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

这一小型企业创新研究(SBIR)第二阶段项目的更广泛影响/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。其目的是利用抗体来增加或降低一种称为“G蛋白偶联受体”(GPCRs)的细胞信号受体的活性。有400多种非嗅觉人类GPCR涉及健康和疾病的方方面面，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，但其余的努力往往失败，因为小分子无法区分相似的GPCR。抗体药物可以克服这一障碍，因为它们对目标的特异性要高得多。该项目将使第一项直接识别调节gpr功能的抗体的技术商业化。这些抗体将通过使目前治疗效果不佳或没有治疗的疾病的治疗成为可能，从而影响医疗保健。它们还将通过促进GPCR相关生理学和疾病的研究来影响科学理解。潜在的商业影响非常大。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实现数十种新的GPCR抗体疗法，为患者、社会和共同开发伙伴创造价值。这个SBIR二期项目的智力价值在于开发一种药物发现技术，用于发现调节G蛋白偶联受体(GPCRs)的抗体。目前的方法受到限制，因为gpcr抗原往往没有正确折叠，而且抗体是根据它们与gpcr结合的紧密程度来选择的，而不是根据它们所发挥的效果来选择的。这些约束通常根本不会产生任何影响。该项目将建立在第一阶段的成功概念验证的基础上，该阶段展示了该平台直接为人类GPCR识别功能性抗体激动剂的能力。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制作用的抗体，使用高度多样化、高质量的单链抗体文库，以及可以快速分离、优化和鉴定数十个候选抗体的工作流程。该项目的目标是改进平台的酵母表达GPCR的方式，并将它们与不同的可选读数进行功能耦合，构建专有的单链抗体文库，并通过整合测序生物信息学和抗体表征(包括细胞结合的流式细胞仪分析和对培养的哺乳动物细胞的功能分析)来优化工作流程。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势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.