Creation of TCR-based Immunotherapeutic Targeting HIV-1

描述(由申请人提供)：这项提案的目标是创造基于两个高亲和力的、HIV特异性的、可溶的T细胞受体(TCR)作为HIV感染细胞靶向分子的免疫疗法。这些人类来源的TCR是根据它们识别HIV多肽抗原的能力以及它们已知的由感染细胞显示的各自变体来选择的。以单链形式(ScTCRs)创建的TCRs将通过基因操作配备细胞因子IL-15/IL-15R1Su或人类免疫球蛋白重链IgG1Fc结构域。由于亲和力的增加，这些基于scTCR的免疫活性分子将以二聚体的形式增强与其目标表位的结合。根据这一第一阶段提案的具体目标，将对这些融合分子进行表征，以确保它们保持其双功能活性。将进一步评估它们对多肽抗原呈递细胞和HIV感染的CD4+细胞的细胞毒活性。此外，这些分子的药代动力学特性将在人源化的转基因小鼠中进行评估。这些数据将帮助Altor为该项目下一阶段的进一步临床前和临床开发选择潜在的基于TCR的免疫治疗分子。两种具有不同抗原识别能力的TCR融合蛋白的成功开发将使一种旨在绕过艾滋病毒逃逸变异株和。广泛针对感染艾滋病毒的细胞。该项目的最终目标是，当患者通过目前的HAART方案维持在最小残留疾病阶段时，将融合作为可注射的疗法来建立强大的、有针对性的先天免疫反应，以消除感染细胞中的艾滋病毒储存库。这一针对病毒感染细胞的新策略与目前主要旨在抑制艾滋病毒复制或传染性的方法有显着不同。与公共卫生相关：这项提议是基于使用两个高亲和力的、HIV特异的、可溶的T细胞受体(TCR)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多肽抗原的能力以及它们已知的由感染细胞显示的各自变体来选择的。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感染细胞的定向、有效的先天免疫反应。我们的最终目标是使用这些分子来消除感染患者中的艾滋病毒宿主。

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.