SBIR Phase II: A platform for identifying antibodies that modulate human membrane receptors involved in disease

这个小企业创新研究（SBIR）二期项目的更广泛的影响/商业潜力是开发一个药物发现平台，将识别新型抗体疗法。目标是利用抗体来增加或减少一种称为“G蛋白偶联受体”（gpcr）的细胞信号受体的活性。有超过400种非嗅觉的人类gpcr涉及健康和疾病的各个方面，包括癌症、自身免疫性疾病、疼痛、炎症等。大约25%的gpcr已被批准的小分子药物靶向，但由于小分子无法区分类似的gpcr，其余的努力往往失败。抗体药物可以克服这一障碍，因为它们对目标具有更高的特异性。该项目将首次实现直接识别调节GPCR功能的抗体的技术商业化。这些抗体将对医疗保健产生影响，为目前缺乏或没有治疗方法的疾病提供治疗方法。它们还将通过研究与gpcr相关的生理和疾病来影响科学认识。商业影响可能非常大。GPCR药物市场超过1000亿美元，大多数抗体疗法的年销售额超过10亿美元。这里描述的平台可以使数十种新的GPCR抗体治疗成为可能，为患者、社会和合作伙伴创造价值。这个SBIR二期项目的智力优势是开发一种药物发现技术，用于发现调节g蛋白偶联受体（gpcr）的抗体。目前的方法是有限的，因为GPCR抗原通常没有正确折叠，而且因为抗体是根据它们与GPCR结合的紧密程度来选择的，而不是根据它们发挥的作用。那些绑定的通常根本没有任何效果。该项目将建立在第一阶段成功的概念验证基础上，该阶段证明了该平台能够直接识别人类GPCR的功能性抗体激动剂。该提案解决了制药客户认为重要的四个主要技术要求：能够处理多种类型的gpcr，能够分离具有不同调节效应的抗体，使用高度多样化，高质量的scFv库，以及能够快速分离，优化和表征数十种候选物的工作流程。该项目的目标是改进该平台的酵母表达gpcr的方式，并将其与不同的可选reads进行功能偶联，构建专有的scFv库，并通过结合测序生物信息学和抗体表征优化工作流程，包括对培养的哺乳动物细胞进行细胞结合的流式细胞分析和功能分析。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project is to develop a drug discovery platform that will identify novel types of antibody therapeutics. The goal is to use antibodies to increase or decrease the activity of a type of cell signaling receptor called "G protein-coupled receptors" (GPCRs). There are more than 400 non-olfactory human GPCRs that are involved in all aspects of health and disease, including cancers, autoimmune diseases, pain, inflammation, and others. About 25% of GPCRs have been targeted by approved small molecule drugs, but efforts for the remaining have often failed because of the inability of small molecules to distinguish between similar GPCRs. Antibody drugs can overcome this hurdle because of their much higher specificity for their targets. This project will bring to commercialization the first technology that directly identifies antibodies that modulate GPCR function. These antibodies will impact healthcare by enabling therapies for diseases with poor or no current treatments. They also will impact scientific understanding by enabling the study of GPCR-related physiology and disease. The commercial impacts are potentially very large. The GPCR drug market is over $100B, and most antibody therapeutics have annual sales over $1B. The platform described here could enable dozens of novel GPCR antibody therapeutics, creating value for patients, society, and co-development partners.The intellectual merit of this SBIR Phase II project is to develop a drug discovery technology for discovering antibodies that modulate G-protein coupled receptors (GPCRs). Current methods are limited because GPCR antigens are often not properly folded, and because antibodies are selected by how tightly they bind GPCRs, rather than by the effect they exert. Those that bind typically do not have any effect at all. This project will build on the successful proof-of-concept from Phase I that demonstrated the platform's ability to identify directly functional antibody agonists for a human GPCR. The proposal addresses the four main technical requirements that pharmaceutical customers cite as important: Ability to work on many types of GPCRs, ability to isolate antibodies with varied modulating effects, use of a highly diverse, high-quality scFv library, and a workflow that can quickly isolate, optimize and characterize dozens of candidates. The goals of this project are to improve how the platform's yeasts express GPCRs and functionally couple them to different selectable readouts, construct a proprietary scFv library, and optimize the workflow by incorporating sequencing bioinformatics and antibody characterization, including flow cytometric analysis of cell-binding and functional assays on cultured mammalian cells.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.