Monoclonal antibodies for invasive aspergillosis

描述（由申请人提供）：烟曲霉是一种普遍存在的真菌病原体，在严重免疫功能低下的患者中引起侵袭性疾病，最常见于嗜中性粒细胞减少症患者。在过去的三十年中，侵袭性曲霉病的发病率稳步上升，目前的死亡率在45- 90%之间。本提案的目的是通过鉴定烟曲霉抗原引发保护性抗体免疫，提高我们对侵袭性曲霉病的宿主免疫和宿主-病原体相互作用的理解。该方法是开发单克隆抗体（mab），以选择烟曲霉抗原，将改变感染过程，使宿主受益。这样鉴定的单克隆抗体将用于研究烟曲霉的有效宿主反应和宿主-病原体相互作用。有益的单克隆抗体可能被开发用作免疫治疗或诊断试剂。MAb免疫疗法的应用越来越成功，不仅用于治疗难治性或耐药的微生物病原体，而且用于多种疾病状态，如恶性肿瘤、哮喘和自身免疫性疾病。这一建议包括两个策略，研究针对特定真菌目标的单克隆抗体，烟曲霉的二肽基肽酶V (DPP V)，以及开发阻止烟曲霉从孢子形式向菌丝形式过渡的药物，这是入侵所必需的。提出了三个具体目标：1。测定单克隆抗体对烟熏弧菌DPP病毒的保护效果；2. 制备防烟曲霉萌发的体外单克隆抗体并进行鉴定；3. 目的：测定Aim 2中产生的单克隆抗体在侵袭性曲霉病小鼠模型中的生物活性。预计这项研究将确定进一步研究的重要目标。

DESCRIPTION (Provided by applicant): Aspergillus fumigatus, a ubiquitous fungal pathogen, causes invasive disease in severely immunocompromised patients, most often in those with profound neutropenia. The incidence of invasive aspergillosis has risen steadily over the past three decades, and mortality rates currently range from 45-90 percent. The goal of this proposal is to advance our understanding of host immunity and host-pathogen interactions in invasive aspergillosis by identifying A. fumigatus antigens that elicit protective antibody immunity. The approach is to develop monoclonal antibodies (MAbs) to selected A. fumigatus antigens that will modify the course of infection to the benefit of the host. MAbs so identified will be used to study both effective host responses to A. fumigatus and host-pathogen interactions. Beneficial MAbs potentially could be developed for use as immunotherapeutic or diagnostic agents. MAb immunotherapy is being applied with increasing success not only to treatment of refractory or resistant microbial pathogens, but to disease states as diverse as malignancy, asthma and autoimmune disorders. This proposal includes two strategies, study of MAbs to a defined fungal target, the dipeptidyl peptidase V (DPP V) of A. fumigatus, and development of agents that prevent the transition of A. fumigatus from the conidial (spore) form to the hyphal form that is required for invasion. Three specific aims are proposed: 1. To determine the protective efficacy of MAbs to A. fumigatus DPP V; 2. To generate and characterize in vitro MAbs to A. fumigatus that prevent germination; 3. To determine the biological activity of MAbs generated in Aim 2 in murine models of invasive aspergillosis. It is anticipated that this study will identify important targets for further investigation.