BLOCKING STD PATHOGEN ENTRY WITH MUCOSAL ANTIBODIES

用粘膜抗体阻断性病病原体进入

• 批准号: 6654007
• 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: 2002-09-01 至 2003-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6654007
• 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.

许多用于预防性传播疾病（std）的阴道杀菌剂具有广谱作用，不限于病原体，例如，洗涤剂可能破坏上皮的完整性；相反，抗体是高度特异性的杀菌剂，然而，通过组合工作可以实现广谱保护，而不会伤害健康组织或共生体。抗体的特异性以及它们的多功能性和多样性使它们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通过阴道粘膜进入。生物技术产品现在正在植物中生产，以实现低成本和高产能的生产，第一个具体目标是确定在玉米中作为“植物体”转基因产生的人类抗HSV2抗体在小鼠和兔子阴道中的药代动力学。在小鼠模型中利用现有小鼠抗体确定了最有效的靶点后，下一个目标是在小鼠模型中产生保护性的人单克隆抗体，接下来的两个目标是通过噬菌体展示产生保护性的人HPV 16单克隆抗体，以及在转基因小鼠中产生保护性的细胞相关HIV、衣原体和淋病单克隆抗体。这些人单克隆抗体将在体外和性病/小鼠模型中评估其保护功效。由于抗体可能有助于创造一个保护性共生体生长的阴道环境，因此最终目的是测试这种概念，即通常应用的抗体可以特异性地减少小鼠体内潜在有害的阴道共生体。这些人类单克隆抗体的组合将为开发广谱而特异的杀微生物剂以预防性传播疾病奠定基础。