Monoclonal antibodies for invasive aspergillosis

描述(申请人提供)：烟曲霉，一种普遍存在的真菌病原体，在免疫功能严重受损的患者中会导致侵袭性疾病，最常见的是那些有严重中性粒细胞减少症的患者。侵袭性曲霉病的发病率在过去30年里稳步上升，目前的死亡率从45%到90%不等。这一建议的目的是通过鉴定能够诱导保护性抗体免疫的烟曲霉菌抗原，促进我们对侵袭性曲霉病宿主免疫和宿主-病原体相互作用的理解。方法是开发针对选定的烟曲霉菌抗原的单抗，以改变感染过程，使宿主受益。所鉴定的单抗将用于研究寄主对烟曲霉菌的有效反应和寄主-病原菌的相互作用。有益的单抗可能被开发用于免疫治疗或诊断试剂。单抗免疫疗法不仅在治疗难治性或耐药微生物病原体方面取得了越来越大的成功，而且在治疗恶性肿瘤、哮喘和自身免疫性疾病等疾病方面也取得了越来越大的成功。这一建议包括两个策略，研究针对特定真菌靶标的单抗，烟曲霉菌的二肽基肽酶V(DPP V)，以及开发阻止烟曲霉菌从分生孢子(孢子)向入侵所需的菌丝形态转变的试剂。我们提出了三个具体的目标：1.确定单抗对烟曲霉DPP V的保护作用；2.体外制备和鉴定防止发芽的单抗；3.在侵袭性曲霉病小鼠模型中测定目的2产生的单抗的生物学活性。预计这项研究将确定进一步调查的重要目标。

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.