SBIR Phase I: Ion Mobility Spectrometer for Macromolecular Analysis

小型企业创新研究(SBIR)项目更广泛的影响/商业潜力是提供分析技术，促进复杂生物制造产品的商业开发。最迫切的需要是减少将最新一代生物治疗药物推向市场的时间和成本。目前，将一种候选药物从发现阶段转移到最终批准阶段需要花费8年以上的时间和10亿美元。在此过程中，用于产品认证的分析测试程序耗费了3亿美元。美国的医疗体系将受益于新的、更便宜的分析技术，这些技术可以降低认证成本，并导致更便宜的药物。使用所提出的技术还可以提高制造效率。生物制造的产品是从培养的细胞中收获的，有时培养过程无法产生完美的产品。在生产过程中检测杂质和腐败将进一步降低制造成本，并通过提供更好的治疗产品和治疗方案直接造福消费者。这个SBIR第一阶段项目建议量化离子迁移谱仪作为筛选生物治疗药物构象变化、纯度和聚集的高通量工具的有效性。构象赋予蛋白质功能，构象的任何变化都意味着生化活性的变化，这是不可取的。离子迁移率是一种确定分子横截面的技术，而分子横截面又是分子构象的量度。确定蛋白质构象的金标准是X射线结晶学，这是一种受吞吐量限制的方法。有一种尚未得到满足的需求，即开发更快的方法来测量蛋白质构象。建议的技术在生物治疗药物开发的所有阶段快速确定蛋白质构象，从发现、表达系统测试、放大到制造。此外，这种离子迁移率光谱仪的专利设计提供了一种测量构象变化的方法，根据药物稳定性和发展性测试的需要，这些变化可能是暴露在热、化学和光诱导压力下的结果。拟议的工作将量化这台台式仪器的分辨率、重复性、准确性和吞吐量。这项评估将使用抗原-抗体对和几种生物治疗药物，与一个学术团体和行业合作伙伴合作进行。这一奖项反映了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) project is to provide analytical technology that will foster the commercial development of complicated biomanufactured products. The most pressing need is to reduce the time and cost to bring the latest generation of biotherapeutic drugs to market. Currently, upwards of eight years and $1B is spent to move a candidate drug from discovery through final approval. Along the way $300M is consumed by analytical testing procedures to certify the product. The American healthcare system will benefit from new and less expensive analytical technologies that reduce certification costs and lead to less expensive drugs. Manufacturing efficiency also can be improved using the proposed technology. Biomanufactured products are harvested from cultured cells, and there are times when the culturing process fails to produce a perfect product. Detecting impurities and spoilage during manufacturing will further reduce manufacturing costs and directly benefit the consumer through the delivery of better therapeutic products and treatment regimens.This SBIR Phase I project proposes to quantify the validity of an ion mobility spectrometer as a high-throughput tool for screening conformational variation, purity, and aggregation of biotherapeutic drugs. Conformation imparts functionality to a protein and any variation in conformation implies there is a variation in biochemical activity, which is undesirable. Ion mobility is a technique that determines molecular cross-section, which in turn is a measure of a molecule's conformation. The gold standard for determining protein conformation is x-ray crystallography, a methodology limited by throughput. There is an unmet need to develop faster ways to measure protein conformation. The proposed technology determines a protein conformation rapidly across all phases of biotherapeutic drug development from discovery, expression system testing, scale up and manufacturing. Additionally, the patented design for this ion mobility spectrometer provides a way to measure changes in conformation that might result as a consequence of exposure to thermal, chemical, and photo-induced stress as needed for drug stability and developability testing. The proposed work will quantify resolution, reproducibility, accuracy, and throughput for this benchtop instrument. The evaluation will be performed using antigen-antibody pairs and several biotherapeutic drugs in collaboration with an academic group and industry partners.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.