Core B: Antibody/Ig fusion protein core

核心B：抗体​​/Ig融合蛋白核心

• 批准号: 10686062
• 负责人: Gordon James Freeman
• 金额: $ 13.24万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10686062
• 关键词: Animal Model; Antibodies; Antibody Response; Autoimmunity; Biological; CD8-Positive T-Lymphocytes; CTLA4 gene; Cells; Characteristics; Chimeric Proteins; Chronic; Clinical Trials; Core Protein; Cytoplasmic Tail; Data; Defect; Development; Disease; Drug Targeting; Epitopes; Experimental Models; FOXP3 gene; Functional disorder; Funding; Generations; Goals; Human; Hybridomas; ITIM; Immune; Immune response; Immune system; Individual; Infection; Knockout Mice; Ligands; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Mediator; Mission; Modeling; Monitor; Monoclonal Antibodies; Mus; Mutate; Nivolumab; PD-1 blockade; PD-1 pathway; Pathway interactions; Pharmaceutical Preparations; Production; Progress Reports; Proteins; Reagent; Recombinant DNA; Recombinants; Recovery; Regulatory T-Lymphocyte; Renal carcinoma; Research Personnel; Role; Signal Transduction; Structure; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Techniques; Therapeutic; Time; Translating; Translations; Transplantation; Tyrosine Phosphorylation; Virus Diseases; Work; acute infection; cancer clinical trial; cancer immunotherapy; cancer therapy; chronic graft versus host disease; chronic infection; cost efficient; crosslink; exhaust; exhaustion; human disease; insight; melanoma; member; novel; novel therapeutics; pembrolizumab; programmed cell death ligand 1; programmed cell death protein 1; programs; reagent standardization; receptor; success; tool; tumor

Core B, the Antibody / Ig Fusion Core, provides an important means by which the PPG will achieve its goals of understanding the immune response in tolerance, autoimmunity and infection. Core B will coordinate the use of mAb and Ig fusion proteins to enable the study of the roles of the PD-1 and other coinhibitory pathways in regulating immune responses during acute and chronic infection, chronic graft versus host disease (cGVHD), and autoimmunity. To achieve these goals Core B has the following aims: Aim 1: To maintain and produce existing and newly generated mAbs and Ig fusion proteins for PPG investigators. An extensive set of mAbs and fusion proteins against coinhibitory molecules has been generated in previous cycles of this PPG and these will continue to be produced as well as characterized for additional activities and uses. Aim 2: To generate novel monoclonal antibodies and Ig fusion proteins to study the function and expression of coinhibitory receptors and ligands. CD112R and CD101 are newly identified co-inhibitory molecules that impact T cell exhaustion and the PD-1 pathway. Core B will generate novel antibodies that will facilitate analysis of the function and expression of coinhibitory molecules particularly CD112R, CD101 and PD-1/PD-L pathway members as well as other coinhibitory pathways. These include novel mouse anti-mouse antibodies made in knockout mice that see novel epitopes and facilitate long-term treatment of mice without anti-antibody responses. These novel mouse anti-mouse mAbs will also be made as recombinant mAbs with mutated Fc to eliminate effects due to cell depletion or FcR signaling. This best models PD-1 mAbs used in clinical trials. Tyrosine phosphorylation of the PD-1 cytoplasmic domain mediates PD-1 biological activity. Core B will make phospho PD-1 ITIM mAbs and together with our phospho PD-1 ITSM mAb, use these to monitor PD-1 signaling and understand the roles of the PD-1 ITSM and ITIM motifs in regulating different T cell subsets in different disease states. The production of these critical reagents by a core not only will be time and cost efficient, but also provide standardized reagents that will facilitate comparison of data by investigators in this PPG. Core B will work closely with all PPG investigators, providing mAbs and Ig fusion proteins and identifying new needs. These reagents will allow PPG investigators to develop a comprehensive understanding of the roles of positive and negative second signals in modulating T cell activation, tolerance and exhaustion.

核心B，抗体/免疫球蛋白融合核心，为PPG实现其目标提供了一个重要的手段 了解耐受、自身免疫和感染方面的免疫反应。核心B将协调使用 MAb和Ig融合蛋白有助于研究PD-1和其他共抑制通路在血管内皮细胞瘤中的作用 调节急性和慢性感染、慢性移植物抗宿主病(CGVHD)期间的免疫反应， 和自身免疫力。为实现这些目标，核心B有以下目标： 目的1：维持和生产用于PPG的现有和新产生的mAbs和Ig融合蛋白 调查人员。 在以前的研究中，已经产生了一套广泛的针对共抑制分子的单抗和融合蛋白 将继续制作该PPG和这些PPG的循环，并将其用于其他活动和 用途。 目的2：制备新型单抗和免疫球蛋白融合蛋白，以研究其功能和功能。 共抑制受体和配体的表达。 CD112R和CD101是新发现的影响T细胞耗竭和PD-1的共同抑制分子 路径。核心B将产生新的抗体，将有助于分析功能和表达 共抑制分子，特别是CD112R、CD101和PD-1/PD-L通路成员等 共抑制通路。这些包括在基因敲除的小鼠中制造的新型小鼠抗小鼠抗体，这些小鼠可以看到 新的表位，便于长期治疗没有抗抗体反应的小鼠。这些新奇的鼠标 抗小鼠单抗也将制成带有突变Fc的重组单抗，以消除细胞影响 耗尽或FCR信号。这是临床试验中使用的PD-1单抗的最佳模型。酪氨酸蛋白的磷酸化 PD-1胞浆结构域介导PD-1的生物学活性。核心B将制造磷化Pd-1 ITIM单抗和 与我们的磷酸化PD-1 ITSM单抗一起，使用这些单抗来监测PD-1信号并了解其作用 PD-1ITSM和ITIM基序在不同疾病状态下调节不同的T细胞亚群。制作 对这些关键试剂按一个核心，不仅会节省时间和成本，而且还会提供标准化的 有助于调查人员在PPG中进行数据比较的试剂。核心B将与所有 PPG调查人员，提供单抗和Ig融合蛋白并确定新的需求。这些试剂将允许 PPG调查人员全面了解积极和消极秒的作用 调节T细胞激活、耐受和衰竭的信号。