A novel platform for mining the repertoire of antigen-specific B cells

描述（由申请人提供）： 癌症仍然是对当今社会的健康和经济的重大威胁。癌症研究的进展是发现癌症生物标志物、开发快速可靠的癌症特异性诊断方法以及开发新治疗方法的关键。多分析物检测平台，如蛋白质微阵列，具有快速、高通量分析复杂样品中小分子和感兴趣蛋白质的潜力。未来几年，这些平台在癌症生物标志物发现和不同癌症的早期诊断方面可能会取得快速进展。然而，尽管多分析物平台的进步，这些方法的整体性能和有用性在很大程度上取决于用于捕获和检测微阵列表面上的感兴趣的分子的单克隆抗体的质量。成功的微阵列开发需要筛选许多单克隆抗体的亲和力，特异性，交叉反应性和平台兼容性。对于给定的诊断癌症靶标，可能需要筛选数十种单克隆抗体，因此用于产生单克隆抗体的技术必须能够产生一组高度多样化的靶标特异性单克隆抗体。由于目前单克隆抗体开发方法的局限性，这种靶特异性单克隆抗体组通常不可用，并且制造起来极其昂贵。 该I期申请的总体目标是产生一种独特的技术，用于从免疫小鼠中挖掘B细胞的克隆库，并产生针对感兴趣的靶标的抗原特异性单克隆抗体组。NeoClone建议调整其成功的ABL-MYC逆转录病毒技术，以开发一种新的体外平台，用于抗原特异性B细胞的克隆扩增、选择和转化。该平台将实现前所未有的克隆多样性，生成单克隆抗体组，可以测试其特异性表位鉴定、亲和力和平台兼容性。此外，本文提出的体外方法将允许选择稀有克隆，从而使NeoClone能够开发针对传统方法失败的重要靶点的抗体。用于检测复杂样品中的稀有靶标的新平台的快速增长需要并行开发用于产生针对这些靶标的亲和试剂的新技术。任何新技术都必须生产具有高亲和力、高选择性和高克隆多样性的试剂。NeoClone独特的体外ABL-MYC技术可以满足这些要求。单克隆抗体对于帮助发现体内的癌症，特别是早期阶段（生物标志物），开发诊断癌症的方法以及寻找疾病的新治疗方法至关重要。NeoClone提出开发一种新的方法，以快速和经济有效地生产大量高质量，多样化，癌症特异性单克隆抗体。这项技术可以潜在地推进诊断癌症的新方法，例如抗体微阵列，它需要高质量的癌症生物标志物特异性抗体才能进入临床。

DESCRIPTION (provided by applicant): Cancer remains a significant threat to the health and economy of today's society. Advances in cancer research are key to cancer biomarker discovery, development of rapid and reliable methods of cancer-specific diagnosis, and development of new treatments. Multi-analyte detection platforms such as protein microarrays have potential for fast, high-throughput analysis of complex samples for small molecules and proteins of interest. The next few years will likely yield rapid advancement in the use of these platforms for cancer biomarker discovery and early-stage diagnosis of different cancers. Despite the advancement of multi-analyte platforms, however, the overall performance and usefulness of these approaches depends heavily on the quality of the monoclonal antibodies used to capture and detect molecules of interest on the microarray surface. Successful microarray development requires screening numerous monoclonal antibodies for affinity, specificity, cross-reactivity, and platform compatibility. For a given diagnostic cancer target, dozens of monoclonal antibodies may need to be screened and, thus the techniques used to generate the monoclonal antibodies must be able to generate a panel of highly diverse target-specific monoclonal antibodies. Because of limitations in current monoclonal antibody development methods, such panels of target-specific monoclonal antibodies often are not available and are prohibitively expensive to make. The overall objective of this Phase I application is to generate a unique technology for mining the clonal repertoire of B cells from immunized mice and generating panels of antigen-specific monoclonal antibodies against targets of interest. NeoClone proposes to adapt its successful ABL-MYC retroviral technology to develop a novel in vitro platform for the clonal expansion, selection, and transformation of antigen-specific B cells. This platform will enable unprecedented clonal diversity, generating panels of monoclonal antibodies that can be tested for specific epitope identification, affinity, and platform compatibility. In addition, the in vitro methods proposed here will allow for the selection of rare clones, thereby enabling NeoClone to develop antibodies against important targets where traditional methods have failed. The rapid growth of new platforms for detecting rare targets in complex samples demands the parallel development of new technologies for generating affinity reagents against those targets. Any new technology must produce reagents with high affinities, high selectivity, and high clonal diversity. NeoClone's unique in vitro ABL-MYC technology can meet these requirements. Monoclonal antibodies are essential for helping to discover cancer in the body, especially in early stages (biomarkers), develop ways to diagnose cancer, and to find new treatments for the disease. NeoClone proposes to develop a new way to create large numbers of high-quality, diverse, cancer-specific monoclonal antibodies both quickly and cost-effectively. This technology can potentially advance new methods for diagnosing cancer, such as antibody microarrays, which need high-quality cancer biomarker-specific antibodies to move into the clinic.