Ultralong CDR3 antibodies targeting exhausted T cells

针对耗尽 T 细胞的超长 CDR3 抗体

基本信息

批准号：
9894677
负责人：
Vaughn Vasil Smider
金额：
$ 30.35万
依托单位：
APPLIED BIOMEDICAL SCIENCE INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-02-11 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9894677
关键词：
Amino Acids Antibodies Antibody Repertoire Antibody Therapy Antigen Targeting Antigens Binding Biology CD Antigens CTLA4 gene Cancer Model Cattle Cell Surface Proteins Cell surface Chronic Colon Carcinoma Color Communicable Diseases Complementarity Determining Regions Cysteine Diagnostic Diagnostics Research Drug Targeting Engineering Enzyme-Linked Immunosorbent Assay Epitopes FDA approved Flow Cytometry Glycocalyx Goals HIV Immune checkpoint inhibitor Immune response Immunity Immunize Immunoprecipitation In Vitro Investigational Therapies Killer Cells Label Left Length Leukocytes Light Lymphocyte Lymphocytic choriomeningitis virus MC38 Malignant Neoplasms Modeling Monoclonal Antibodies Pathway interactions Pharmaceutical Preparations Phenotype Play Polysaccharides Positioning Attribute Preparation Proteins Proteome Reagent Recombinants Refractory Reporter Research Rodent Role Structure Surface Surface Antigens T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Therapeutic antibodies Transgenic Mice base cancer immunotherapy chronic infection cytokine deep sequencing disulfide bond env Glycoproteins exhaust exhaustion in vivo melanoma mouse model new therapeutic target novel novel therapeutics prevent programmed cell death ligand 1 programmed cell death protein 1 receptor therapeutic candidate tool tumor tumor immunology

项目摘要

Abstract T cell exhaustion prevents effective immune responses against many tumors and chronic infectious diseases. Several antibody drugs termed “checkpoint inhibitors” target receptors (e.g. PD-1, PD-L1, CTLA4) on exhausted T cells and can reverse their phenotype, leading to re-activation and the ability to function as killer cells. While molecules such as PD-1, PD-L1, LAG-3, Tim-3, TIGIT and ICOS have been described as markers of exhausted T cells, the cell surface phenotype is insufficiently defined; thus, more markers and possible drug targets may exist on the surface of exhausted T cells. Cluster of Differentiation (or “CD”) molecules were traditionally defined based on the reactivity of monoclonal antibodies to the cell surface of leukocytes. These antibodies were identified by immunizing rodents with preparations of white blood cells. It has recently become clear that the antibody repertoires of different species are dramatically different with regards to their structural diversity. Cows, in particular, have heavy chain complementarity determining regions (CDR H3s) of up to 70 amino acids in length comprised of novel -ribbon “stalk” and disulfide bonded “knob” mini domain structures. This contrasts with rodents, where antibodies for most CD molecules were discovered, whose antibodies have flat binding surfaces comprised of very short (10 amino acids) CDR H3 loops. Cow antibodies have the ability to bind epitopes that are relatively refractory to other species’ repertoires, and provide a novel opportunity to further define the exhausted T cell surface. To this end, we will immunize cattle with exhausted T cells and identify unique antibody:antigen pairs and demonstrate functional activity of the antibodies by in vitro and in vivo reversal of the exhausted T cell phenotype. Antibodies from this research could serve as experimental therapeutics for cancer or chronic infection, diagnostics, or important research tools to further define exhausted T cell subsets and differentiation pathways.

抽象的 T细胞耗尽可防止有效的免疫复杂，以防止许多肿瘤和慢性传染性疾病。几种称为“检查点抑制剂”靶受体的抗体药物（例如PD-1，PD-L1， CTLA4）在耗尽的T细胞上，可以逆转其表型，导致重新激活和能力充当杀手细胞。而诸如PD-1，PD-L1，LAG-3，TIM-3，TIGIT和ICOS等分子已经描述为耗尽的T细胞的标记，细胞表面表型不足定义；因此，耗尽的T细胞表面可能存在更多的标记和可能的药物靶标。传统上根据反应性定义了分化（或“ CD”）分子的簇白细胞细胞表面的单克隆抗体。这些抗体通过用白细胞制剂对啮齿动物进行免疫。最近已经很清楚关于它们的结构，不同物种的抗体库有很大的不同多样性。牛特别是重链完整性确定区域（CDR H3S）新型ribbon“ stalk”和二硫键粘合的“旋钮” mini的长度最多70个氨基酸域结构。这与啮齿动物形成对比，大多数CD分子的抗体是发现的，其抗体具有扁平结合表面，非常短（10个氨基酸） CDR H3循环。牛抗体具有结合相对难治性的表位的能力物种的曲目，并提供了一个新的机会，可以进一步定义耗尽的T细胞表面。为此，我们将用耗尽的T细胞免疫牛并识别独特的抗体：抗原对并通过体外和体内逆转来证明抗体的功能活性 T细胞表型。这项研究的抗体可以作为癌症的实验疗法或慢性感染，诊断或重要的研究工具，以进一步定义耗尽的T细胞子集和分化途径。