Discovery Platform for Cancer Antigens

癌症抗原发现平台

基本信息

批准号：
8322775
负责人：
Kevin P. Claffey
金额：
$ 44.28万
依托单位：
UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-16 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8322775
关键词：
Antibodies Antibody Formation Antigen Targeting Antigens Automobile Driving Avastin Biochemistry Bioinformatics Biological Markers Biological Response Modifier Therapy Biology Breast Bypass Cancer Biology Cancer Detection Cancer Diagnostics Cell Surface Proteins Characteristics Clinical Clonal Expansion Communities Complex Detection Development Diagnosis Diagnostic Diagnostic Reagent Disease ERBB2 gene Epitopes Event Freezing Goals Heterogeneity Human Immune Immune response Immune system Immunoglobulin Somatic Hypermutation Individual Intention Laboratories Lesion Libraries Malignant Neoplasms Masks Methods Modality Molecular Molecular Biology Morbidity - disease rate Normal Cell Pathway interactions Patients Peptides Post-Translational Protein Processing Protein Array Proteins Proteomics Radiation Reaction Reagent Recombinant Antibody Recombinants Research Personnel Resistance Roche brand of trastuzumab Sampling Screening procedure Sentinel Lymph Node Site Technology Therapeutic anticancer research base bevacizumab cDNA Library cancer cell cancer recurrence cancer stem cell chemotherapy glycosylation humanized antibody improved malignant breast neoplasm mutant new therapeutic target novel novel therapeutics population based programs protein expression protein folding protein structure public health relevance sugar tool tumor tumor progression

项目摘要

DESCRIPTION (provided by applicant): Spontaneous breast and other cancers are often complex and heterogeneous. A current driving theme in the field of cancer biology is to refine our methods to characterize patient tumors on a molecular level such that therapies can be tailored to each individual patient. We have developed a method to utilize the patient's own immune response to isolate antibodies that they make against their cancer proteins. In the laboratory we synthesize these antibodies and identify novel cancer proteins targeted by these antibodies. The main goal of this application is to implement a platform-based method to isolate and identify tumor-specific antibodies and their cancer-specific antigens. This platform technology has the potential to yield hundreds of antibodies that can be used to target individual cancers that express the antigen recognized by these antibodies. It is the intention of these investigators to use these reagents to expand our understanding of breast cancer biology, detection of cancer specific biomarkers and as novel therapeutic treatments. These single domain antibodies are infinitely renewable and hold great promise as tools for population based biomarker screening and individualized patient-specific targeted therapy for advanced and metastatic disease. The specific aims of this application will focus on four specific goals: Specific Aim 1- Perform throughput platform screening of at least 40 breast cancer cases representing up to 65 total libraries and identification of an estimated 1000-1500 novel VH antibodies. Specific Aim 2- Identify the cognate antigens for 200-400 antigen driven VH single domain antibodies identified in Aim 1 based upon clonal expansion and somatic hypermutation scores. Specific Aim 3 - Validate identified antigens and their presentation in human breast cancer using multiplex large scale arrays. Specific Aim 4 - Assemble multiplex protein arrays of recombinant soluble domain antibodies and matching arrays of their cognate antigens for use in cancer diagnostic, screening and clinical targeting applications. PUBLIC HEALTH RELEVANCE: Discovery Platform for Cancer Antigens applies a unique biochemistry and molecular biology technology that we have developed that recovers antibodies from patients and identifies cancer proteins that the immune system has targeted as "abnormal". The incorporation of this platform will facilitate the development of reagents which will be useful in understanding cancer biology, detection reagents for diagnostic biomarker screening, as well as long-term potential for individualized therapeutics based upon the expression of these "abnormal" proteins in any patient. The platform will be applied primarily to breast cancer but holds great promise for applications to most other cancers. Finally, these reagents will be made available to the broad cancer research community to rapidly define their utility and application in multiple diagnostic and clinical therapeutic approaches.

描述（由申请人提供）：自发的乳房和其他癌症通常是复杂且异质的。癌症生物学领域的当前驾驶主题是完善我们在分子水平上表征患者肿瘤的方法，以便可以针对每个患者量身定制疗法。我们已经开发了一种方法来利用患者对抗癌蛋白产生的分离抗体的免疫反应。在实验室中，我们合成这些抗体并鉴定这些抗体靶向的新型癌症。该应用的主要目标是实施一种基于平台的方法来隔离和鉴定肿瘤特异性抗体及其癌症特异性抗原。该平台技术有可能产生数百种抗体，这些抗体可用于针对表达这些抗体识别的抗原的个体癌症。这些研究者的目的是使用这些试剂来扩展我们对乳腺癌生物学的理解，对癌症特定生物标志物的检测以及作为新型治疗方法。这些单域抗体是无限的可再生能源，并且具有巨大的希望，作为基于人群的生物标志物筛查和个性化患者特定于患者的靶向疗法的工具。该应用程序的具体目的将集中在四个特定目标上：具体目标1-执行至少40例乳腺癌病例，代表多达65个库的乳腺癌病例，并鉴定了估计的1000-1500个新型VH抗体。具体目标2-根据克隆扩张和体细胞超成本分数，在AIM 1中鉴定的200-400抗原驱动的VH单域抗体的同源抗原。特定的目标3-使用多重大规模阵列验证已鉴定的抗原及其在人类乳腺癌中的表现。具体目标4-组装重组可溶性结构域抗体的多重蛋白质阵列和其同源抗原的匹配阵列用于癌症诊断，筛查和临床靶向应用。公共卫生相关性：癌症抗原的发现平台采用了独特的生物化学和分子生物学技术，我们开发了从患者中恢复抗体并鉴定免疫系统已针对“异常”的癌症。该平台的结合将有助于开发试剂，这些试剂将有助于理解癌症生物学，用于诊断生物标志物筛查的检测试剂以及基于任何患者中这些“异常”蛋白的表达的个性化治疗剂的长期潜力。该平台将主要用于乳腺癌，但对大多数其他癌症的应用持巨大希望。最后，这些试剂将提供给广泛的癌症研究界，以迅速定义其在多种诊断和临床治疗方法中的实用性和应用。