Monoclonal Antibodies for Orphan GPCRs in the CNS

CNS 孤儿 GPCR 的单克隆抗体

• 批准号: 8315701
• 负责人: Pat W Gray
• 金额: $ 34.85万
• 依托单位: OMEROS CORPORATION
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-12 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8315701
• 关键词: Affinity; Agonist; Alzheimer' s Disease; Antibodies; Antigens; Autistic Disorder; Binding; Biochemical; Biological; Biological Assay; Brain; Cell Surface Proteins; Cell Surface Receptors; Cell surface; Cells; Central Nervous System Diseases; Clinical; Communities; Crystallization; Diagnostic; Disease; Dissociation; Drug Delivery Systems; Evaluation; Extracellular Domain; Family; Funding; G-Protein-Coupled Receptors; Generations; Government; Gray unit of radiation dose; Immunoglobulin Genes; Immunohistochemistry; Individual; Knockout Mice; Length; Life; Link; Malignant Neoplasms; Malignant neoplasm of central nervous system; Membrane; Membrane Proteins; Methods; Molecular; Monoclonal Antibodies; Multiple Sclerosis; Neurobiology; Neurologic; Orphan; Pain; Parkinson Disease; Pathway interactions; Persons; Phase; Positioning Attribute; Reagent; Receptor Cell; Recombinants; Research; Schizophrenia; Signal Transduction; Specificity; Technology; Therapeutic; Tissues; base; cell growth; commercial application; drug development; drug discovery; human GPRC5C protein; immunogenicity; in vivo; innovation; member; neoplastic cell; nervous system disorder; novel; receptor; small molecule; technological innovation; therapeutic target; tool; tumor

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.

描述(申请人提供)：CNS GPCRs中的孤儿GPCRs的单抗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，它们是关键的治疗目标。然而，GPCR大家庭中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氏症以及自闭症在内的一系列神经系统症状都与孤儿GPCR有关，这使它们成为有吸引力的治疗目标。然而，针对孤儿GPCRs的特异性试剂的缺乏阻碍了药物的开发。单抗被认为是优秀的研究工具，并已被证明是高效的治疗方法。然而，GPCRs是出了名的难以产生抗体的抗原，原因包括免疫原性差，物种间高度保守，以及细胞膜轮廓低。Xori公司建立了一个创新的平台，用于快速识别和优化体外单抗，该平台有可能绕过GPCRs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的高亲和力单抗(KD&lt；5 NM)而得到验证，其中包括一种GPCR。我们建议产生针对在神经组织中高表达的孤儿GPCRs的单抗。具体地说，我们将(1)分离脑内表达的10个孤儿GPCRs氨基末端区域的特异性单抗，(2)通过细胞表面选择分离10个全长重组孤儿GPCRs的单抗，(3)通过生化和细胞特性确定孤儿GPCR单抗的功能。这些抗体将提供宝贵的新研究工具，并将为Xori第二阶段资金提供定位，以评估体内的诊断和治疗潜力。第一阶段交付：10个针对孤儿GPCRs的单抗和3个具有孤儿GPCRs特异性激动剂或拮抗剂活性的单抗。这些单抗将为了解孤儿受体的功能打开大门，并将具有诊断和治疗作用的潜力。相关性：G蛋白偶联受体(GPCRs)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体外抗体发现技术来生成针对一些“孤儿”GPCRs的单抗，该技术绕过了针对GPCRs的抗体生成的主要挑战。这些抗体将提供重要的研究试剂，并可能具有诊断和治疗作用。 公共卫生相关性：G蛋白偶联受体(GPCRs)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体外抗体发现技术来生成针对一些“孤儿”GPCRs的单抗，该技术绕过了针对GPCRs的抗体生成的主要挑战。这些抗体将提供重要的研究试剂，并可能具有诊断和治疗作用。