏感染细胞的病毒血症 发展起来的。作为另一种方法，我们还建议利用艾滋病毒特异性CAR的潜在潜力-- 与单链抗体等重组免疫受体识别抗原的T细胞，而不是MHC限制性的T细胞 TCRs，通过开发一种与CAR-T免疫受体结合的替代生物、SynTac样分子来实现 提供最佳的共刺激和/或细胞因子信号，以放大体内HIV特异性CAR-T细胞的功能。