Natural Glycans for Functional Glycomics

用于功能糖组学的天然聚糖

• 批准号: 10217203
• 负责人: David Fletcher Smith
• 金额: $ 78.02万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10217203
• 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.

用于功能糖组学的天然聚糖 项目概要/摘要 在 21 世纪的第一个十年，NIH 在糖组学方面进行了大量投资。该联盟为 功能糖组学（由 NIGMS 2001-2012 支持）领导了一项重大的国际努力，使用微阵列 611 个已定义的聚糖，用于识别与正常生理和疾病相关的蛋白-聚糖相互作用 （http://www.functiongicomics.org/CFGparadigms/index.php/Welcome_to_the_CFG_Paradigm_Pages）。这 611 聚糖文库改变了蛋白质-聚糖相互作用的研究，并揭示了定义的重要性 人类糖组，估计有 10,000 个决定因素。微阵列包含所有可能的 聚糖将使我们能够检测和定义所有生理相关的聚糖结合蛋白（GBP），但是 CFG 文库现在只有 575 个聚糖，从而可以生产大量纯的、确定的聚糖 功能研究对于推进糖组学至关重要；例如，毫克级纯母乳低聚糖 (HMO)， 自 1950 年代以来支持的研究使我们了解了 HMO 在母乳喂养中的益处 婴儿配方奶粉制造商根据临床情况，于 2014 年将 HMO 引入其产品中 支持其功效的试验。另一方面，在所有细胞表面表达的哺乳动物聚糖是 通常数量很少；让它们像 HMO 一样可供研究界使用 快速推进对它们在动物细胞中的功能的理解。现在可以使用我们的专有技术 天然聚糖氧化释放 (ORNG) 技术，通过化学方式释放聚糖 使用家用漂白剂的任何天然材料的糖复合物。 NatGlycan, LLC (NGC) 成立是为了 可靠、经济、大量地提供生物学相关的天然聚糖。在第一阶段我们 证明了生产毫克级高甘露糖 N-聚糖并出售给糖科学的可行性 第一次社区。我们相信规模经济将支持合理的价格。西格玛奥德里奇出售 20μg Man9GlcNAc2 售价为 688 美元，而 NGC 的售价为 750 美元，5 毫克 Man9GlcNAc2-AEAB。在本次第二阶段 项目中，我们将建成一个生产设施，生产 100 毫克（纯度 >95%）的所有高甘露糖 N- 对糖生物学界有用的聚糖和衍生物。此外，我们计划推出高度 纯化的 N-聚糖代表在人和重组 IgG 上表达的所有结构，用作 QC 单克隆抗体生产标准；目前制药行业的需求尚未得到满足。自 ORNG 发布以来 同时从天然产品中提取所有类别的聚糖，我们将迅速扩大我们的产品范围。我们将 纯化需求量很大但目前无法以合理成本获得的主要 O-聚糖。我们预计 到第二阶段结束时，我们将提供数百种 N-聚糖和 O-聚糖（纯度 >95%）和有用的 数毫克量的衍生物。基于我们初始产品目录后的大量销售和订单 推出后，我们预计能够支持我们的聚糖制造成本并增加利润率，因为我们 未来将扩大生产规模。