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Core B: Antibody/Ig fusion protein core

核心B：抗体/Ig融合蛋白核心

基本信息

批准号：
10470785
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
项目类别：
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/10470785
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 of activation protein 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

项目摘要

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/ IG融合核心，提供了PPG实现其目标的重要手段，了解耐受性、自身免疫和感染中的免疫反应。核心B将协调使用 mAb和IG融合蛋白，以使研究PD-1和其他共抑制途径的作用，在急性和慢性感染期间调节免疫应答，慢性移植物抗宿主病（cGVHD），和自身免疫为实现这些目标，核心B有以下目标：目的1：维持和生产PPG的现有和新产生的mAb和IG融合蛋白 investigators. 在先前的研究中已经产生了针对共抑制分子的一组广泛的mAb和融合蛋白。本PPG的周期，这些周期将继续生产，并针对其他活动进行表征，使用. 目的2：制备新型单克隆抗体和IG融合蛋白，研究其功能和生物学特性。共抑制受体和配体的表达。 CD 112 R和CD 101是新发现的影响T细胞耗竭和PD-1的共抑制分子。通路核心B将产生新的抗体，这将有助于分析的功能和表达，共抑制分子，特别是CD 112 R、CD 101和PD-1/PD-L通路成员以及其他共抑制通路这些包括在基因敲除小鼠中制备的新型小鼠抗小鼠抗体，新的表位，并促进长期治疗小鼠而无抗抗体应答。这些新奇的老鼠抗小鼠mAb也将被制备为具有突变Fc的重组mAb，以消除由于细胞毒性引起的效应。耗尽或FcR信号传导。这是临床试验中使用的PD-1 mAb的最佳模型。的酪氨酸磷酸化 PD-1胞质结构域介导PD-1生物活性。核心B将产生磷酸PD-1 ITIM mAb，与我们的磷酸化PD-1 ITSM mAb一起，使用这些来监测PD-1信号传导，并了解 PD-1 ITSM和ITIM基序在不同疾病状态下调节不同T细胞亚群。生产这些关键试剂的核心不仅将是时间和成本效益，而且还提供标准化的有助于研究者在本PPG中比较数据的试剂。核心B将与所有 PPG研究人员，提供单克隆抗体和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的第二个作用在调节T细胞活化、耐受性和耗竭中的信号。