Natural Glycans for Functional Glycomics

用于功能糖组学的天然聚糖

• 批准号: 10081713
• 负责人: David Fletcher Smith
• 金额: $ 109.07万
• 依托单位: NATGLYCAN, LLC
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10081713
• 关键词: Acetonitriles; Address; Agreement; Aliquot; Animals; Binding Proteins; Biological; Biological Process; Budgets; Catalogs; Cattle; Cells; Chemistry; Clinical Trials; Colostrum; Communities; Complex; Contracts; Development; Disease; Drug Industry; Egg White; Egg Yolk; Equipment; Equipment and supply inventories; Exhibits; Functional disorder; Funding; Future; Glycobiology; Glycoconjugates; Glycolipids; Glycosaminoglycans; Goals; Heparin; High Pressure Liquid Chromatography; Household; Human; Human Milk; Hybrids; Immunoglobulin G; Incubators; Industrialization; Industry; Infant; Infant formula; International; Investments; Isomerism; Kilogram; Laboratories; Letters; Libraries; Link; Mannose; Manufacturer Name; Mission; Monoclonal Antibodies; Mucins; National Institute of General Medical Sciences; Natural Products; Oligosaccharides; Peptide Nucleic Acids; Pharmacologic Substance; Phase; Physiological; Physiology; Play; Polysaccharides; Powder dose form; Preparation; Price; Process; Production; Proteins; Protocols documentation; Quality Control; Reagent; Recombinants; Reproducibility; Research; Research Personnel; Research Support; Role; Sales; Sampling; Societies; Source; Structure; Surface; System; Technology; Time; United States National Institutes of Health; Vendor; Vial device; Water; Work; base; chemical release; commercialization; cost; experience; in vivo; indexing; interest; mannosyl(9)-N-acetylglucosamine2; manufacturing facility; manufacturing process; meetings; method development; milligram; oxidation; quality assurance; synthetic peptide

Natural Glycans for Functional Glycomics Project Summary/ Abstract During the first decade of the 21st century, NIH made significant investments in glycomics. The Consortium for Functional Glycomics (supported by NIGMS 2001-2012) led a major international effort using a microarray of 611 defined glycans to identify the protein-glycan interactions associated with normal physiology and disease (http://www.functionalglycomics.org/CFGparadigms/index.php/Welcome_to_the_CFG_Paradigm_Pages). This 611 glycan library transformed studies on protein-glycan interactions and revealed the importance of defining the human glycome, estimated to be in the range of 10,000 determinants. A microarray comprised of all possible glycans would allow us to detect and define all physiologically relevant glycan binding proteins (GBP), but the CFG library is now only 575 glycans making the production of large quantities of pure, defined glycans for functional studies critical for advancing glycomics; e.g, mgs of pure human milk oligosaccharides (HMO), available since the 1950’s supported research that led to our understanding of the benefits of HMO in breasfed infants, resulting in infant formula manufacturers introducing HMO into their products in 2014, based on clinical trials supporting their efficacy. Mammalian glycans,on the other hand, expressed on the surfaces of all cells, are generally available only in minute quantities; making them as available as HMO to the research community would rapidly advance understanding of their functions in animal cells. This is now possible using our proprietary technology, Oxidative Release of Natural Glycans (ORNG), which chemically releases glycans from glycoconjugates of any natural material using household bleach. NatGlycan, LLC (NGC) was established to provide biologically relevant natural glycans reliably, economically, and in large quantities. In Phase I we demonstrated the feasibility of producing high mannose N-glycans in mg quantities for sale to the glycoscience community for the first time. We believe the economy of scale will support reasonable prices. Sigma-Aldrich sells 20µg of Man9GlcNAc2 for $688, while NGC is selling 5 mg of Man9GlcNAc2-AEAB for $750. In Phase II of this project we will complete a manufacturing facility to produce 100’s of mg (purity >95%) of all high mannose N- glycans and derivatives that will be useful to the glycobiology community. In addition, we plan to launch highly purified N-glycans representing all of the structures expressed on human and recombinant IgG for use as QC standards in mAb manufacturing; currently an unmet need in the pharmaceutical industry. Since ORNG releases all classes of glycans simultaneously from natural products, we will rapidly expand our product offerings. We will purify the major O-glycans that are in great demand, but not currently available at reasonable cost. We anticipate that by the end of Phase II, we will be offering hundreds of N-glycans and O-glycans (purity >95%) and useful derivatives in multi-miligram amounts. Based on significant sales and orders after our initial product catalog launch, we anticipate being able to support our glycan manufacturing costs and increase profit margins as we increase manufacturing scale in the future.

用于功能性糖类的天然多糖 项目摘要/摘要 在21世纪的第一个十年里，美国国立卫生研究院在糖组学方面进行了重大投资。联合企业联盟 Functional Glycomics(由NIGMS 2001-2012支持)领导了一项重大的国际努力，使用了 确定与正常生理和疾病相关的蛋白质-多聚糖相互作用 (http://www.functionalglycomics.org/CFGparadigms/index.php/Welcome_to_the_CFG_Paradigm_Pages).这 611糖链文库改变了蛋白质-糖链相互作用的研究，揭示了确定 人类的糖类，估计在10,000个决定因素的范围内。由所有可能的基因组成的微阵列 多聚糖可以让我们检测和定义所有生理上相关的多聚糖结合蛋白(GBP)，但 CFG文库现在只有575个多糖，可以大量生产纯的、有定义的多糖用于 对推进糖组分至关重要的功能研究；例如，纯人乳寡糖(HMO)的毫克， 自20世纪50年代以来，S支持了一些研究，这些研究使我们了解了HMO对母乳喂养的好处 婴儿，导致婴儿配方奶粉制造商在2014年将HMO引入他们的产品，基于临床 支持其有效性的试验。另一方面，哺乳动物的多糖表达在所有细胞的表面，是 通常只有很少的数量；让它们像HMO一样提供给研究界将 迅速推进了对它们在动物细胞中的功能的了解。现在可以使用我们的专有技术 技术，天然多糖的氧化释放(ORNG)，从化学上释放多糖 使用家用漂白剂的任何天然材料的糖结合物。NatGlycan，LLC(NGC)成立的目的是 以可靠、经济和大量的方式提供与生物相关的天然多糖。在第一阶段，我们 论证了生产镁含量的高甘露糖N-葡聚糖出售给糖科学公司的可行性 社区，这是第一次。我们相信，规模经济将支撑合理的价格。Sigma-Aldrich销售 20微克的Man9GlcNAc2售价为688美元，而NGC的5毫克Man9GlcNAc2-AEAB的售价为750美元。在这个项目的第二阶段 项目我们将完成一个生产设施，以生产100‘S镁(纯度和>95%)的所有高甘露糖N- 将对糖生物界有用的葡聚糖及其衍生物。此外，我们计划推出高度 表达在人和重组免疫球蛋白上的所有结构的纯化N-糖链用作QC 单抗制造中的标准；目前制药业尚未满足的需求。自ORNG发布以来 所有类别的多糖同时来自天然产品，我们将迅速扩大我们的产品供应。我们会 提纯需求量很大，但目前无法以合理价格获得的主要O-葡聚糖。我们期待着 到第二阶段结束时，我们将提供数百种N-多糖和O-多糖(纯度和95%)和有用的 以毫克为单位的衍生品。基于我们最初的产品目录之后的大量销售和订单 推出后，我们预计能够支持我们的多糖制造成本并提高利润率，因为我们 未来扩大制造规模。