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）：该提案的目的是基于两个高亲和力，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。这些人源性的TCR是根据识别HIV肽抗原以及被感染细胞显示的各自的变异的能力选择的。以单链格式（SCTCR）创建的TCR将配备细胞因子IL-15/IL-15R1SU或人类免疫球蛋白重链链IgG1 FC FC结构域，通过遗传操纵。这些基于SCTCR的免疫活性分子将以二聚体形式以增强其靶向表位的结合，这是由于它们的自发增长。在本阶段提案的具体目的下，这些融合分子将被表征以确保它们保留其双功能活动。他们将进一步评估其针对肽载的抗原细胞和HIV感染的CD4+细胞的细胞毒性活性的能力。另外，将在人源化转基因小鼠中评估分子的药代动力学特性。这些数据将有助于Altor在该项目的下一阶段中选择基于TCR的免疫治疗分子，以进一步进行临床和临床发育。成功开发具有不同抗原识别能力的两种TCR融合蛋白将允许旨在绕过HIV逃生变体的联合治疗。广泛靶向HIV感染的细胞。该项目的最终目的是将融合作为可注射疗法，以实现强大的，有针对性的，先天的免疫反应，以消除受感染细胞中的HIV储量，当时患者通过当前的Haart治疗剂将患者保持在最小的残基疾病疾病阶段。这种针对病毒感染细胞的新型策略与主要旨在抑制HIV复制或感染性的目前方法明显不同。公共卫生相关性：该建议是基于使用两个高亲和力，特异性，可溶性T细胞受体（TCR）作为HIV感染细胞的靶向分子而创建免疫治疗剂。这些TCR是根据它们识别HIV肽抗原以及被感染细胞显示的已知变体的能力选择的。如果成功，这些基于SCTCR的免疫活性分子将用于一种被动免疫治疗方法，以刺激针对感染HIV感染的细胞的靶向，有效，先天的免疫反应。我们的最终目标是使用这些分子消除受感染患者的HIV库。