Monoclonal antibodies to inhibit Aspergillus germination

抑制曲霉发芽的单克隆抗体

• 批准号: 7759644
• 负责人: Marta L. Feldmesser
• 金额: $ 39.14万
• 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 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7759644
• 关键词: Alveolar Macrophages; Antifungal Agents; Antigens; Aspergillosis; Aspergillus; Aspergillus fumigatus; Asthma; Autoimmune Diseases; Binding; Development; Diagnosis; Diagnostic; Disease; Germination; Goals; Immune response; Immunity; Immunocompromised Host; Immunotherapeutic agent; Immunotherapy; In Vitro; Incidence; Infection; Kinetics; Lung; Malignant Neoplasms; Monoclonal Antibodies; Mus; Neutropenia; Organ Transplantation; Patients; Phase Transition; Protein Binding; Proteins; Refractory; Reproduction spores; Resistance; Therapeutic; Tissues; drug development; immune function; in vivo; microbial; mortality; novel; pathogen; protective efficacy; protein expression; success

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. Tounderstand the interaction between conidia and MAb 318 in vitro in the presence and absence of alveolar macrophages; 3. Tounderstand 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.

烟曲霉是一种普遍存在的真菌病原体，可引起严重的侵袭性疾病 免疫功能低下的患者，最常见的是患有严重中性粒细胞减少症或接受过器官移植的患者 移植。过去三十年来，侵袭性曲霉病（IA）的发病率稳步上升， 目前死亡率为 45-90%。该提案的目的是增进我们的理解 使用单克隆抗体 (MAb) 评估侵袭性曲霉病中的宿主免疫和宿主-病原体相互作用 318）抑制发芽，从孢子形式到菌丝形式的相变，这是必需的 侵袭，并延长患有侵袭性肺曲霉病的小鼠的生存期。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。 MAb 免疫疗法是 不仅越来越成功地应用于难治性或耐药性微生物病原体的治疗，而且 多种疾病状态，如恶性肿瘤、哮喘和自身免疫性疾病。此外，识别 保护性单克隆抗体结合的真菌分子可能会确定药物开发的新靶标。三具体 提出的目标是： 1. 鉴定 MAb 318 结合的蛋白质并确定其动力学 发芽期间的表达； 2. 体外了解分生孢子与 MAb 318 之间的相互作用 肺泡巨噬细胞的存在和不存在； 3. 了解保护功效的机制 被动施用针对 50 kDa 抗原的 MAb。预计这项研究将鉴定真菌 对发芽很重要的分子，并开始定义它们与宿主免疫反应的相互作用。