Creation of TCR-based Immunotherapeutic Targeting HIV-1

创建基于 TCR 的靶向 HIV-1 的免疫疗法

• 批准号: 7685555
• 负责人: HING C. WONG
• 金额: $ 16.4万
• 依托单位: ALTOR BIOSCIENCE. LLC
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-04 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7685555
• 关键词: Affinity; Antigen-Presenting Cells; Antigens; Avidity; Binding; CD4 Positive T Lymphocytes; Cells; Chimeric Proteins; Clinical; Clinical Trials; Complex; Data; Development; Drug Kinetics; Ensure; Epitopes; Evaluation; Fc domain; Gagging; Genetic; Goals; HIV; HIV-1; Heavy-Chain Immunoglobulins; Highly Active Antiretroviral Therapy; Human; IgG1; Immune response; Immunotherapeutic agent; Immunotherapy; In Vitro; Injectable; Interleukin-15; Methods; Mus; Patients; Peptides; Pharmaceutical Preparations; Pharmacodynamics; Phase; Production; Property; Residual Neoplasm; Staging; T-Cell Receptor; Therapeutic; Toxicology; Transgenic Mice; Treatment Protocols; Variant; Viral Physiology; base; cytokine; cytotoxic; design; genetic manipulation; novel strategies; pre-clinical; public health relevance; therapy design

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.

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）作为HIV感染细胞靶向分子的免疫治疗剂。基于它们识别HIV肽抗原的能力以及由感染细胞展示的它们的已知的相应变体来选择这些人源TCR。以单链形式产生的TCR（scTCR）将通过遗传操作配备细胞因子IL-15/IL-15 R1 Su或人免疫球蛋白重链IgG 1 Fc结构域。这些基于scTCR的免疫活性分子将呈二聚体形式，以由于其亲合力的增加而增强与其靶向表位的结合。根据第一阶段提案的具体目标，将对这些融合分子进行表征，以确保它们保留其双功能活性。将进一步评估它们引发针对负载肽的抗原呈递细胞和HIV感染的CD 4+细胞的细胞毒性活性的能力。此外，将在人源化转基因小鼠中评价分子的药代动力学性质。这些数据将有助于Altor选择潜在的基于TCR的免疫抑制分子，用于该项目下一阶段的进一步临床前和临床开发。两种具有不同抗原识别能力的TCR融合蛋白的成功开发将允许设计用于规避HIV逃逸变体的联合治疗。广泛针对HIV感染细胞。该项目的最终目标是使用融合物作为可注射治疗剂，以建立强大的，有针对性的先天免疫反应，以消除感染细胞中的HIV储库，当患者通过当前的HAART方案维持在最小残留疾病阶段时。这种针对病毒感染细胞的新策略与目前主要旨在抑制HIV复制或感染性的方法明显不同。公共卫生相关性：该提议是基于使用两种高亲和力、HIV特异性、可溶性T细胞受体（TCR）作为HIV感染细胞的靶向分子来产生免疫治疗剂。这些TCR是基于它们识别HIV肽抗原的能力以及由感染细胞展示的它们已知的相应变体来选择的。如果成功，这些基于scTCR的免疫活性分子将用于被动免疫治疗方法，以刺激针对HIV感染细胞的靶向，强效，先天性免疫反应。我们的最终目标是利用这些分子来消除感染患者体内的HIV宿主。