Discovery Platform for Cancer Antigens

癌症抗原发现平台

• 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
• 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

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）：自发性乳腺癌和其他癌症通常是复杂且异质的。当前癌症生物学领域的一个驱动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治疗方法。我们开发了一种方法，利用患者自身的免疫反应来分离他们针对癌症蛋白产生的抗体。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蛋白。该应用的主要目标是实施基于平台的方法来分离和识别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，可用于针对表达这些抗体识别的抗原的个体癌症。这些研究人员的目的是使用这些试剂来扩大我们对乳腺癌生物学、癌症特异性生物标志物检测以及作为新型治疗方法的理解。这些单域抗体具有无限可再生性，作为基于人群的生物标志物筛查和针对晚期和转移性疾病的个体化患者特异性靶向治疗的工具具有广阔的前景。该应用程序的具体目标将集中于四个具体目标： 具体目标 1- 对代表多达 65 个总库的至少 40 个乳腺癌病例进行通量平台筛查，并鉴定估计 1000-1500 种新型 VH 抗体。具体目标 2-根据克隆扩增和体细胞超突变评分，识别目标 1 中识别的 200-400 个抗原驱动的 VH 单域抗体的同源抗原。具体目标 3 - 使用多重大规模阵列验证已识别的抗原及其在人类乳腺癌中的表现。具体目标 4 - 组装重组可溶域抗体的多重蛋白质阵列及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。 公共健康相关性：癌症抗原发现平台应用了我们开发的独特的生物化学和分子生物学技术，可从患者体内回收抗体并识别免疫系统将其视为“异常”的癌症蛋白。该平台的合并将有助于开发有助于理解癌症生物学的试剂、用于诊断生物标志物筛选的检测试剂，以及基于这些“异常”蛋白质在任何患者中的表达的个体化治疗的长期潜力。该平台将主要应用于乳腺癌，但也有望应用于大多数其他癌症。最后，这些试剂将提供给广泛的癌症研究界，以快速确定它们在多种诊断和临床治疗方法中的效用和应用。

项目成果

Patient-derived heavy chain antibody targets cell surface HSP90 on breast tumors.

• DOI: 10.1186/s12885-015-1608-z
• 发表时间: 2015-09-03
• 期刊: BMC cancer
• 影响因子: 3.8
• 作者: Devarakonda CV;Kita D;Phoenix KN;Claffey KP
• 通讯作者: Claffey KP