Monoclonal antibodies to inhibit Aspergillus germination

描述（由申请方提供）：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患者中引起侵袭性疾病，最常见于严重中性粒细胞减少症患者或接受过器官移植的患者。侵袭性曲霉病（IA）的发病率在过去三十年中稳步上升，目前死亡率为45- 90%。本提案的目的是利用单克隆抗体（MAb 318）来促进我们对侵袭性曲霉病中宿主免疫和宿主-病原体相互作用的理解，该单克隆抗体抑制萌发，即从孢子形式到菌丝形式的相变， 侵袭性肺曲霉菌病小鼠的侵袭性和存活率。发芽抑制单克隆抗体可能被开发用作免疫预防剂或诊断剂。单克隆抗体免疫疗法不仅在治疗难治性或耐药性微生物病原体方面，而且在治疗恶性肿瘤、哮喘和自身免疫性疾病等多种疾病方面都取得了越来越大的成功。此外，鉴定由保护性单克隆抗体结合的真菌分子可以为药物开发定义新的靶点。提出了三个具体目标：1。鉴定单抗318结合的蛋白质，并确定其在萌发过程中的表达动力学;为了了解单克隆抗体318与分生孢子在体外的相互作用， 肺泡巨噬细胞的存在和不存在; 3.了解被动给予抗50 kDa抗原单克隆抗体的保护作用机制。预计这项研究将确定真菌分子的重要发芽和开始，以确定其与宿主免疫反应的相互作用。

DESCRIPTION (provided by applicant): Aspergillus fumigatus, a ubiquitous fungal pathogen, causes invasive disease in severely immunocompromised patients, most often in those with profound neutropenia or who have undergone organ transplantation. The incidence of invasive aspergillosis (IA) has risen steadily over the past three decades, and mortality rates currently range from 45-90%. The goal of this proposal is to advance our understanding of host immunity and host-pathogen interactions in invasive aspergillosis using a monoclonal antibody (MAb 318) that inhibits germination, the phase transition from the spore form to hyphal form that is required for invasion, and prolongs survival in mice with invasive pulmonary aspergillosis. Germination-inhibitory MAbs potentially could be developed for use as immunoprophylactic 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. Additionally, identification of fungal molecules bound by protective MAbs may define novel targets for drug development. Three specific aims are proposed: 1. To identify the protein bound by MAb 318 and determine the kinetics of its expression during germination; 2. To understand the interaction between conidia and MAb 318 in vitro in the presence and absence of alveolar macrophages; 3. To understand the mechanism of protective efficacy of passively administered MAbs to the 50 kDa antigen. It is anticipated that this study will identify fungal molecules important for germination and begin to define their interaction with host immune responses.