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（由申请人提供）：治疗性肽用于治疗从 HIV 到糖尿病等多种人类疾病，并且具有小分子和重组蛋白药物的一些最佳特性。治疗性肽的年药品销售额达 130 亿美元，并且是该药物的一部分。不幸的是，治疗性肽在人体内的稳定性差且半衰期短，这限制了其高剂量和频繁使用的价值。注射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）取决于大聚合物链的体外或重组连接，这会极大地影响肽活性或（ ii) 要求 体外加工步骤增加了制造成本并使纯化变得复杂，目前已经证实，通过与人源寡糖缀合可以大大提高肽药物的稳定性和半衰期（例如艾塞那肽、胰高血糖素样肽 1）。 ）通过增加蛋白酶抗性、延长活性和改善生物分布，从类人小聚糖的糖基化中显着受益。然而，这需要在体外​​出现多种并发症。反应和纯化使得这一有希望的概念无法达到工业规模。在 Glycobia，我们开发了用于表达与类人寡糖缀合的重组肽的新型大肠杆菌菌株。在该项目的第一阶段，我们将我们的糖工程细菌用作通过以下方式生物合成治疗性糖肽的平台：(1) 表达一组治疗性肽糖缀合物并筛选糖基化效率，以及 (2) 筛选我们展示了几种重组肽在经过糖基化修饰后稳定性和/或活性得到改善的概念验证，这是该项目第二阶段的主要候选药物。提案是通过以下方式合成我们的第一个糖基化大肠杆菌靶点并将其推进临床前测试：(1) 在大肠杆菌中表达、放大、纯化和表征糖基化人类肽药物(2) 在动物模型中测试糖基化人类肽药物的药理学、钙血反应和药代动力学。我们将在该药物上附加两种不同的类人聚糖，并将其与非糖基化版本的药物进行比较。该项目成功的基准是。产生积极的临床前验证数据，以进一步推进这种糖工程技术的商业化，我们的细菌表达平台代表了为患者生产改进的治疗肽这一尚未解决的生物医学挑战的变革性解决方案。