Monoclonal antibodies to inhibit Aspergillus germination

抑制曲霉发芽的单克隆抗体

• 批准号: 7039283
• 负责人: Marta L. Feldmesser
• 金额: $ 37.26万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039283
• 关键词: Aspergillus; alveolar macrophages; antigens; aspergillosis; binding proteins; immune response; infection; lung; monoclonal antibody; protein binding; spores; transplantation

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.

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，最常见的是有严重的中性粒细胞减少症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30年中稳步上升，目前死亡率在45%-90%之间。这项建议的目的是使用一种能抑制发芽的单抗(单抗318)来促进我们对侵袭性曲霉病中宿主免疫和宿主与病原体相互作用的理解。 侵袭性肺曲霉菌病小鼠的侵袭性，并延长存活时间。萌发抑制单抗有可能被开发用于免疫预防或诊断试剂。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。此外，识别保护性单抗结合的真菌分子可能为药物开发定义新的靶点。1.鉴定单抗318结合的蛋白并测定其在萌发过程中的表达动力学；2.了解分生孢子与单抗318的体外相互作用。 肺泡巨噬细胞的存在和不存在；3.了解被动给予单抗对50 kDa抗原保护作用的机制。预计这项研究将识别对萌发重要的真菌分子，并开始定义它们与宿主免疫反应的相互作用。