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HIV到糖尿病的人类疾病，并具有小分子和重组蛋白药物的一些最佳特征。治疗肽占130亿美元的年度药品销售，是生物制药市场不断增长的领域的一部分。不幸的是，治疗性肽通常会遭受人体稳定性和半衰期较短的损失，这限制了其价值。需要进行高剂量和频繁注射的要求，这可能是不方便，昂贵且危险的。尽管已经开发了解决这些问题的方法，但它们要么要么：（i）大型聚合物链的体外或重组附着的铰链，这极大地影响了肽活性，要么（ii）需要进行体外加工步骤，以增加制造成本并使纯化复杂化。现在，通过与人体无免疫原性的寡糖结合，可以极大地改善肽药物的稳定性和半衰期的稳定性和半衰期。几种治疗性肽（例如，艾烯肽，胰高血糖素样肽1）通过增加蛋白酶的耐药性，延长活性和改善生物分布，从糖基化中受益匪浅。但是，这需要多个复杂的体外反应和净化，这使这一有希望的概念无法达到工业规模。糖生物通过工程细菌作为治疗性糖肽的生物合成的平台来为这个不可解力的问题开发了一种变革性的解决方案。这些新型的大肠杆菌菌株可用于表达与非免疫原性的，类人类寡糖结合的重组肽。这里要检验的假设是，大肠杆菌的非致病性糖化菌株可以产生负担得起的重组肽药物，具有提高的稳定性，生物相容性和血清中长时间寿命。该阶段项目的主要目的是在该项目的第二阶段中识别和表征用于动物和临床前研究的肽药物候选物。这将通过以下特定目的完成：（1）表达一组治疗性肽糖缀合物和筛选以表达和糖基化效率； （2）筛选糖缀合物候选物质的生物物理特性和体外活性。这里要研究的肽面板包括七个FDA批准的治疗肽，这些肽将在糖化大肠杆菌系统中进行评估以表达。在这七个肽中，目前使用重组表达系统生产五个肽，并占年销售额超过26亿美元。每个靶标都将用于溶解度，稳定性和体外活性。该信息将与每种肽的商业潜力一起考虑，从而导致该项目第二阶段的候选肽鉴定。