Host Directed Orynotide for MDR Gram Negative Bacterial Infections

宿主定向 Orynotide 用于治疗耐多药革兰氏阴性细菌感染

基本信息

批准号：
10674221
负责人：
Justin Blaine Schaal
金额：
$ 100.6万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-07-21 至 2028-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10674221
关键词：
ADME Study Acinetobacter baumannii Address Anti-Infective Agents Antibiotic Therapy Antibiotics Antibodies Applications Grants Bacteremia Bacteria Bacterial Antibiotic Resistance Bacterial Infections Bacterial Model Biochemical Pathway Biological Biology Blood Canis familiaris Carbapenems Cell Communication Cells Cercopithecidae Cessation of life Chemistry Combined Modality Therapy Communicable Diseases Consensus Cyclization Data Defensins Development Disease Outbreaks Dose Drug Kinetics E. coli bacteremia Engineering Escherichia coli Evaluation Flow Cytometry Goals Gram-Negative Bacterial Infections Hand Health Host Defense Human Immune Immune response Immunotherapeutic agent In Vitro Infection Inflammation Inflammatory Intraperitoneal Injections Investments Klebsiella pneumoniae Lead Leukocytes Libraries Malignant Neoplasms Mass Spectrum Analysis Maximum Tolerated Dose Mediating Methods Modeling Molecular Molecular Target Multi-Drug Resistance Multidrug-resistant Acinetobacter Multiple Bacterial Drug Resistance Mus Neutrophil Infiltration Neutrophilia Nosocomial Infections Peptide Hydrolases Peptides Peritoneal Peritoneal Sepsis Peritoneal lavage Phagocytes Phagocytosis Pharmaceutical Preparations Pharmacodynamics Pharmacologic Substance Pharmacology Study Plasma Preventive Production Property Protein Isoforms Proteins Protocols documentation Public Health Publishing Radiolabeled Rattus Reagent Research Resistance Risk Route Safety Sepsis Septic Shock Septicemia Signal Pathway Spleen Therapeutic Toxic effect Toxicokinetics Toxicology United States Vertebral column Whole Blood antibody test antimicrobial antimicrobial drug bacterial resistance carbapenem resistance carbapenem-resistant Enterobacteriaceae colistin resistance combat cytokine design drug candidate fungus immunogenicity improved in vivo intraperitoneal microbial microorganism mouse model novel novel therapeutics pathogen pathogenic bacteria pharmacokinetics and pharmacodynamics pharmacologic pre-clinical preclinical development recruit response response biomarker safety study theta-defensin uptake

项目摘要

PROJECT SUMMARY The goal of this grant proposal is to advance the preclinical development of a novel macrocyclic peptide, Orynotide™ MTD12813, for treatment of multidrug resistant (MDR) Gram negative bacterial infections, with the initial focus being on infections caused by carbapenem-resistant Enterobacteriaceae (CRE). The emergence of infections by multiple CRE pathogens has created an urgent public health threat, because carbapenems are drugs of last resort for infections caused by an increasing fraction of MDR bacterial pathogens. Just two species, Klebsiella pneumoniae and Escherichia coli, cause an estimated 140,000 nosocomial infections per year in the United States alone, and many are carbapenem resistant. There is global consensus that new preventive and therapeutic strategies are urgently needed to combat the growing problem of MDR bacterial infections. The applicants, leaders in the field of θ-defensin biology, are responding to this need by developing Orynotides, a new class of host-directed antimicrobial macrocyclic peptides bioinspired by the structural and biological properties of theta (θ)-defensins, macrocyclic peptides expressed exclusively in Old World monkeys (but not humans). Exploiting the pleiotropic host defense properties of θ-defensins, we produced a library of novel Orynotides that includes several compounds that are highly effective in MDR Gram negative septicemia models. Hit-to-lead studies identified MTD12813 as the lead Orynotide candidate for preclinical development as a first- in-class immunotherapeutic agent for MDR Gram negative infections. In the mouse peritoneal sepsis model, single dose administration of MTD12813 is highly effective (enhanced survival with concomitant bacterial clearance) against multiple strains of CRE-K. pneumoniae and CRE-E. coli, and additionally was shown to be effective in septicemia caused by MDR Acinetobacter baumannii. Consistent with the range of pathogens against which MTD12813 is active in vivo, we showed that the peptide’s mode of action is immunotherapeutic, promoting host-mediated bacterial clearance, stimulating phagocytosis and neutrophil recruitment, while modulating levels of otherwise dysregulated proinflammatory cytokines. These data indicate that MTD12813 is a novel immunotherapeutic agent effective in the treatment of Gram negative bacterial pathogens. The peptide is readily manufacturable ( ~1.5 g on hand), highly stable in human plasma and whole blood, resistant to bacterial proteases, and well tolerated when administered by numerous routes. In the proposed studies, we will advance the preclinical characterization of MTD12813. Aim 1 studies will include production of GLP MTD12813 and other critical reagents, pharmacokinetic (PK) and PK/pharmacodynamic analyses, and ADME studies. Aim 2 will focus on illuminating mechanism(s) of action at the cellular and molecular level. Aim 3 objectives will include preclinical non-GLP safety and toxicokinetic studies in rats and beagle dogs, evaluation of immunogenicity, development of an antidrug antibody assay, and culminate with formal GLP safety studies. The goal of these aims is to advance the preclinical development of MTD12813 to IND filing with the FDA.

项目概要该拨款提案的目标是推进新型大环肽的临床前开发， Orynotide™ MTD12813，用于治疗多重耐药 (MDR) 革兰氏阴性细菌感染，最初的焦点是由耐碳青霉烯类肠杆菌科细菌（CRE）引起的感染。多种 CRE 病原体感染已造成紧迫的公共卫生威胁，因为碳青霉烯类抗生素由越来越多的耐多药细菌病原体引起的药物，只有两种，肺炎克雷伯菌和大肠杆菌每年估计造成 140,000 例医院感染仅美国，许多国家就对碳青霉烯类药物产生耐药性，全球已达成共识，即新的预防和治疗方法。迫切需要治疗策略来应对日益严重的耐多药细菌感染问题。申请人是 θ-防御素生物学领域的领导者，他们正在通过开发 Orynotides 来满足这一需求，受结构和生物学启发的新型宿主定向抗菌大环肽 θ (θ)-防御素的特性，大环肽仅在旧大陆猴子中表达（但不利用 θ-防御素的多效性宿主防御特性，我们产生了一个新的库。 Orynotides 包含多种对 MDR 革兰氏阴性败血症模型非常有效的化合物。 Hit-to-Lead 研究确定 MTD12813 是临床前开发的主要 Orynotide 候选药物。用于治疗 MDR 革兰氏阴性感染的同类免疫治疗剂在小鼠腹膜脓毒症模型中， MTD12813 的单剂量给药非常有效（伴随细菌的存活率提高）清除）针对多种 CRE-K 肺炎菌株和 CRE-E 菌株。对MDR鲍曼不动杆菌引起的败血症有效，与病原体范围一致。 MTD12813 在体内具有活性，我们表明该肽的作用方式是免疫治疗，促进宿主介导的细菌清除，刺激吞噬作用和中性粒细胞募集，同时这些数据表明 MTD12813 可以调节原本失调的促炎细胞因子的水平。一种有效治疗革兰氏阴性细菌病原体的新型免疫治疗剂肽。易于制造（现有约 1.5 克），在人血浆和全血中高度稳定，对细菌具有抵抗力蛋白酶，并且通过多种途径给药时具有良好的耐受性，在拟议的研究中，我们将推进。 MTD12813 的临床前表征研究将包括 GLP MTD12813 和其他产品的生产。关键试剂、药代动力学 (PK) 和 PK/药效分析以及 ADME 研究将重点关注。目标 3 的目标将包括临床前研究。大鼠和比格犬的非 GLP 安全性和毒代动力学研究、免疫原性评估、开发抗药物抗体测定，并以正式的 GLP 安全性研究告终。这些目标的目标是：推进MTD12813的临床前开发并向FDA提交IND备案。