Creation of TCR-based Immunotherapeutic Targeting HIV-1

描述（由申请人提供）：本提案的目标是创建基于两种高亲和力，hiv特异性，可溶性T细胞受体（tcr）的免疫疗法，作为hiv感染细胞的靶向分子。这些人类衍生的tcr是根据它们识别HIV肽抗原的能力以及它们在感染细胞中显示的已知变体来选择的。通过基因操作，以单链格式（scTCRs）创建的TCRs将配备细胞因子IL-15/IL-15R1Su或人免疫球蛋白重链IgG1 Fc结构域。这些基于sctcr的免疫活性分子将以二聚体形式存在，以增强其与目标表位的结合，因为它们的亲和力增加。根据第一阶段提案的具体目标，这些融合分子将被表征，以确保它们保留其双功能活性。将进一步评估它们对肽负载抗原呈递细胞和hiv感染的CD4+细胞引发细胞毒性活性的能力。此外，这些分子的药代动力学性质将在人源化转基因小鼠中进行评估。这些数据将帮助Altor选择潜在的基于tcr的免疫治疗分子，用于该项目下一阶段的临床前和临床开发。成功开发两种具有不同抗原识别能力的TCR融合蛋白将允许设计一种联合治疗，以绕过HIV逃逸变体和。广泛靶向hiv感染细胞。该项目的最终目标是，当患者通过目前的HAART治疗方案维持在最小残留疾病阶段时，将融合物作为可注射疗法，建立强大的、靶向的先天免疫反应，以消除受感染细胞中的HIV储存库。这种针对病毒感染细胞的新策略明显不同于目前主要旨在抑制HIV复制或传染性的方法。公共卫生相关性：该建议是基于使用两种高亲和力、HIV特异性、可溶性T细胞受体（TCRs）作为HIV感染细胞的靶向分子来创建免疫疗法。这些tcr是根据它们识别HIV肽抗原的能力以及它们在感染细胞中显示的已知变体来选择的。如果成功，这些基于sctcr的免疫活性分子将被用于被动免疫治疗方法，以刺激针对hiv感染细胞的靶向、有效的先天免疫反应。我们的最终目标是利用这些分子消除感染患者体内的HIV病毒库。

DESCRIPTION (provided by applicant): The goal of this proposal is to create immunotherapeutics based on two high-affinity, HIV-specific, soluble T cell receptors (TCRs) as targeting molecules for HIV-infected cells. These human-derived TCRs were selected based on their ability to recognize HIV peptide antigens as well as their known respective variants displayed by the infected cells. The TCRs, created in a single-chain format (scTCRs), will be equipped with cytokine IL-15/IL-15R1Su or the human immunoglobulin heavy chain IgG1 Fc domain, through genetic manipulation. These scTCR-based immuno-active molecules will be in a dimeric form to enhance binding to their targeted epitopes due to their increase in avidity. Under the specific aims of this Phase I proposal, these fusion molecules will be characterized to ensure that they retain their bi-functional activities. They will be further assessed for their ability to elicit cytotoxic activity against peptide-loaded antigen- presenting cells and HIV-infected CD4+ cells. Additionally, the pharmacokinetic properties of the molecules will be evaluated in humanized transgenic mice. These data will assist Altor in selecting potential TCR-based immunotherapeutic molecules for further pre-clinical and clinical development under the next phase of this project. Successful development of two TCR fusion proteins with different antigen-recognition capabilities will allow for a combined therapy designed to circumvent HIV escape variants and. broadly target HIV-infected cells. The ultimate objective of this project is to use the fusions as injectable therapeutics to mount robust, targeted, innate immune responses to eliminate HIV reservoirs in infected cells when patients are maintained at the minimal-residual-disease stage via current HAART regimens. This novel strategy targeting virally infected cells is markedly different from current approaches aimed primarily at suppressing HIV replication or infectivity. PUBLIC HEALTH RELEVANCE: This proposal is to create immunotherapeutics based on the use of two high-affinity, HIV- specific, soluble T cell receptors (TCRs) as targeting molecules for HIV-infected cells. These TCRs were selected based on their ability to recognize HIV peptide antigens as well as their known respective variants displayed by the infected cells. If successful, these scTCR-based immuno-active molecules will then be used in a passive immune therapy approach to stimulate targeted, potent, innate immune responses against HIV-infected cells. Our ultimate goal is to use these molecules to eliminate the HIV reservoir in infected patients.