Development of an Oral Carrier

口腔载体的开发

• 批准号: 7500846
• 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/7500846
• 关键词: Adverse effects; Affinity; Antibody Formation; Antigens; Binding; Biologic Characteristic; Biological; Botulinum Toxins; Cells; Chimeric Proteins; Cholinergic Agents; 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; Purpose; Range; 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; concept; experience; glycosylation; immunogenic; immunogenicity; in vivo; interest; monolayer; mutant; neurotropic; new technology; novel; oral status; oral vaccine; polypeptide; receptor mediated endocytosis; research study; size; 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（由申请方提供）：开发了一种用于生产口服疫苗的新技术。这项技术是基于一种多肽的发现（约。50 kDa），具有结合和穿透肠上皮屏障的能力。该过程中的具体步骤是：顶端膜结合;受体介导的内吞作用;转胞吞作用;和基底外侧释放。该多肽穿过上皮屏障而不经历任何结构或功能修饰。 新的多肽结构域可用作载体装置以将异源物质转运到体内。通过将载体与大小不同的物质（mw= ca）连接起来，已经实现了概念验证。200人左右。45，000）和生物活性（即，配体、酶、抗原）。所得的载体-货物构建体已经显示在体外（例如人肠上皮细胞的单层）和体内（例如，小鼠和大鼠模型）。在每种情况下，载体-货物构建体保留其天然结构和其特征性生物活性。已经确定了一种将利用新技术的主导产品。该产品将是一种融合蛋白，其结合了与破伤风抗原连接的载体多肽，以产生针对破伤风毒素的口服疫苗。在与美国食品和药物管理局举行正式会议之前，将对主要产品进行一系列研究。建议研究的主要目标是：1。消除载体与非上皮细胞2.降低或消除载体的免疫原性3.证实非亲神经性、非免疫原性载体4的功效。为了证明修饰的载体和修饰的载体-破伤风抗原构建体没有毒性，如果成功，这项工作应该证明粘膜破伤风疫苗值得作为临床产品进行评价。