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.

美国疾病控制与预防中心估计，至少有 200 万人患病，23,000 人死亡在美国，每年的细菌感染都是由革兰氏阴性 (G-) 病原体引起。特别值得关注，因为它们每年造成大约 99,000 人死亡，并造成 20B 美元的医疗费用。由于多种药物的迅速出现，G-感染的治疗选择变得越来越有限对现有和新批准的抗菌药物的耐药性（MDR），强调需要替代品此外，尽管 MDR G 感染很少见，但 MDR 可能是一个严重的问题。鉴于 G- 细菌中 MDR 决定簇的高度传播性以及以下事实，G- 选择药剂因此，选择的药剂在环境中持续存在，因此是一种利用免疫学的广谱药剂。预防和治疗高危人群高威胁 G 细菌感染的机制创新的Cloudbreak™抗体药物将在满足这一需求方面拥有独特的优势。 Cidara Therapeutics 开发的缀合物 (ADC) 平台是一种广谱 G 活性候选药物它使用一种全新的基于免疫的方法来预防和治疗 G-感染，与成功的类似。癌症双特异性药物，ADC 通过靶向部分 (TM) 结合病原体上的保守靶点，同时 TM 通过效应器部分 (EM) 同时参与免疫系统的多个臂。与脂多糖 (LPS) 紧密结合并赋予广谱 G 覆盖的二聚肽 EM 是一种人类 IgG1 Fc，可共同激活补体。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 受体的识别从宿主中清除高威胁 G-病原体这种创新方法涉及有效的细胞靶向和固有的细胞杀伤，可催化强大的细胞杀伤作用。通过更有效地将病原体呈现给免疫成分进行清除来产生免疫反应。是我们的主要 ADC 候选药物，并已表现出作为免疫预防和治疗药物的非常有前景的特性。治疗剂：具有内在和免疫驱动的广谱抗菌活性，具有极高的安全性啮齿类动物，在大肠杆菌败血症和鲍曼不动杆菌肺炎小鼠模型中的体内疗效，以及小鼠体内 67 小时的血浆半衰期，进一步优化效力和谱并深入评估。本申请提出了该先导化合物的药理学和毒理学特性。该提案的目的是在第 3 年确定合格的先导开发候选药物和研究性新药 (IND) 候选者在第 5 年末满足以下标准：1) IV 可接受的稳定性和溶解度配方，2) 对克雷伯菌属、不动杆菌属、不动杆菌临床分离株（包括 MDR）的 MIC90 ≤ 1 µM 假单胞菌、大肠杆菌和选择土拉弗朗西斯菌、鼠疫耶尔森菌和布鲁氏菌属，3) MIC90 针对 MCR-1、MCR-2 和其他粘菌素耐药性 G 临床分离株≤1 µM，4) 强大的体内预防作用在感染前48-72小时的时间窗口内对MDR G-感染有效，并且具有强大的治疗效果优于标准护理，感染后治疗窗≥3倍，5) PK/PD参数支持每周一次或在人类中更好的给药剂量，6) 大鼠和食蟹猴 GLP 毒理学研究中的 NOAEL 比目标临床剂量至少高出五倍，以及 7) 可扩展合成 GMP 产品。