Human Monoclonal Antibodies

直接从免疫供体中分离抗体具有充分利用抗体的优势。 人类对疫苗接种或感染的抗体反应。通过追随抗原特异性的发展命运 通过对B细胞群体抗体的分析，我们可以直接调查B细胞 功能。在我们的人类克隆技术开发项目(TOP)的这次竞争性更新中 抗体我们结合了最近开发的两项独特而强大的新技术，这是第一次 允许对人类B细胞团的特异性进行有效分析。其中一个方法是由Dr。 Lanzavecchia通过高效地生产单抗，提供了对B细胞特异性的整个历史的分析 来自长期记忆的B细胞室。威尔逊和艾哈迈德的第二项技术 实验室仔细检查当前正在进行的浆母细胞特异性，并产生大量的抗原性 在短时间内主要针对抗原的抗体。我们将使用这些工具来 解决有关人类B细胞对黄热病病毒和登革热的基本反应问题 病毒。通过结合这些产生人类单抗(浆母细胞和记忆B细胞)的强大平台 我们应该能够全面分析人类B细胞对这些病毒的反应，并探索 记忆B细胞与抗体分泌浆细胞的关系 因为产生的抗体完全是人类的，所以它们可以做出有价值的诊断，并允许更安全 药物而不是嵌合抗体或人源化抗体。因此，除了解决这些基本问题外， 问题，我们提议的研究也应该导致开发一大批人类单抗 预防YFV和登革热-这两种黄病毒是重要的公共卫生问题，并是高度优先的 生物防御病原体。提出了三个具体的目标：1)原代人类B细胞的特征 对YFV-17D的应答导致ASCs和长期记忆B细胞的产生；2)分析 Booster诱导的ASC和记忆细胞的动力学、可变基因库和特异性 接种YFV-17D疫苗。3)描述人类B细胞对急性登革热病毒感染的反应 孩子们。

The isolation of antibodies directly from immune donors offers the advantage of fully exploiting the strength of the human antibody response to vaccination or infection. By following the developmental fate of antigenspecific B cell populations through analysis of their antibodies we can generate a direct survey of B cell function. In this competitive renewal of our Technology Development Project (TOP) on Human Monoclonal Antibodies we combine two uniquely powerful new technologies recently developed that for the first time allow the efficient analysis of human B cell specificity en mass. One approach pioneered by Dr. Lanzavecchia, provides an analysis of the entire history of B cell specificities by efficiently producing mAbs from the long-term memory B cell compartment. The second technology from the Wilson and Ahmed laboratories scrutinizes current, ongoing plasmablast specificities and generates large numbers of antigenspecific antibodies in a short time that are predominantly specific to the antigens. We will use these tools to address fundamental questions about the human B cell response to yellow fever virus (YFV) and dengue virus. By combining these powerful platforms of generating human mAbs (plasmablasts and memory B cells) we should be able to comprehensively analyze the human B cell response to these viruses and to probe the relationship between memory B cells and antibody secreting plasma cells. Because the antibodies produced are fully human they can yield valuable diagnostics and allow for safer Pharmaceuticals than chimeric or humanized antibodies. Thus, in addition to addressing these fundamental questions, our proposed studies should also result in the development of a large panel of human mAbs against YFV and dengue - two flaviviruses that are of important public health concern and are high priority biodefense pathogens. Three specific aims are proposed: 1) Characterize the primary human B cell response to YFV-17D leading to the generation of ASCs and long-term memory B cells; 2) Analyze the dynamics, variable gene repertoire, and the specificity of ASC and memory cells induced by booster vaccination with YFV-17D. 3) Characterize the human B cell response to acute dengue virus infection of Children.