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：治疗性肽用于治疗从艾滋病毒到糖尿病等人类疾病，并具有小分子和重组蛋白药物的一些最佳特性。治疗性肽占年度药品销售额 130 亿美元，是生物制药市场不断增长的领域的一部分。不幸的是，治疗性肽通常稳定性差且在人体内半衰期短，这限制了它们的价值。随之而来的是高剂量和频繁注射的要求，这对患者来说可能不方便、昂贵且危险。虽然已经开发出解决这些问题的方法，但它们要么：（i）依赖于大聚合物链的体外或重组附着，这极大地影响肽活性，要么（ii）需要体外加工步骤，这增加了制造成本并使复杂化纯化。现在已经确定，肽药物的稳定性和半衰期可以通过与人体内非免疫原性的寡糖缀合而大大提高。几种治疗性肽（例如艾塞那肽、胰高血糖素样肽 1）通过使用小型类人聚糖进行糖基化，可增加蛋白酶抗性、延长活性并改善生物分布，从而显着受益。然而，这需要多次复杂的体外反应和纯化，这使得这个有前途的概念无法达到工业规模。 Glycobia 通过将细菌改造为治疗性糖肽生物合成的平台，针对这一日益严重的未解决问题开发了一种革命性的解决方案。这些新的大肠杆菌菌株可用于表达与非免疫原性类人寡糖缀合的重组肽。这里要测试的假设是，非致病性、糖工程化的大肠杆菌菌株可以生产价格实惠的重组肽药物，并具有改善的稳定性、生物相容性和延长的血清半衰期。该第一阶段项目的主要目标是识别和表征用于该项目第二阶段动物和临床前研究的候选肽药物。这将通过以下具体目标来实现：（1）表达一组治疗性肽糖缀合物并筛选表达和糖基化效率； (2)筛选复合糖药物候选物的生物物理特性和体外活性。这里要研究的肽组包括七种 FDA 批准的治疗性肽，将评估它们在糖工程大肠杆菌系统中的表达。在这七种肽中，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。将检测每个靶标的溶解度、稳定性和体外活性。这些信息将与每种肽的商业潜力一起考虑，从而确定该项目第二阶段的候选肽。