Glycoconjugate therapeutic peptides for improved treatment of human diseases

用于改善人类疾病治疗的糖缀合物治疗肽

• 批准号: 8525563
• 负责人: Adam Charles Fisher
• 金额: $ 19.78万
• 依托单位: GLYCOBIA, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8525563
• 关键词: ABO blood group system; Accounting; Address; Anabolism; Animal Model; Animals; Bacteria; Biodistribution; Biological Assay; Biological Availability; Biological Products; Blood Transfusion; Blood typing procedure; Cells; Diabetes Mellitus; Dose; Engineering; Escherichia coli; Evolution; FDA approved; Glycoconjugates; Glycopeptides; Glycoproteins; Goals; HIV; Half-Life; Hormones; Human; Human body; Immune; In Vitro; Injection of therapeutic agent; Insulin; Laboratories; Lead; Light; Link; Manufacturer Name; Marketing; Methods; Modification; Oligosaccharides; Patients; Peptide Hydrolases; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Polymers; Polysaccharides; Positioning Attribute; Preclinical Testing; Process; Production; Property; Proteins; Reaction; Recombinant Proteins; Recombinants; Resistance; Sales; Serum; Solubility; Solutions; System; Technology; Teriparatide; Testing; Therapeutic; Thrombin; Viral Tumor Antigens; Work; bacterial H antigen; base; biomaterial compatibility; bivalirudin; blood group; candidate identification; cost; cost effective; drug candidate; exenatide; glucagon-like peptide; glycosylation; human disease; improved; in vitro activity; inhibitor/antagonist; novel; phase 2 study; pre-clinical; preclinical study; public health relevance; recombinant peptide; small molecule; sugar

DESCRIPTION: Therapeutic peptides are used to treat human diseases ranging from HIV to diabetes and have some of the best features of small molecule and recombinant protein drugs. Therapeutic peptides account for $13 billion of annual pharmaceutical sales and are part of a growing sector of the biopharmaceutical market. Unfortunately, therapeutic peptides typically suffer from poor stability and short half-lives in the human body, which limits their value. The requirement for high dosing and frequent injections follows, which can be inconvenient, expensive, and dangerous for patients. While there have been methods developed to address these issues, they either: (i) hinge on in vitro or recombinant attachment of a large polymer chain, which dramatically impacts peptide activity or (ii) require in vitro processing steps which increase manufacturing costs and complicate purification. It is now well-established that the stability and half-life of peptide drugs can be greatly improved by conjugation to oligosaccharides that are nonimmunogenic in the human body. Several therapeutic peptides (e.g., Exenatide, Glucagon-like peptide 1) have benefitted significantly from glycosylation with small, human-like glycans by increasing protease resistance, prolonging activity, and improving biodistribution. However, this requires multiple complicated in vitro reactions and purifications which have kept this promising concept from reaching the industrial scale. Glycobia has developed a transformative solution to this growing, unsolved problem by engineering bacteria as a platform for the biosynthesis of therapeutic glycopeptides. These novel strains of Escherichia coli are useful for the expression of recombinant peptides conjugated to nonimmunogenic, human-like oligosaccharides. The hypothesis to be tested here is that non-pathogenic, glycoengineered strains of E. coli can produce affordable recombinant peptide drugs with improved stability, biocompatibility, and prolonged half-life in serum. The main objective of this Phase I project is to identify and characterize peptide drug candidates for animal and preclinical studies in Phase II of this project. This will be accomplished through the following specific aims: (1) express a panel of therapeutic peptide glycoconjugates and screen for expression and glycosylation efficiency; and (2) screen glycoconjugate drug candidates for biophysical properties and in vitro activity. The panel of peptides to be studied here includes seven FDA- approved therapeutic peptides that will be evaluated for expression in the glycoengineered E. coli system. Of these seven peptides, five are currently produced using recombinant expression systems and account for over $2.6 billion in annual sales. Each of the targets will be assayed for solubility, stability, and in vitro activity. This information will be considered along with the commercial potential of each peptide, leading to the identification of candidate peptides for Phase II of this project.

描述：治疗性多肽用于治疗从艾滋病毒到糖尿病的各种人类疾病，具有小分子和重组蛋白药物的一些最佳特性。治疗性多肽占年药品销售额的130亿美元，是生物制药市场日益增长的一部分。不幸的是，治疗性多肽在人体内的稳定性差，半衰期短，这限制了它们的价值。接下来是对高剂量和频繁注射的要求，这可能会给患者带来不便、昂贵和危险。虽然已经开发了一些方法来解决这些问题，但它们要么是依赖于大分子链的体外或重组连接，这会极大地影响肽的活性，要么是需要体外加工步骤，增加了制造成本和复杂的纯化。现在公认的是，多肽药物的稳定性和半衰期可以通过与在人体内不具免疫原性的低聚糖结合来大大改善。几种治疗性多肽(如埃塞那肽、胰高血糖素样肽1)通过与类人小聚糖糖基化而显著受益，因为它们增加了对蛋白水解酶的抵抗力，延长了活性，改善了生物分布。然而，这需要多次复杂的体外反应和纯化，这使得这一有希望的概念无法达到工业规模。Glycobia已经开发出一种变革性的解决方案，通过将细菌工程化为生物合成治疗性糖肽的平台，来解决这个日益增长的、尚未解决的问题。这些新的大肠杆菌菌株可用于表达与非免疫原性类人低聚糖结合的重组多肽。这里要测试的假设是，非致病性的糖工程大肠杆菌菌株可以生产出价格合理的重组多肽药物，具有更好的稳定性、生物相容性和延长的血清半衰期。这个第一阶段项目的主要目标是确定和表征在该项目第二阶段进行动物和临床前研究的候选多肽药物。这将通过以下特定目标来完成：(1)表达一组治疗性多肽糖偶联物并筛选其表达和糖基化效率；以及(2)筛选具有生物物理性质和体外活性的候选糖结合物药物。这里要研究的一组多肽包括7个FDA批准的治疗性多肽，它们将在糖工程大肠杆菌系统中进行表达评估。在这七种多肽中，有五种目前是使用重组表达系统生产的，年销售额超过26亿美元。将对每个靶标进行溶解度、稳定性和体外活性的检测。这些信息将与每种多肽的商业潜力一起考虑，从而为该项目的第二阶段确定候选多肽。