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.

患有晚期HIV感染的患者有隐球菌病的风险，这是一种毁灭性的真菌感染，影响主要是以难以治疗脑膜脑炎的形式的中枢神经系统。许多研究在过去的二十年中，抗体（AB）介导的免疫力可以做出关键的贡献为了防御加密球菌。单克隆抗体（mAb）是有希望的治疗性的隐球菌病的试剂。这种真菌在病原真菌中是不寻常的，因为它具有较大的多糖胶囊将大量的多糖抗原释放到感染组织中可以干扰免疫反应，从而促进感染的持久性。组织抗原是与免疫结构炎症综合征的发病机理有关，这通常使与抗逆转录病毒疗法有关的免疫力反弹与同时艾滋病毒和加密噬菌患者相关感染。当前，尚无疗法去除组织中的多糖。我们的小组发现一些对新生梭状芽孢杆菌胶囊的mAb具有催化活性，可降解囊囊多糖。这这是一个令人兴奋的发现，因为它增加了开发新型疗法的隐球菌病的可能性基于使隐球菌细胞通过去除胶囊和退化而容易受到免疫系统的影响组织抗原沉积。该申请提出了实验以确定AB介导的贡献催化为AB介导的保护，目的是为患者制定新的治疗策略基于组织抗原沉积的清除，与艾滋病相关的隐球菌病。隐球菌的组织清除抗原将在正常和免疫缺陷的小鼠中进行，以确定炎症的贡献为此，艾滋病患者的效果和模拟组织反应。我们的方法是评估一个大型现有的收集mAB，以识别最有效的催化AB并探索AB-的机制介导的催化会影响隐球菌细胞。我们将使用AB结合位点的定向诱变位点绘制催化域并生成具有无效催化活性的变体，这将使我们能够区分从催化活性引起的经典AB功能之间。将研究催化抗体在小鼠模型中，以确定其从组织中去除多糖的能力。提出了三个目标：1）建立AB介导的催化对CN胶囊的影响； 2.确定AB介导的位点催化并产生具有和没有催化活性的mAb； 3）建立AB的后果介导的GXM水解。我们预计，在完成这项工作时，我们将有能力部署一种针对与艾滋病相关的隐球菌患者的新型抗体疗法。