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.

许多正在评估的用于防止性传播疾病(STD)的阴道杀菌剂具有广谱作用，这些作用并不局限于病原体，例如洗涤剂可能破坏上皮完整性：相比之下，抗体是高度特异的杀微生物剂，然而，通过联合使用可以在不损害健康组织或共生体的情况下实现广谱保护。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定杀菌剂的主要候选者(以及工具)，这些杀菌剂可以阻止病原体进入阴道粘膜。目前正在植物中生产生物技术产品，以实现低成本和高产能的生产，第一个具体目标是确定通过转基因玉米生产的HSV2人抗体在小鼠和兔阴道中的药代动力学。在利用小鼠模型中现有的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类单抗，接下来的两个目标是通过噬菌体展示产生保护性的人对HPV16的单抗，以及在转基因小鼠中产生对细胞相关的艾滋病毒、衣原体和淋病的单抗。这些人类单抗将在体外和STD/小鼠模型中进行保护效果评估。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共生体可以蓬勃发展，最终目标是测试通常应用抗体可以特别减少小鼠潜在有害的阴道共生体这一概念。这些人类单抗的组合将形成一种广谱但特异的杀微生物剂的基础，以防止性传播疾病。