Serum Hepcidin Immunoassay: Laboratory to Marketplace

描述(申请人提供)：铁代谢障碍是最常见的人类疾病之一。在过去的十年里，对铁稳态及其紊乱的分子基础的了解取得了迅速的进展。多肽荷尔蒙海普西丁已成为铁代谢的主要调节剂。海普西丁的失调是大多数全身性铁紊乱的主要或致病因素。有一个公认的尚未得到满足的需求，即一种强大的和广泛可用的血清庚西丁临床检测方法，但由于庚西丁的免疫原性较差，这一目标的进展已经放缓。内在生命科学公司(ILS)组建了一支由这一领域的顶级专家组成的团队，并开发并验证了世界上第一个血清肝素免疫分析。在这项修订后的申请中，要求SBIR提供资金，以生产开发下一代快速传播到医疗和药剂界的检测所需的单抗。在这项建议的第一阶段，我们将：1)生产适用于高容量自动化C-ELISA的小鼠单抗；2)与战略联盟合作伙伴BioAtla合作，使用新的抗体工程方法生产兔单抗。我们提出的重叠方法旨在克服标准化临床海普西丁免疫分析所需的单抗开发中的关键瓶颈。第一阶段的成功完成将使ILS能够开发一种血清海普西丁免疫分析，可以满足临床医生和制药研究人员对血清海普西丁免疫分析的全球需求。公共卫生意义：海普西丁是一种维持健康血铁水平所必需的小荷尔蒙。海普西丁调节饮食中铁的吸收和体内贮藏物中铁的释放。异常高的血清海普西丁水平会限制可用于制造血细胞的血红蛋白的铁，从而导致虚弱的贫血。在另一种极端情况下，血清中低水平的海普西丁会导致铁在组织中的有毒积聚，从而导致包括肝脏和心脏在内的器官衰竭。尽管海普西丁在影响全球数百万患者的疾病中起着关键作用，尽管对血清海普西丁测试的需求很大，但目前还没有FDA批准的血清海普西丁免疫分析方法用于研究和临床医学。血清海普西丁测试将填补一个重要的未得到满足的医疗需求。内在生命科学公司(ILS)开发并验证了世界上第一个使用ILS技术与加州大学洛杉矶分校医学研究实验室生产的抗体相匹配的血清海普西丁免疫分析方法。被压抑的需求导致了这种新型免疫分析的合同销售给世界各地的临床和制药研究人员。然而，抗体供应不足以使海普西丁试验商业化，也不足以使其在医学上的常规使用。ILS要求NIH SBIR第一阶段资金实施新技术，以生产永生化的杂交细胞克隆(杂交瘤)，这种杂交瘤可以分泌无限数量的针对海普西丁的抗体。针对海普西丁的单抗的开发将使商业规模的抗体生产和适合FDA批准的准确的海普西丁免疫分析成为可能。有了标准化和无限的单抗供应，海普西丁检测将在药物开发、生物医学研究和临床医学中实现全球应用。

DESCRIPTION (Provided by Applicant): Disorders of iron metabolism are among the most common human diseases. During the last decade, rapid progress has been made in the understanding of the molecular basis or iron homeostasis and its disorders. The peptide hormone hepcidin has emerged as the master regulator of iron metabolism. Dysregulation of hepcidin is the principal or contributing factor in most systemic iron disorders. There is a well recognized unmet need for a robust and widely available clinical assay for serum hepcidin but progress towards this goal has been slowed by the poor immunogenicity of hepcidin. Intrinsic LifeSciences (ILS) has assembled a team of top experts in this area and has developed and validated the world's first serum hepcidin immunoassay. SBIR funding is requested in this revised application to produce monoclonal antibodies necessary to develop the next generation assay for rapid dissemination to the medical and pharmaceutical communities. Under Phase I of this proposal we will: 1) Produce murine monoclonal antibodies suitable for use in high-capacity automated C-ELISA 2) Produce rabbit monoclonal antibodies in collaboration with a strategic alliance partner, BioAtla, using novel antibody engineering methods The overlapping approaches that we propose are designed to overcome the critical bottleneck in the development of monoclonal antibodies necessary for a standardized clinical hepcidin immunoassay. Successful completion of Phase I will enable ILS to develop a serum hepcidin immunoassay that can quench the global unmet need for a serum hepcidin immunoassay by clinicians and pharmaceutical researchers. PUBLIC HEALTH RELEVANCE: Hepcidin is a small hormone essential for the maintenance of healthy blood iron levels. Hepcidin regulates iron absorption from the diet and its release from body stores. Abnormally high serum hepcidin levels cause a debilitating anemia by limiting iron available to make hemoglobin for blood cells. At the other extreme, low serum hepcidin levels cause toxic accumulation of iron in tissues with consequent organ failure including the liver and heart. Despite hepcidin's key role in disorders affecting millions of patients worldwide, and despite great demand for a serum hepcidin test, no FDA-approved serum hepcidin immunoassay is currently available for use in research and clinical medicine. A serum hepcidin test will fill an important unmet medical need. Intrinsic LifeSciences (ILS) has developed and validated the world's first immunoassay for serum hepcidin using ILS technologies matched with antibodies produced in a UCLA medical research laboratory. Pent-up demand has led to contract sales of this novel immunoassay to clinical and pharmaceutical investigators worldwide. However, the antibody supply is not sufficient for commercialization of the hepcidin assay and its routine use in medicine. ILS requests NIH SBIR Phase I funding to implement novel technologies to produce immortalized, hybrid cell clones (hybridomas) that secrete unlimited amounts of antibodies specific to hepcidin. Development of monoclonal antibodies specific to hepcidin will enable commercial scale antibody production and accurate hepcidin immunoassay's suitable for FDA-approval. With a standardized and unlimited monoclonal antibody supply, hepcidin tests will achieve worldwide use in pharmaceutical development, biomedical research, and clinical medicine.