Pn3Pase as an Effective Enzyme Therapeutic for Streptococcus Pneumoniae type 3 Infection

Pn3Pase 作为治疗 3 型肺炎链球菌感染的有效酶疗法

基本信息

批准号：
10448437
负责人：
Fikri Y Avci
金额：
$ 29.95万
依托单位：
PNEUMOTACTIX, LLC
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：
2021-07-09 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10448437
关键词：
Acetylation Aftercare Animals Antibiotic Resistance Antibiotic Therapy Antibiotics Autoimmune Responses Bacteria Bacterial Infections Biological Assay Biological Sciences Blood Circulation Boston COVID-19 Cell-Mediated Cytolysis Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Child Clinical Clinical Trials Communicable Diseases Conjugate Vaccines Data Death Rate Defense Mechanisms Detection Disease Dose Drug Kinetics Drug resistance Effectiveness Elderly Enzymes Epidemiologist Fermentation Genes Genetic Recombination Goals HL-60 Cells Half-Life Hydrolysis Immune Immune response Immunocompromised Host Immunodeficient Mouse In Vitro Incidence Individual Infection Infectious Agent Influenza Lead Legal patent Length Mammalian Cell Mediating Modeling Modification Monosaccharides Morbidity - disease rate Mus Patients Phagocytes Phagocytosis Pharmacotherapy Pneumococcal Infections Pneumococcal vaccine Polysaccharides Population Prevention Primates Proteins Publishing Resistance Role Sampling Sepsis Serotyping Severities Streptococcus pneumoniae System Testing Therapeutic Therapeutic Agents Therapeutic Uses Time Toxic effect Universities Vaccination Vaccine Research Vaccines Virulence Virulent Virus Diseases bacterial resistance base capsule commercialization cytotoxicity dosage drug resistant pathogen epidemiology study experimental study immune clearance immunogenic immunogenicity in vivo in vivo Model intraperitoneal macrophage mortality novel novel therapeutics pandemic disease pathogen prevent prophylactic research and development secondary infection therapeutic enzyme therapy design vaccine acceptance

项目摘要

Project Summary Streptococcus pneumoniae (Spn) remains one of the deadliest infectious agents responsible for more than a million deaths worldwide per year as well as making up a majority of secondary infections in immunocompromised patients. One of the major virulence mechanisms associated with this pathogen is its polysaccharide capsule, which determines successful colonization and infection of the bacterium as well as serving as a defense mechanism against immune-mediated killing of the pathogen. Spn serotype 3 (Spn3) is considered one of the most virulent serotypes of Spn, and despite current multivalent vaccines that include conjugate targets against Spn3, the overall proportion of this serotype in Spn infection cases has actually increased over the last ten years. Furthermore, Spn3 is directly associated with increased antibiotic resistance. Thus, the severity of the impact of Spn3, as well as the difficulties arising in designing therapies against it, cannot be overstated. Pneumozyme (Pn3Pase) is an enzyme product that we have previously shown to be highly effective in degrading the capsular polysaccharide of type 3 Spn. Our in vitro studies have shown that treating Spn3 with Pneumozyme will render the bacterium more susceptible to killing mechanisms by phagocytic cells. Furthermore, mice that are lethally challenged with Spn3 can be rescued following treatment with Pneumozyme: 100% of mice receiving Pneumozyme treatment survival the challenge whereas 100% of mice that receive inactive enzyme or vehicle die within two days of Spn3 lethal challenge. These results indicate that Pneumozyme has extremely high efficacy in sensitizing Spn3 to host immune mechanisms and that the enzyme has remarkable potential as a therapeutic. As part of Pneumotactix, LLC, our aims for this project are thus: Aim 1: Characterize the pharmacokinetics, potential immunogenicity and cytotoxicity of the enzyme. Aim 2: Elucidate the therapeutic value of the enzyme against Spn3 infection. In our published studies, we have used the native, full-length protein product to degrade the capsule of one virulent strain of Spn3 to great effect, and have further shown that this enzyme product does not induce cellular toxicity against host mammalian cells in both in vitro and in vivo experiments. Our immediate goals for this project are therefore to expand these studies to test pharmacokinetics, assess enzyme efficacy against additional strains of serotype 3 Spn, and perform continued experiments to confirm the therapeutic value of Pneumozyme and concurrent lack of off-target effects upon administration. The long-term goals for Pneumozyme are to establish it as a therapeutic agent by testing its efficacy in higher animal systems (i.e., primates) with significant sample numbers of Spn type 3 clinical isolates, and move towards clinical trials to develop this enzyme as a highly relevant therapeutic against this incredibly virulent pathogen.

项目概要肺炎链球菌 (Spn) 仍然是最致命的传染原之一，导致超过全球每年有 100 万人死亡，并且占继发感染的大部分免疫功能低下的患者。与该病原体相关的主要毒力机制之一是其多糖胶囊，决定细菌的成功定植和感染以及作为抵抗免疫介导的病原体杀灭的防御机制。 Spn 血清型 3 (Spn3) 是被认为是 Spn 毒性最强的血清型之一，尽管目前的多价疫苗包括针对 Spn3 的结合物，该血清型在 Spn 感染病例中的总体比例实际上近十年来有所增加。此外，Spn3 与抗生素耐药性增加直接相关。因此，Spn3 影响的严重性以及设计针对它的疗法所产生的困难无法解释被夸大了。 Pneumozyme (Pn3Pase) 是一种酶产品，我们之前已证明其具有高度有效降解 3 型 Spn 的荚膜多糖。我们的体外研究表明，治疗 Spn3 与 Pneumozyme 将使细菌更容易受到吞噬细胞的杀伤机制的影响。此外，受到 Spn3 致命攻击的小鼠可以在用 Pneumozyme 治疗后获救：接受 Pneumozyme 治疗的小鼠 100% 在挑战中存活下来，而接受 Pneumozyme 治疗的小鼠 100% 无活性的酶或媒介物在 Spn3 致死攻击后两天内死亡。这些结果表明，Pneumozyme 在使 Spn3 对宿主免疫机制敏感方面具有极高的功效，并且该酶具有显着的作用作为治疗的潜力。作为 Pneumotactix, LLC 的一部分，我们该项目的目标是：目标 1：表征酶的药代动力学、潜在免疫原性和细胞毒性。目标 2：阐明该酶对 Spn3 感染的治疗价值。在我们发表的研究中，我们使用天然的全长蛋白质产品来降解一种胶囊 Spn3 的强毒菌株具有很大的效果，并进一步表明该酶产品不会诱导细胞在体外和体内实验中对宿主哺乳动物细胞的毒性。我们的近期目标因此，该项目将扩大这些研究，以测试药代动力学，评估酶的功效血清型 3 Spn 的其他菌株，并进行持续的实验以确认其治疗价值 Pneumzyme 并同时缺乏给药后的脱靶效应。的长期目标 Pneumozyme 将通过测试其在高等动物系统（即，灵长类动物）具有大量 Spn 3 型临床分离株样本，并转向临床试验开发这种酶作为针对这种极其致命的病原体的高度相关的治疗方法。