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High-throughput immunoproteomics for cancer biomarker discovery

用于癌症生物标志物发现的高通量免疫蛋白质组学

基本信息

批准号：
10688268
负责人：
Karen Sue Anderson
金额：
$ 96.22万
依托单位：
ARIZONA STATE UNIVERSITY-TEMPE CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2027-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10688268
关键词：
ART protein Academic Medical Centers Address Adoption Antibodies Autoantibodies Autoantigens B-Lymphocyte Epitopes B-Lymphocytes Benign Binding Biological Assay Biological Markers Blinded Blood Tests Boston Breast CLIA certified Cancer Center Cancer Control Cancer Detection Cancer Patient Cancer Vaccines Carcinogenesis Mechanism Clinical Collaborations Collection Complement Data Development Diagnostic Disease Early Detection Research Network Early Diagnosis Environment Enzyme-Linked Immunosorbent Assay Epitopes Funding Future Genes German population Glycoproteins Goals Heterogeneity Human Human Papillomavirus Image Immune Immune Sera Immune response Immunity Immunoassay Immunoglobulin G Immunologic Markers Immunology Individual Laboratories Length Lung nodule Malignant - descriptor Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of ovary Measures Methods Migration Assay Monitor Morbidity - disease rate Mutation NCI Center for Cancer Research Nodule Nucleic Acids Ovarian Persons Phase Phase III Clinical Trials Plasmids Polysaccharides Post-Translational Protein Processing Predictive Value Production Protein Array Protein Glycosylation Proteins Proteome Proteomics Reproducibility Sampling Screening for Ovarian Cancer Screening for cancer Serology Serology test Serum Specificity Speed Structural Protein Structure Symptoms System Technology Tumor Antigens Universities Vaccine Design Vaccines Validation antimicrobial assay development base biomarker discovery biomarker panel biomarker signature cancer biomarkers cancer diagnosis candidate marker circulating biomarkers clinical application clinical assay development clinical diagnosis clinical diagnostics clinical implementation coronavirus disease density design diagnostic platform disease heterogeneity experience glycosylation glycosyltransferase immunogenic immunogenicity improved improved outcome innovation instrument lung cancer screening microbial microorganism antigen migration mortality multiplex assay novel operation polypeptide prevent protein biomarkers protein expression protein structure rapid detection rapid technique repository respiratory pathogen screening serological marker skills specific biomarkers structural glycoprotein technology development tumor validation studies

项目摘要

Project Summary/Abstract The goal of the ASU Biomarker Characterization Center is to improve ovarian and lung cancer screening through the development of biologically-relevant circulating immune biomarkers. The scientific approach of our Center is based on several fundamental principles. First, that altered cancer protein expression, structure, and post- translational modifications induce host autoantibodies to create circulating biomarkers. Second, that alterations in microbial antigen expression (such as respiratory pathogens) also induce immunity, often detected in benign rather than malignant disease. Third, that the protein modifications, as well as the immune response to these neoantigenic structures, are heterogeneous between people, and that serologic biomarkers may complement circulating protein biomarkers. We will take a systems immunology approach to discover three types of antibodies, anti-microbial antibodies, autoantibodies and anti-aberrant glycoprotein antibodies. Our proposal builds on our extensive experiences with cancer biomarker discovery and immunoproteomics technology development. Our previous results on autoantibody biomarkers have been confirmed in blinded phase 2 multicenter validation studies and led to a CLIA-certified commercial blood test. Our results have shown that multiplexed panels of autoantibodies are required for adequate predictive value. With prior EDRN support, we have developed a set of innovative immunoproteomics technologies, namely high-density nucleic acid programmable protein array (HD-NAPPA), contra-capture protein array (CCPA) and multiplexed in solution protein array (MISPA), that, together with the largest full-length human and microbial gene collection at our DNASU plasmid repository, enable us to study antibodies against the full human proteome, microbial proteomes and the human O-glycoproteome for antibody biomarker signatures in cancer. Our Meso Scale Diagnostics (MSD) team has fielded over 3,000 instruments worldwide, and over 700 commercially available biomarker assay kits. Our expertise at serologic assay development was selected by Operation Warp Speed to use the V-PLEX® serology panels as the basis of its standard binding assays for immunogenicity assessments in all funded Phase III clinical trials of COVID vaccines. We will use our MSD MultiArray platform to migrate the top serologic and protein markers for their utility in our target clinical applications. We will collaborate with experts on lung and ovarian cancer screening at Vanderbilt University Medical Center, Boston University, MD Anderson Cancer Center, and German Cancer Research Center, who will also provide access to high-quality well-characterized samples to develop circulating biomarkers to enhance ovarian cancer screening or to distinguish benign from malignant pulmonary nodules. Adhering to the principles of PRoBE design, we will perform Phase I discovery by screening protein arrays with cancer patient and control sera for cancer or control-specific antibodies. Candidate biomarkers for both lung and ovarian cancers will undergo Phase 2 validation.

项目概要/摘要亚利桑那州立大学生物标志物表征中心的目标是通过以下方式改善卵巢癌和肺癌筛查：生物学相关循环免疫生物标志物的开发。我们中心的科学方法是基于几个基本原则。首先，这改变了癌症蛋白质的表达、结构和后翻译修饰诱导宿主自身抗体产生循环生物标志物。二、修改之处微生物抗原的表达（例如呼吸道病原体）也会诱导免疫，通常在良性中检测到而不是恶性疾病。第三，蛋白质修饰以及对这些蛋白质的免疫反应新抗原结构在人与人之间存在异质性，血清学生物标志物可以补充循环蛋白质生物标志物。我们将采用系统免疫学方法来发现三种类型抗体、抗微生物抗体、自身抗体和抗异常糖蛋白抗体。我们的建议建立在我们在癌症生物标志物发现和免疫蛋白质组学技术方面的丰富经验之上发展。我们之前关于自身抗体生物标志物的结果已在盲法第 2 阶段得到证实多中心验证研究并导致了 CLIA 认证的商业血液测试。我们的结果表明需要多重自身抗体组才能获得足够的预测价值。凭借先前的 EDRN 支持，我们开发了一套创新的免疫蛋白质组学技术，即高密度核酸可编程蛋白质阵列 (HD-NAPPA)、反捕获蛋白质阵列 (CCPA) 和溶液中多重分析蛋白质阵列 (MISPA)，以及我们最大的全长人类和微生物基因库 DNASU 质粒存储库，使我们能够研究针对完整人类蛋白质组、微生物蛋白质组的抗体以及用于癌症抗体生物标志物特征的人类 O-糖蛋白组。我们的细观尺度诊断 (MSD) 团队已在全球部署了 3,000 多台仪器和 700 多种商用生物标志物检测套件。我们在血清学检测开发方面的专业知识被Operation Warp Speed 选择使用 V-PLEX® 血清学小组作为其标准结合测定的基础，用于所有资助阶段的免疫原性评估新冠疫苗III期临床试验。我们将使用我们的 MSD MultiArray 平台来迁移顶级血清学和蛋白质标记物在我们的目标临床应用中的实用性。我们将与肺科专家合作范德比尔特大学医学中心、波士顿大学、MD 安德森癌症中心的卵巢癌筛查中心和德国癌症研究中心，他们还将提供高质量的、特征明确的研究用于开发循环生物标志物的样本，以增强卵巢癌筛查或区分良性和恶性恶性肺部结节。秉承 PRoBE 设计原则，我们将通过以下方式进行第一阶段发现：使用癌症患者和对照血清筛选蛋白质阵列中的癌症或对照特异性抗体。候选人肺癌和卵巢癌的生物标志物将接受第二阶段验证。