Exploiting antibody catalysis for treating Cryptococcosis

利用抗体催化治疗隐球菌病

基本信息

批准号：
10326944
负责人：
Arturo Casadevall
金额：
$ 73.41万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-25 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10326944
关键词：
AIDS-Related Cryptococcosis Acquired Immunodeficiency Syndrome Affect Anthrax disease Antibodies Antibody Binding Sites Antibody Formation Antibody Therapy Antibody-mediated protection Antifungal Agents Antigen-Antibody Complex Antigens Asthma Basic Science Biological Biological Response Modifier Therapy Catalysis Catalytic Antibodies Catalytic Domain Cell surface Cells Cessation of life Clinical Clostridium difficile Colitis Collection Communicable Diseases Complement Activation Crohn&apos s disease Cryptococcosis Cryptococcus Cryptococcus neoformans Deposition Disease Dose Epidemic Epitopes Etiology Excision Future Goals HIV HIV Infections HIV Seronegativity HIV Seropositivity Hematuria Host Defense Human Hydrolysis Hydrophobic Surfaces Immune response Immune system Immunity Immunodeficient Mouse Immunoglobulins Immunosuppression In Vitro Individual Infection Inflammation Inflammatory Malignant Neoplasms Maps Mediating Medicine Meningoencephalitis Modality Modern Medicine Monoclonal Antibodies Morbidity - disease rate Mus Mycoses Neuraxis Pathogenesis Patients Phagocytosis Phase I/II Trial Physicians Polysaccharides Positioning Attribute Predisposition Prevalence Prevention Property Reagent Reporting Research Resistance Respiratory syncytial virus Rheumatism Rheumatoid Arthritis Risk Safety Serum Site Site-Directed Mutagenesis Syndrome Therapeutic Time Tissues Toxic effect Variant Virulence Work antibody engineering antimicrobial antimicrobial drug antiretroviral therapy base capsule cost drug efficacy experimental study fungus human monoclonal antibodies immune reconstitution immunosuppressed mortality mouse model natural antibodies novel therapeutic intervention novel therapeutics pathogenic fungus programs response tool

项目摘要

Patients with advanced HIV infection are at risk for cryptococcosis, a devastating fungal infection that affects primarily the central nervous system in the form of a difficult to treat meningoencephalitis. Numerous studies over the past two decades have shown that antibody (Ab)-mediated immunity can make a critical contribution to host defense against Cryptococcus neoformans. Monoclonal antibodies (mAbs) are promising therapeutic reagents for cryptococcosis. This fungus is unusual among pathogenic fungi in that it has a large polysaccharide capsule that releases copious amounts of polysaccharide antigen into infected tissues, where it can interfere with the immune response and thus facilitate the persistence of infection. Tissue antigens are implicated in the pathogenesis of immune reconstitution inflammatory syndrome, which often complicates the rebound in immunity associated with antiretroviral therapy in patients with concurrent HIV and cryptococcal infection. Currently, there is no therapy to remove polysaccharide from tissues. Our group discovered that some mAbs to the C. neoformans capsule have catalytic activity that degrades the capsular polysaccharide. This is an exciting finding because it raises the possibility of developing a new type of therapy for cryptococcosis based on making cryptococcal cells vulnerable to the immune system by removing their capsule and degrading tissue antigen deposits. This application proposes experiments to ascertain the contribution of Ab-mediated catalysis to Ab-mediated protection with the goal of developing a new therapeutic strategy for patients with AIDS-associated cryptococcosis based on clearance of tissue antigen deposits. Tissue clearance of cryptococcal antigen will be done in both normal and immunodeficient mice to ascertain the contribution of inflammation to this effect and mimic tissue responses in patients with AIDS. Our approach is to evaluate a large existing collection of mAbs to identify the most effective catalytic Ab and explore the mechanisms by which Ab- mediated catalysis affects cryptococcal cells. We will use site directed mutagenesis of the Ab-binding site to map the catalytic domain and to generate variants with null catalytic activity that will allow us to discriminate between classical Ab functions from those resulting from catalytic activity. Catalytic antibodies will be studied in mouse models to ascertain their capacity to remove polysaccharide from tissue. Three aims are proposed: 1) To establish the effect of Ab-mediated catalysis on the capsule of CN; 2.To identify the site of Ab-mediated catalysis and generate mAbs with and without catalytic activity; and 3) To establish the consequences of Ab- mediated GXM hydrolysis.. We anticipate that at the completion of this work we will be in a position to deploy a new type of antibody therapy for patients with AIDS-related cryptococcosis.

晚期艾滋病毒感染患者面临隐球菌病的风险，这是一种破坏性的真菌感染，影响主要是中枢神经系统，以难以治疗的脑膜脑炎的形式出现。大量研究过去二十年的研究表明，抗体 (Ab) 介导的免疫可以做出关键贡献宿主防御新型隐球菌。单克隆抗体 (mAb) 是有前途的治疗药物隐球菌病试剂。这种真菌在病原真菌中很不寻常，因为它有一个大的多糖胶囊将大量多糖抗原释放到受感染的组织中，可以干扰免疫反应，从而促进感染的持续存在。组织抗原是涉及免疫重建炎症综合征的发病机制，该综合征常常使病情复杂化 HIV 和隐球菌并发患者抗逆转录病毒治疗相关的免疫力反弹感染。目前，还没有从组织中去除多糖的疗法。我们小组发现一些针对新型隐球菌荚膜的单克隆抗体具有降解荚膜多糖的催化活性。这这是一个令人兴奋的发现，因为它提高了开发新型隐球菌病疗法的可能性基于通过去除荚膜和降解来使隐球菌细胞容易受到免疫系统的攻击组织抗原沉积。该申请提出了实验来确定抗体介导的贡献催化抗体介导的保护，目标是为患有以下疾病的患者开发新的治疗策略基于组织抗原沉积清除的艾滋病相关隐球菌病。隐球菌的组织清除将在正常和免疫缺陷小鼠中进行抗原测定，以确定炎症的影响达到这种效果并模仿艾滋病患者的组织反应。我们的方法是评估现有的大型收集单克隆抗体以确定最有效的催化抗体并探索抗体的机制介导的催化作用影响隐球菌细胞。我们将使用抗体结合位点的定点诱变来绘制催化结构域并生成具有无效催化活性的变体，这将使我们能够区分经典 Ab 功能与催化活性产生的功能之间的差异。将研究催化抗体在小鼠模型中确定其从组织中去除多糖的能力。提出三个目标：1) 确定抗体介导的催化作用对 CN 胶囊的影响； 2.确定Ab介导的位点催化并生成具有或不具有催化活性的单克隆抗体； 3）确定Ab-的后果介导的 GXM 水解..我们预计，在完成这项工作后，我们将能够部署一种针对艾滋病相关隐球菌病患者的新型抗体疗法。