Development of an Oral Carrier

口腔载体的开发

• 批准号: 7679390
• 负责人: LANCE L SIMPSON
• 金额: $ 32.16万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7679390
• 关键词: Adverse effects; Affinity; Antibody Formation; Antigens; Binding; Biologic Characteristic; Biological; Botulinum Toxins; Cells; Chimeric Proteins; Clinical; Cosmetics; Data; Development; Devices; Disease; Dystonia; Engineering; Ensure; Enzymes; Epithelial; Epithelial Cells; Esthetics; Evaluation; Goals; Grant; Human; Immune system; Immunity; In Vitro; Injection of therapeutic agent; Investigational Drugs; Lead; Ligands; Link; Modeling; Modification; Molecular; Molecular Weight; Mus; Nerve; Nerve Endings; Neurons; Oral; Penetration; Peptides; Principal Investigator; Process; Property; Rattus; Research; Route; Series; Site; Staging; Structure; Targeted Toxins; Techniques; Technology; Tetanus; Tetanus Toxin; Tetanus Vaccine; Toxic effect; Toxin; United States Food and Drug Administration; Work; absorption; apical membrane; base; botulinum toxin type E; cholinergic; experience; glycosylation; immunogenic; immunogenicity; in vivo; interest; meetings; monolayer; mutant; neurotropic; new technology; novel; oral status; oral vaccine; polypeptide; receptor mediated endocytosis; research study; transcytosis

DESCRIPTION (provided by applicant): A new technology has been developed for the creation of oral vaccines. This technology is based on the discovery of a polypeptide (ca. 50 kDa) that possesses the ability to bind and penetrate gut epithelial barriers. The specific steps in the process are: apical membrane binding; receptor-mediated endocytosis; transcytosis; and basolateral release. The polypeptide crosses epithelial barriers without undergoing any structural or functional modifications. The novel polypeptide domain can be utilized as a carrier device to transport heterologous substances into the body. Proof of concept has been achieved by linking the carrier to a host of substances that differ in size (mw= ca. 200 to ca. 45,000) and in biological activity (i.e., ligand, enzyme, antigen). The resulting carrier~cargo constructs have been shown to cross epithelial barriers in vitro (e.g. monolayers of human gut epithelial cells) and in vivo (e.g., mouse and rat models). In every case, the carrier~cargo constructs retained their native structure and their characteristic biological activity. A lead product has been identified that will utilize the new technology. This product will be a fusion protein that incorporates the carrier polypeptide linked to a tetanus antigen to create an oral vaccine against tetanus toxin. A series of studies will be performed with the lead product in anticipation of a formal meeting with the Food and Drug Administration. The major goals of the proposed studies will be: 1. To eliminate carrier binding to non-epithelial cells 2. To reduce or abolish the immunogenicity of the carrier 3. To confirm the efficacy of the non-neurotropic, non-immunogenic carrier 4. To demonstrate an absence of toxicity of the modified carrier and the modified carrier~tetanus antigen construct If successful, this work should demonstrate that a mucosal tetanus vaccine is worthy of evaluation as a clinical product.

描述(由申请人提供)：已经开发出一种用于制造口服疫苗的新技术。这项技术的基础是发现了一种多肽(约50 kDa)，它具有结合和穿透肠道上皮屏障的能力。这一过程的具体步骤是：顶膜结合；受体介导的内吞作用；跨细胞作用；以及基侧释放。这种多肽无需进行任何结构或功能修饰即可跨越上皮屏障。该新型多肽结构域可以作为载体装置将异源物质输送到体内。通过将载体与许多大小不同(MW=约200至约45,000)和生物活性(即配体、酶、抗原)的物质相连接，实现了概念验证。在体外(例如，人类肠道上皮细胞的单层)和体内(例如，小鼠和大鼠模型)，已经证明所得到的载体~Cargo构建物能够跨越上皮屏障。在每种情况下，载体~货物结构都保留了它们的天然结构和它们特有的生物活性。已经确定了一种将利用这项新技术的主导产品。该产品将是一种融合蛋白，它结合了与破伤风抗原相连的载体多肽，以创建针对破伤风毒素的口服疫苗。将对这种主要产品进行一系列研究，以期与食品和药物管理局举行正式会议。本研究的主要目标是：1.消除载体与非上皮细胞的结合；2.降低或取消载体的免疫原性；3.证实非神经亲和性、非免疫原性载体的有效性；4.证明改良载体和改良载体-破伤风抗原构建成功后的无毒性，这项工作将证明黏膜破伤风疫苗作为临床产品是值得评价的。