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Tailoring the Hydroxyl Radical Foot-Printing Approach to Provide a Solution for the Higher Order Structural Analysis Needs of the Biopharmaceutical Industry

定制羟基自由基足迹方法，为生物制药行业的高阶结构分析需求提供解决方案

基本信息

批准号：
9902463
负责人：
Scot Randy Weinberger
金额：
$ 99.66万
依托单位：
GENNEXT TECHNOLOGIES, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2021-12-31
项目状态：
已结题

项目摘要

The GenNext Phase II SBIR submssion entitled “Tailoring the Hydroxy Radical Foot-Printing Approach to Provide a Solution for the Higher Order Structural Analysis Needs of the Biopharmaceutical Industry” is responsive to the ackowledged need for new and improved tools for higher order structural analysis (HOS) of biopharmaceuticals. Unlike conventional drugs, biopharmaceuticals are complex, heterogeneous mixtures of 3-dimensional biomolecules, whose safety and efficacy is reliant upon proper HOS. The presence of proteins with improper higher order structure (HOS) has been linked to severe adverse drug reactions, alerting the biopharmaceutical industry to the critical role of HOS, while establishing the need for new and improved HOS analytics. An emerging HOS analysis technique is hydroxyl radical foot-printing (HRPF). HRPF involves the irreversible labeling of a protein’s exterior by reaction with hydroxyl radicals with subsequent MS analysis to identify the outer portions of the protein. The most widely used method for generating OH radicals employs a quick burst of UV light, and is appropriately called fast photochemical oxidation of proteins (FPOP). Typically, a powerful and expensive UV laser is used. Academic laboratories have demonstrated the utility of FPOP for HOS analysis; however adoption in pharma has been minuscule at best. We have identified barriers that have limited the adoption of the HRPF approach in the biopharmaceutical industry. These impediments include: 1) The use of expensive lasers that demand substantial safety precautions; and 2) the irreproducibility of FPOP caused by background scavenging of OH radicals that complicate and limit comparative studies. As such, there are no commercial sample preparation devices for FPOP analysis, despite the demonstrated need for the HOS analytical power. The GenNext proposal creates an improved means of performing HRPF analysis by replacing expensive, hazardous lasers with a flash oxidation system. Moreover, a custom internal standard (dosimetry) system will be included to facilitate ease of use and improve reproducibility. These innovative advancements will decrease the barrier to adoption of HRPF for HOS analysis and will result in accelerated adoption with concomitant impact on biopharmaceutical research and development. In addition to instrumentation sales, GenNext will offer a fee-for-service option for its clients who wish to constrain upfront cost and risk, as they evaluate FOX HOS impact to their program.

GenNext Phase II SBIR Submssion题为“定制羟基自由基足迹法为高阶结构分析提供一种解决方案生物制药行业的需求”是对公认的需求，高阶结构分析（HOS）的新的和改进的工具，生物制药与传统药物不同，生物制药是复杂的，三维生物分子的异质混合物，其安全性和有效性依赖于合适的居屋存在不适当的高级结构的蛋白质 (HOS)与严重的药物不良反应有关，房地产行业对居屋的关键作用，同时建立新的和改善的需求， HOS分析。一种新兴的HOS分析技术是羟基自由基足迹法（HRPF）。 HRPF涉及通过与羟基反应对蛋白质的外部进行不可逆标记随后进行MS分析以鉴定蛋白质的外部部分。的最广泛使用的产生OH自由基的方法采用紫外光的快速爆发，并被适当地称为蛋白质的快速光化学氧化（FPOP）。通常使用强大而昂贵的UV激光器。学术实验室已经证明， FPOP用于HOS分析的实用性;然而，在制药行业的采用率微乎其微，最好我们已经查明了限制采用HRPF方法的障碍，生物制药行业。这些障碍包括：1）使用昂贵的需要大量安全预防措施的激光; 2）FPOP的不可再现性这是由于OH自由基的背景清除造成的，问题研究因此，没有用于FPOP的商业样品制备装置分析，尽管证明需要HOS分析能力。 GenNext提案创建了执行HRPF分析的改进方法用闪光氧化系统代替昂贵的危险激光器。而且将包括定制内标（剂量测定）系统，以便于使用，提高再现性。这些创新性的进步将减少采用HRPF进行居屋计划分析，并会加快采用，对生物制药研究和开发的共同影响。除了仪器销售，GenNext将提供一个收费的服务选择，其客户谁希望以限制前期成本和风险，因为他们评估FOX HOS对其计划的影响。