Discovery Platform for Cancer Antigens

描述（由申请人提供）：自发性乳腺癌和其他癌症通常是复杂和异质的。癌症生物学领域目前的一个驱动主题是改进我们的方法，在分子水平上表征患者肿瘤，以便为每个患者量身定制治疗。我们已经开发出一种方法，利用患者自身的免疫反应来分离他们针对癌症蛋白质产生的抗体。在实验室中，我们合成这些抗体，并识别这些抗体靶向的新型癌症蛋白。本申请的主要目标是实现基于平台的方法来分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，可用于靶向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的理解，检测癌症特异性生物标志物，并作为新的治疗方法。这些单结构域抗体是无限可再生的，并且作为用于晚期和转移性疾病的基于群体的生物标志物筛选和个体化患者特异性靶向治疗的工具具有很大的前景。本申请的具体目的将集中于四个具体目标：具体目的1-对代表多达65个总文库的至少40个乳腺癌病例进行通量平台筛选，并鉴定估计1000-1500种新型VH抗体。具体目标2-基于克隆扩增和体细胞超突变评分，鉴定目标1中鉴定的200-400个抗原驱动的VH单结构域抗体的同源抗原。特异性目的3 -使用多重大规模阵列鉴定人乳腺癌中的抗原及其呈递。具体目标4 -组装重组可溶性结构域抗体的多重蛋白阵列及其同源抗原的匹配阵列，用于癌症诊断、筛选和临床靶向应用。 公共卫生相关性：癌症抗原发现平台应用我们开发的独特生物化学和分子生物学技术，从患者体内回收抗体，并识别免疫系统靶向为“异常”的癌症蛋白。该平台的并入将促进试剂的开发，所述试剂将用于理解癌症生物学、用于诊断生物标志物筛选的检测试剂以及基于任何患者中这些“异常”蛋白质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，但对大多数其他癌症的应用前景广阔。最后，这些试剂将提供给广泛的癌症研究界，以快速确定其在多种诊断和临床治疗方法中的效用和应用。

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.