Discovery Platform for Cancer Antigens

描述(申请人提供)：自发性乳腺癌和其他癌症通常是复杂和不同的。目前癌症生物学领域的一个推动主题是改进我们的方法，在分子水平上描述患者肿瘤的特征，以便可以为每个患者量身定做治疗方法。我们已经开发出一种方法，利用患者自己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，我们合成了这些抗体，并识别了这些抗体所针对的新的癌症蛋白。该应用程序的主要目标是实现一种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。这一平台技术有可能产生数百种抗体，这些抗体可用于靶向表达这些抗体识别的抗原的个别癌症。这些研究人员的目的是利用这些试剂来扩大我们对乳腺癌生物学、癌症特异性生物标记物的检测以及作为新的治疗方法的了解。这些单域抗体是无限可再生的，并有望成为基于人群的生物标记物筛选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。这项应用的具体目标将集中在四个具体目标上：具体目标1-对至少40例乳腺癌病例进行平台筛选，代表多达65个文库，并识别估计1000-1500种新型VH抗体。特定目标2-根据克隆扩增和体细胞高突变评分，鉴定目标1中鉴定的200-400抗原驱动的VH单域抗体的同源抗原。特定目标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呈现。特定目的4-组装用于癌症诊断、筛查和临床靶向应用的重组可溶性结构域抗体及其同源抗原的匹配阵列的多重蛋白质阵列。 公共卫生相关性：癌症抗原发现平台应用了我们开发的一种独特的生物化学和分子生物学技术，该技术可以从患者身上回收抗体，并识别免疫系统已瞄准的“异常”癌症蛋白。这一平台的加入将促进试剂的开发，这些试剂将有助于了解癌症生物学、用于诊断生物标记物筛选的检测试剂，以及基于这些“异常”蛋白在任何患者身上的表达而进行个性化治疗的长期潜力。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很大。最后，这些试剂将提供给广泛的癌症研究社区，以快速确定它们在多种诊断和临床治疗方法中的用途和应用。

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.