Monoclonal Antibodies for Orphan GPCRs in the CNS

描述（由申请方提供）：CNS GPCR中孤儿GPCR的单克隆抗体包括一个结构相关的膜蛋白大家族，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，全球PCR大家庭的许多成员仍然是孤儿。广泛的神经适应症，包括精神分裂症，疼痛，帕金森病和阿尔茨海默病以及自闭症都与孤儿GPCR有关，使其成为有吸引力的治疗目标。然而，缺乏针对孤儿GPCR的特异性试剂阻碍了药物开发。单克隆抗体（MAb）被认为是优秀的研究工具，并已被证明是非常有效的治疗。然而，众所周知，GPCR是难以产生抗体的抗原，原因包括免疫原性差、物种之间的高度保守性和低膜分布。XORI公司已经建立了一个创新的平台，用于快速识别和优化单克隆抗体的体外，有可能规避GPCR带来的挑战。该平台已通过发现和优化针对五种细胞表面蛋白（包括一种GPCR）的高亲和力mAb（KD<5 nM）进行了验证。我们建议产生针对在神经组织中高度表达的孤儿GPCR的单克隆抗体。具体而言，我们将（1）分离对脑中表达的10个孤儿GPCR的氨基末端结构域具有特异性的MAb，（2）通过细胞表面选择分离10个全长重组孤儿GPCR的MAb，以及（3）通过生物化学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XORI定位为II期资金，以评估体内诊断和治疗潜力。 第一阶段可交付成果：10种特异于孤儿GPCR的单克隆抗体和3种具有孤儿GPCR特异性激动或拮抗活性的单克隆抗体。这些单克隆抗体将为理解孤儿受体的功能打开大门，并将具有诊断和治疗效用的潜力。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效用。

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.