Monoclonal Antibodies for Orphan GPCRs in the CNS

描述（由申请人提供）：CNS中孤儿gpcr的单克隆抗体gpcr包括一个大的结构相关的膜蛋白家族，在神经生物学中具有关键功能。因此，它们是关键的治疗靶点。然而，庞大的GPCR家族的许多成员仍然是孤儿。包括精神分裂症、疼痛、帕金森氏症和阿尔茨海默病以及自闭症在内的广泛的神经系统适应症都与孤儿gpcr有关，这使它们成为有吸引力的治疗靶点。然而，针对孤儿gpcr特异性试剂的缺乏阻碍了药物的开发。单克隆抗体（mab）是公认的优秀的研究工具，并已被证明是非常有效的治疗方法。然而，众所周知，gpcr是一种很难产生抗体的抗原，其原因包括免疫原性差、物种之间的高度保守性和低膜谱。XORI公司已经建立了一个创新的平台，用于快速鉴定和优化单抗体外，有可能规避gpcr带来的挑战。通过发现和优化针对5种细胞表面蛋白（包括1种GPCR）的高亲和力单抗（KD<5 nM），验证了该平台的有效性。我们建议针对在神经组织中高度表达的孤儿gpcr产生单克隆抗体。具体来说，我们将(1)分离针对10个在大脑中表达的孤儿GPCR氨基末端结构域的单克隆抗体，(2)通过细胞表面选择分离10个全长重组孤儿GPCR的单克隆抗体，以及(3)通过生化和细胞表征确定孤儿GPCR单克隆抗体的功能。这些抗体将提供宝贵的新研究工具，并将为XORI提供二期资助，以评估体内诊断和治疗潜力。I期可交付：10个孤儿gpcr特异性单克隆抗体和3个孤儿gpcr特异性激动或拮抗活性单克隆抗体。这些单克隆抗体将为了解孤儿受体的功能打开大门，并具有诊断和治疗用途的潜力。相关性：G蛋白偶联受体（gpcr）是神经系统疾病中一类重要的药物靶点，但其中很大一部分仍然知之甚少。我们建议使用一种新的离体抗体发现技术来产生针对许多“孤儿”gpcr的单克隆抗体，该技术规避了gpcr特异性抗体产生的主要挑战。这些抗体将提供重要的研究试剂，并可能具有诊断和治疗用途。

DESCRIPTION (provided by applicant): Monoclonal Antibodies for Orphan GPCRs in the CNS GPCRs comprise a large family of structurally related membrane proteins with critical functions in neurobiology. As such, they are key therapeutic targets. However, many members of the vast GPCR family remain orphans. A broad range of neurological indications, including schizophrenia, pain, Parkinson's and Alzheimer's diseases, and autism have been linked to orphan GPCRs, making them attractive targets for therapy. The paucity of reagents specific for the orphan GPCRs, however, has stymied drug development. Monoclonal antibodies (MAbs) are known as excellent research tools and have proven to be highly effective therapeutics. However, GPCRs are notoriously difficult antigens against which to raise antibodies, for reasons that include poor immunogenicity, high conservation between species, and a low membrane profile. XORI Corporation has established an innovative platform for rapid identification and optimization of MAbs ex vivo that has the potential to circumvent the challenges presented by GPCRs. The platform has been validated by discovery and optimization of high affinity mAbs (KD<5 nM) against five cell surface proteins, including one GPCR. We propose to generate MAbs against orphan GPCRs that are highly expressed in neurological tissues. Specifically, we will (1) isolate MAbs specific for amino terminal domains of ten orphan GPCRs expressed in the brain, (2) isolate MAbs for ten full length recombinant orphan GPCRs by cell surface selection, and (3) determine functionality of the orphan GPCR monoclonal antibodies by biochemical and cellular characterization. These antibodies will provide invaluable new research tools and will position XORI for Phase II funding to evaluate diagnostic and therapeutic potential in vivo. Phase I deliverable: ten monoclonal antibodies specific for orphan GPCRs and three monoclonal antibodies with orphan GPCR-specific agonistic or antagonistic activity. These MAbs will open doorways to understanding function of the orphan receptors and will have the potential for diagnostic and therapeutic utility. Relevance: G protein-coupled receptors (GPCRs) comprise an important class of drug targets in neurological disease, but a large percentage of them remain poorly understood. We propose to generate monoclonal antibodies against a number of the "orphan" GPCRs using a novel ex vivo antibody discovery technology that circumvents the main challenges to antibody generation specific to GPCRs. These antibodies will provide important research reagents and may have diagnostic and therapeutic utility. PUBLIC HEALTH RELEVANCE: G protein-coupled receptors (GPCRs) comprise an important class of drug targets in neurological disease, but a large percentage of them remain poorly understood. We propose to generate monoclonal antibodies against a number of the "orphan" GPCRs using a novel ex vivo antibody discovery technology that circumvents the main challenges to antibody generation specific to GPCRs. These antibodies will provide important research reagents and may have diagnostic and therapeutic utility.