Novel bi-specific immunotherapeutic against high-threat Gram-negative pathogens

针对高威胁革兰氏阴性病原体的新型双特异性免疫疗法

基本信息

批准号：
10337197
负责人：
David S Perlin
金额：
$ 114.2万
依托单位：
HACKENSACK UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-21 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10337197
关键词：
Acinetobacter Acinetobacter baumannii Acinetobacter baumannii pneumonia Acute Address Adverse effects Anti-Bacterial Agents Antibodies Antibody-drug conjugates Antimicrobial Resistance Bacteria Bacterial Infections Binding Brucella Cardiovascular system Cells Centers for Disease Control and Prevention (U.S.)Cessation of life Clinical Colistin Collaborations Colony-forming units Complement-Dependent Cytotoxicity Development Dose Dose Fractionation Drug Kinetics Drug resistance Enterobacter Environment Escherichia coli Evaluation Fc domain Formulation Francisella tularensis Goals Half-Life Health Care Costs Health system Hour Human IgG1 Immune Immune response Immune system Immunologics Immunotherapeutic agent In Vitro Infection Infection prevention Investigational Drugs Kidney Klebsiella Klebsiella pneumoniae Lead Life Lipopolysaccharides Lung infections Macaca fascicularis Malignant Neoplasms Mediating Methods Microbiology Modeling Monkeys Multi-Drug Resistance Mus Mutation Nature New Agents New Jersey Peptides Phagocytosis Pharmaceutical Preparations Pharmacology Pharmacology Study Pharmacology and Toxicology Plasma Property Prophylactic treatment Pseudomonas Pseudomonas aeruginosa Public Health Rattus Resistance Rodent Safety Sepsis Septicemia Solubility Systemic infection Therapeutic Therapeutic Agents Time Tissues Toxicokinetics Toxicology Treatment Efficacy United States Universities Validation Whole Blood Work Yersinia pestis antibody-dependent cell cytotoxicity antimicrobial antimicrobial drug arm bacterial resistance base cell killing clinical efficacy colistin resistance dimer drug candidate drug metabolism drug synthesis experimental study high risk population improved in vivo innovation lead series medical schools mouse model neonatal Fc receptor novel pathogen pathogenic bacteria prevent programs prophylactic receptor receptor binding resistant strain respiratory safety study screening standard of care

项目摘要

The Centers for Disease Control and Prevention estimates that at least two million illnesses and 23,000 deaths annually are caused by antimicrobial-resistant bacteria in the United States. The Gram-negative (G-) pathogens are of particular concern, as they account for roughly 99,000 deaths and $20B in health care costs a year. Treatment options for G- infections have become increasingly limited due to rapid emergence of multi-drug resistance (MDR) to existing and newly approved antimicrobial agents, highlighting the need for alternative strategies to prevent MDR G- infections. Further, although it’s rare, MDR can potentially be a serious problem in G- Select Agents, given the highly transmissible nature of the MDR determinants in G- bacteria and the fact that select agents are persisting in the environment. Thus, a broad spectrum agent that leverages immunological mechanisms to prevent as well as to treat high-threat G- bacterial infections in high risk populations would possess a unique advantage in addressing this need. The innovative Cloudbreak™ Antibody Drug Conjugates (ADCs) platform, developed at Cidara Therapeutics, is a broad-spectrum G- active drug candidate that uses a fundamentally new immune-based approach to prevent and treat G- infections. Similar to successful cancer bispecific agents, ADCs bind conserved targets on pathogens via a Targeting Moiety (TM) while simultaneously engaging multiple arms of the immune system via an Effector Moiety (EM). The TM is comprised of a dimeric peptide that binds tightly to lipopolysaccharide (LPS) and confers broad spectrum G- coverage with potent intrinsic antimicrobial activity. The EM is a human IgG1 Fc, which collectively activates complement dependent cytotoxicity (CDC), antibody (Ab)-dependent cell-mediated cytotoxicity (ADCC), and Ab-dependent cell phagocytosis (ADCP) to clear high-threat G- pathogens from the host, via recognition by Fcγ receptors on host cells. This innovative approach involving efficient cell targeting with inherent cell killing catalyzes a robust immune response by more effectively presenting the pathogen to immune components for clearance. CTC-026 is our lead ADC candidate and has demonstrated highly promising properties as an immunoprophylactic and therapeutic agent: broad spectrum antibacterial activity that is both intrinsic and immune-driven, acute safety in rodents, in vivo efficacy in mouse models of Escherichia coli sepsis and Acinetobacter baumannii pneumonia, and a 67 hour plasma half-life in mice. Further optimization of potency and spectrum and in-depth evaluation of pharmacological and toxicological properties of this lead are proposed in this application. The overarching goal of this proposal is to identify a qualified lead development candidate in Year 3 and an Investigational new drug (IND) candidate by the end of Year 5, that meets these criteria: 1) acceptable stability and solubility for IV formulation, 2) MIC90s ≤1 µM against clinical isolates (including MDR) of Klebsiella, Acinetobacter, Pseudomonas, E. coli and select agents Francisella tularensis, Yersinia pestis and Brucella species, 3) MIC90s ≤1 µM against MCR-1, MCR-2 and other colistin-resistant G- clinical isolates, 4) robust in vivo prophylactic efficacy against MDR G- infections in a time window 48-72h prior to infection, and potent therapeutic efficacy better than standard of care with a ≥3-fold therapeutic window after the infection, 5) PK/PD parameters to support once weekly or better dosing in humans, 6) a NOAEL in GLP toxicology studies in rats and Cynomolgus monkeys at least fivefold higher than the targeted clinical dose, and 7) a scalable synthesis to GMP product.

疾病控制与预防中心估计至少有200万疾病和23,000人死亡一种方法是由美国抗菌细菌引起的。革兰氏阴性（G-）病原体特别关心，因为它们每年约占99,000人死亡和20B美元的医疗费用。由于多药的迅速出现，G感染的治疗选择变得越来越受到限制对现有和新批准的抗菌剂的抗性（MDR），强调了替代的需求防止MDR G感染的策略。尽管很少见，但MDR可能是一个严重的问题 g-精选代理，鉴于MDR确定剂在G-BACTERIA中的高度可传播性以及这一事实精选代理在环境中持续存在。那是一种利用免疫学的广谱剂预防和治疗高风险人群中高威胁G-细菌感染的机制在满足这一需求方面将具有独特的优势。创新的CloudBreak™抗体药物在Cidara Therapeutics开发的共轭（ADCS）平台是一位广谱G-活性药物这采用了根本新的基于免疫的方法来预防和治疗G感染。类似于成功癌症双特异性药物ADC通过靶向部分（TM）在病原体上结合了保守的靶标，而通过效应子部分（EM）类似地与免疫系统的多臂互动。 TM已完成与脂多糖（LPS）紧密结合的二聚体胡椒潜在的内在抗菌活性。 EM是人类IgG1 FC，该FC共同激活完成依赖性细胞毒性（CDC），抗体（AB）依赖性细胞介导的细胞毒性（ADCC）和AB依赖性细胞吞噬作用（ADCP）通过Fcγ受体识别宿主清除宿主的高威胁性G-病原体宿主细胞。这种创新的方法涉及有效的细胞靶向遗传细胞杀伤的催化免疫反应通过更有效地呈现对清除的免疫成分的病原体。 CTC-026 是我们的主要ADC候选者，并且表现出具有高度有希望的特性，作为免疫原性和治疗剂：固有和免疫驱动的急性安全性的广谱抗菌活性啮齿动物，在大肠杆菌败血症和鲍曼尼杆菌肺炎的小鼠模型中体内效率，和67小时的血浆半衰期在老鼠中。进一步优化效力和频谱以及深入评估在此应用中提出了该铅的药理和毒理学特性。总体目标该提案的内容是在第3年确定合格的铅开发候选人和调查新药（IND）候选人在第5年底符合以下标准：1）可接受的稳定性和可溶于IV 公式，2）MIC90S≤1µM针对克雷伯菌的临床分离株（包括MDR），acinetobacter，假单胞菌，大肠杆菌和精选药物Francisella tularensis，耶尔森尼亚柴油和布鲁氏菌，3）MIC90S 针对MCR-1，MCR-2和其他抗colistin的G-临床分离株≤1µm，4）体内预防性稳健感染前48-72H的时间窗口中对MDR G感染的功效，并潜在的治疗效率感染后使用≥3倍的治疗窗口的护理标准，5）PK/PD参数支持每周一次或更好的给药，6）在大鼠和cynomolgus猴子中GLP毒理学研究中的NOAEL 至少比靶向临床剂量高五倍，以及7）与GMP产品的可扩展合成。