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: 8903017
• 负责人: Judith H Merritt
• 金额: $ 63.69万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8903017
• 关键词: ABO blood group system; Accounting; Address; Anabolic Agents; Anabolism; Animal Model; Animals; Bacteria; Benchmarking; Biochemical Reaction; Biodistribution; Biological; Biological Products; Bioreactors; Blood Transfusion; Blood typing procedure; Chemicals; Clinical; Collaborations; Data; Development; Diabetes Mellitus; Dose; Drug Kinetics; Drug Targeting; Engineering; Escherichia coli; FDA approved; Frequencies; Generations; Glucagon; Glycoconjugates; Glycopeptides; Goals; HIV; Half-Life; Hormone use; Hormones; Human; Human body; Hypercalcemia; Hypoparathyroidism; Immune; In Vitro; Industry; Injection of therapeutic agent; Lead; Marketing; Methods; Oligosaccharides; Osteoporosis; Parathyroid gland; Patients; Peptide Hydrolases; Peptides; Performance; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phase; Polymers; Polysaccharides; Positioning Attribute; Preclinical Testing; Process; Production; Property; Proteins; Reaction; Recombinant Proteins; Recombinants; Relative (related person); Resistance; Sales; Sampling; Serum; Solubility; Solutions; Subcutaneous Injections; Synthesis Chemistry; Technology; Teriparatide; Testing; Therapeutic; Time; Treatment Efficacy; Validation; analog; bacterial H antigen; blood group; commercialization; cost; cost effective; drug candidate; exenatide; glucagon-like peptide; glycosylation; human PTH protein; human disease; improved; in vitro activity; microorganism; mouse model; novel; pathogenic Escherichia coli; physical property; pre-clinical; public health relevance; recombinant peptide; research clinical testing; response; scale up; screening; small molecule; success; sugar

 DESCRIPTION (provided by applicant): 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 suffer from poor stability and short half-lives in the human body, which limits their value. The requirement for high dosing and frequent injections can be inconvenient, expensive, and dangerous for patients. While there have been methods developed to address these issues, they either: (i) hinge on the 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 humanlike oligosaccharides. 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. At Glycobia we have developed novel strains of Escherichia coli for the expression of recombinant peptides conjugated to humanlike oligosaccharides. In Phase I of this project, we applied our glycoengineered bacteria as a platform for the biosynthesis of therapeutic glycopeptides by: (1) expressing a panel of therapeutic peptide glycoconjugates and screening for glycosylation efficiency and (2) screening glycoconjugate drug candidates for physical properties and in vitro activity. We show proof-of-concept of several recombinant peptides with improved stability and/or activity when modified with glycosylation. Now having identified lead candidates for Phase II of this project, the objective of this proposal is to synthesize and advance our first drug targets from glycoengineered E. coli into preclinical testing by: (1) expressing, scaling up, purifying, and characterizing a glycosylated human peptide drug from in E. coli and (2) testing pharmacology, calcemic response and pharmacokinetics of a glycosylated human peptide drug in animal models. We will attach two different humanlike glycans to the drug and compare performance to an aglycosylated version of the drug. The benchmark of success for this project is the generation of positive preclinical validation data to further advance commercialization of this glycoengineering technology. Our bacterial expression platform represents a transformative solution to the unanswered biomedical challenge of producing improved therapeutic peptides for patients.

 描述（由适用提供）：治疗性胡椒用于治疗从HIV到糖尿病等的人类疾病，并具有小分子和重组蛋白药物的一些最佳特征。治疗性辣椒的年度药品销售额为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，治疗性辣椒的稳定性较差，人体中的半衰期短，这限制了其价值。高剂量和经常注射的需求对患者来说可能是不方便的，昂贵的和危险的。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）在 体外处理步骤，增加制造成本并使纯化复杂化。现在，通过与类似人类的寡糖结合，可以大大改善胡椒药的稳定性和半衰期。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，这使这一诺言概念无法达到工业规模。在糖过程中，我们开发了新型的大肠杆菌菌株，用于表达与人类寡糖相结合的重组胡椒。 In Phase I of this project, we applied our glycoengineered bacteria as a platform for the biosynthesis of thermal glycopeptides by: (1) expressing a panel of Therapeutic Peptide Glycoconjugates and screening for glycosylation efficiency and (2) screening Glycoconjugate Drug Candidates for physical properties and in vitro activity.当用糖基化修饰时，我们显示了几种重组肽的概念证明，具有改善的稳定性和/或活性。 Now having identified lead candidates for Phase II of this project, the objective of this proposal is to synthesize and advance our first drug targets from glycoengineered E. coli into preclinical testing by: (1) expressing, scaling up, purifying, and characterizing a glycosylated human peptide drug from in E. coli and (2) testing pharmacology, calcemic response and pharmacokinetics of a glycosylated human peptide动物模型中的药物。我们将在药物上附上两种不同的人类聚糖，并将性能与该药物的型糖基化版本进行比较。该项目成功的基准是生成积极的临床前验证数据，以进一步推进这种糖工技术的商业化。我们的细菌表达平台代表了针对未解决的生物医学挑战的一种变革解决方案，该挑战是为患者产生改善的治疗性宠物。