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）第二阶段项目的更广泛的影响/商业潜力是开发一个药物发现平台，该平台将识别新型抗体疗法。 目标是使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种非嗅觉人类GPCR参与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，因为它们对靶点的特异性要高得多。该项目将使第一项直接鉴定调节GPCR功能的抗体的技术商业化。这些抗体将通过为目前治疗效果差或没有治疗的疾病提供治疗来影响医疗保健。它们还将通过研究GPCR相关的生理学和疾病来影响科学理解。商业影响可能非常大。GPCR药物市场超过1000亿美元，大多数抗体治疗药物的年销售额超过10亿美元。本文所描述的平台可以实现数十种新型GPCR抗体疗法，为患者，社会和共同开发合作伙伴创造价值。SBIR II期项目的智力价值是开发药物发现技术，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，并且因为抗体是通过它们结合GPCR的紧密程度来选择的，而不是通过它们发挥的作用。那些结合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的基础上，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：能够研究多种类型的GPCR，能够分离具有不同调节作用的抗体，使用高度多样化的高质量scFv文库，以及可以快速分离，优化和表征数十种候选物的工作流程。该项目的目标是改善平台酵母表达GPCR的方式，并将其功能性地与不同的选择性读数偶联，构建专有的scFv文库，并通过整合测序生物信息学和抗体表征来优化工作流程，包括细胞的流式细胞术分析，该奖项反映了NSF的法定使命，并被认为值得通过评估来支持使用基金会的知识价值和更广泛的影响审查标准。

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.