SBIR Phase II: A single-cell-interaction platform for accelerating discovery of bispecific antibodies

这个小型企业创新研究（SBIR）第二阶段项目的更广泛的影响/商业潜力是加速免疫治疗药物的开发，并使其广泛提供给有需要的患者。免疫治疗通过免疫系统来治疗疾病，已经证明了治愈或改善癌症，自身免疫或其他疾病患者生活质量的巨大潜力。不幸的是，目前只有少数这些治疗方法可用。此外，免疫治疗是昂贵的，并且对于医疗保健系统和患者（包括弱势群体）是负担不起的。这些挑战可归因于传统药物筛选平台的昂贵且低效的治疗发现过程。该项目旨在开发一种高通量、基于单细胞的功能筛选技术，该技术可以快速发现许多免疫治疗药物，特别是双特异性抗体（“BsAb”），以治疗广泛的衰弱性疾病，因此可以产生重大和广泛的社会影响。 与此同时，BsAb市场正处于指数增长的早期阶段，未来几年全球销售额将达到100亿美元。该项目旨在进一步开发、优化和推出首个用于发现双特异性抗体（“BsAb”）功能的专用商业平台。传统的试错法，其中BsAb是经验性设计的，然后必须单独评估其功能，是繁琐的，耗时的，昂贵的。所提出的技术通过采用超高通量、基于单细胞的功能筛选代表了BsAb发现的新范例，使得能够有效地发现具有可区分性质的稀有功能性BsAb。该项目的目标是开发、优化和质量控制（QC）整个平台工作流程，包括上游BsAb文库和报告细胞制备、中游液滴测定和分选以及下游靶标验证和表征。到本研究结束时，一个强大而精简的系统将准备用于商业发布，使制药公司合作伙伴能够发现新的BsAb免疫治疗药物。该项目将在单细胞治疗发现中产生新的工具和方法，并做出重大的智力贡献，包括复杂的细胞库构建，多重报告和潜在的新治疗候选人。此外，以组合和高通量方式询问许多变量的独特能力可以导致对作用模式的新见解，并为未来的免疫治疗设计提供信息。该奖项反映了NSF的法定使命，并被认为值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估来支持。

The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase II project is to accelerate development of immunotherapeutics and make them broadly available and affordable to patients in need. Immunotherapeutics, which work by engaging the immune system to tackle diseases, have demonstrated tremendous potential to cure, or improve quality-of-life of patients with cancer, autoimmunity, or other disorders. Unfortunately, only a handful of these treatments are currently available. Furthermore, immunotherapeutics are costly and unaffordable for the healthcare system and patients including the disadvantaged populations. These challenges can be attributed to the costly and inefficient therapeutic discovery processes with conventional drug screening platforms. This project aims to develop a high-throughput, single-cell based functional screening technology that can enable rapid discovery of many immunotherapeutics, specifically bispecific antibodies (“BsAbs”), to treat a broad range of debilitating diseases, and therefore can make significant and broad societal impact. Meanwhile, the BsAb market is in its early exponential growth phase and will reach $10 billion global sales in the next few years. The proposed technology will be quickly deployed to enable pharmaceutical and biotechnology clients to identify their therapeutic leads with unprecedentedly rapid turnaround and high success rate (commercial value).The proposed project aims to further develop, optimize and launch the first dedicated commercial platform for functional discovery of bispecific antibodies (“BsAbs”). The conventional trial-and-error approach, in which BsAbs are empirically designed and then must be evaluated individually for their functionality, is tedious, time-consuming, and expensive. The proposed technology represents a new paradigm in BsAb discovery by employing an ultra-high throughput, single cell-based functional screening, enabling efficient discovery of rare functional BsAbs with differentiable properties. The objectives of this project are to develop, optimize and quality control (QC) the entire platform workflow including upstream BsAb library and reporter cell preparations, midstream droplet assay and sorting, and downstream target validation and characterization. By the conclusion of this study, a robust and streamlined system will be ready for commercial launch, enabling pharmaceutical company partners to discover new BsAb immunotherapeutics. This project will result in new tools and methods in single-cell therapeutic discovery and make significant intellectual contributions including complex cell library construction, multiplexed reporters, and potentially new therapeutic candidates. Furthermore, the unique ability to interrogate many variables in a combinatory and high throughput fashion can lead to new insights of the modes of action and inform future design of immunotherapeutics.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.