BLOCKING STD PATHOGEN ENTRY WITH MUCOSAL ANTIBODIES

用粘膜抗体阻断性病病原体进入

• 批准号: 6602128
• 负责人: Kevin John Whaley
• 金额: $ 18.05万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6602128
• 关键词: Chlamydiaceae; Neisseria gonorrhoeae; antibacterial agents; antiviral agents; biotechnology; disease /disorder model; genetically modified animals; herpes simplex virus 2; human papillomavirus; laboratory mouse; laboratory rabbit; monoclonal antibody; mucosal immunity; pharmacokinetics; sexually transmitted diseases; topical drug application; vagina

Many vaginal microbicides being evaluated for the prevention of sexually transmitted diseases (STDs) have broad-spectrum actions that are not limited to pathogens, e.g. detergents may disrupt epithelial integrity: In contrast, antibodies are microbicides that are highly specific, yet, by working in combination can achieve broad spectrum protection without injuring healthy tissues or commensals. The specificity of antibodies together with their versatility and diversity make them leading candidates (as well as tools) for developing specific microbicides that can block pathogen entry across the vaginal mucosa. Biotechnology products are now being produced in plants both to achieve low cost and high capacity production, and the first specific aim is to determine the pharmacokinetics in the mouse and rabbit vagina of a human antibody to HSV2 produced transgentically in corn as a "plantibody". After determining the most efficacious targets using existing mouse antibodies in mouse models, the next aims are to generate protective human monoclonal antibodies in mouse models, the next two aims are to generate protective human monoclonal antibodies to HPV 16 by phage display and to cell-associated HIV, chlamydia and gonorrhea in transgenic mice. These human monoclonal antibodies will be evaluated in vitro and in STD/mouse models for protective efficacy. Since antibodies may help create a vaginal environment in which protective commensals can flourish, the final aim is to test the concept that typically applied antibodies can specifically reduce a potentially harmful vaginal commensal in mice. A combination of these human monoclonal antibodies will form the basis for the development of a broad-spectrum yet specific microbicide to prevent sexually transmitted diseases.

许多被评估用于预防性传播疾病（STD）的阴道杀微生物剂具有广谱作用，不限于病原体，例如洗涤剂可能破坏上皮完整性：相反，抗体是高度特异性的杀微生物剂，但通过组合工作可以实现广谱保护而不伤害健康组织或组织。抗体的特异性及其多功能性和多样性使其成为开发特异性杀微生物剂的主要候选者（以及工具），这些杀微生物剂可以阻止病原体进入阴道粘膜。生物技术产品目前正在植物中生产，以实现低成本和高产能生产，第一个具体目标是确定在玉米中作为“植物体”转基因产生的HSV 2人抗体在小鼠和兔阴道中的药代动力学。在小鼠模型中使用现有的小鼠抗体确定最有效的靶标之后，下一个目标是在小鼠模型中产生保护性人单克隆抗体，接下来的两个目标是通过噬菌体展示产生针对HPV 16的保护性人单克隆抗体，以及在转基因小鼠中产生针对细胞相关的HIV、衣原体和淋病的保护性人单克隆抗体。将在体外和STD/小鼠模型中评价这些人单克隆抗体的保护效力。由于抗体可能有助于创造一个阴道环境，在这个环境中，保护性阴道炎可以蓬勃发展，最终的目标是测试通常应用的抗体可以特异性地减少小鼠中潜在有害的阴道炎的概念。这些人类单克隆抗体的组合将构成开发广谱但特异性杀微生物剂以预防性传播疾病的基础。