Novel bi-specific immunoprophylactics against multi-drug resistant Gram-negativebacterial infections

针对多重耐药革兰氏阴性细菌感染的新型双特异性免疫预防剂

基本信息

批准号：
10380759
负责人：
David S Perlin
金额：
$ 107.68万
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：
2019-03-22 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380759
关键词：
Acinetobacter Acinetobacter baumannii Acinetobacter baumannii pneumonia Acute Address Adverse effects Anti-Bacterial Agents Antibodies Antibody-drug conjugates Antimicrobial Resistance Bacteria Binding 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 Escherichia coli Evaluation Fc domain Formulation Goals Half-Life Health Care Costs Health system Hour Human IgG1 Immune Immune response Immune system Immunologics 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 New Agents New Jersey Peptides Phagocytosis Pharmaceutical Preparations Pharmacology Pharmacology Study Pharmacology and Toxicology Plasma Property Pseudomonas Pseudomonas aeruginosa Public Health Rattus Research Institute Resistance Rodent Safety Sepsis Septicemia Solubility Systemic infection Therapeutic Therapeutic Uses Time Tissues Toxicokinetics Toxicology United States Universities Validation Whole Blood Work 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 public health research receptor receptor binding resistant strain respiratory safety study screening

项目摘要

The Centers for Disease Control and Prevention (CDC) 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. More alarming, 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. Thus, an agent that leverages immunological mechanisms to prevent infection in high risk populations from drug susceptible and MDR strains would possess a unique advantage in addressing this need. The innovative Cloudbreak™ Antibody Drug Conjugates (ADCs) platform, developed at Cidara Therapeutics, 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 MDR 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 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 and E. coli, 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, 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 (CDC) 估计，至少有 200 万种疾病和 23,000 在美国，每年都有革兰氏阴性菌（G-）导致死亡。病原体尤其值得关注，因为它们导致大约 99,000 人死亡，并造成 20B 美元的医疗费用更令人担忧的是，G-感染的治疗选择由于快速传播而变得越来越有限。对现有和新批准的抗菌药物出现多重耐药性（MDR），凸显了因此，需要一种利用免疫学手段来预防 MDR G 感染的替代策略。预防高危人群因药物敏感性和耐多药菌株而感染的机制创新的Cloudbreak™抗体药物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) 平台采用全新的基于免疫的技术与成功的癌症双特异性药物类似，ADC 结合保守。通过靶向部分 (TM) 靶向病原体，同时作用于免疫系统的多个分支通过效应器部分 (EM) 系统 TM 由紧密结合的二聚肽组成。脂多糖 (LPS) 并赋予广谱 G-覆盖范围和强大的内在抗菌活性。 EM 是人类 IgG1 Fc，它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) 清除 MDR 来自宿主的 G- 病原体，通过宿主细胞上的 Fcγ 受体识别。！这种创新方法涉及具有固有细胞杀伤作用的高效细胞靶向通过更有效地呈现来催化强大的免疫反应 CTC-026 是我们的主要 ADC 候选药物，并已得到证实。作为免疫预防剂非常有前途的特性：广谱抗菌活性内在和免疫驱动的、啮齿类动物的急性安全性、大肠杆菌脓毒症小鼠模型的体内功效和鲍曼不动杆菌肺炎，以及小鼠体内 67 小时的血浆半衰期进一步优化效力。并提出了该先导物的谱图和药理毒理特性的深入评价本申请的总体目标是确定合格的先导开发候选者。并在第 5 年末成为符合以下标准的研究性新药 (IND) 候选药物：1) IV 制剂可接受的稳定性和溶解度，2) 针对临床分离株（包括 MDR）的 MIC90 ≤1 µM 克雷伯菌属、不动杆菌属、假单胞菌属和大肠杆菌，3) 针对 MCR-1、MCR-2 和其他粘菌素的 MIC90 ≤1 µM 耐药 G- 临床分离株，4) 在一个时间窗口内对 MDR G- 感染具有强大的体内预防功效感染前 48-72 小时，5) PK/PD 参数支持每周一次或更好的人体给药剂量，6) NOAEL 大鼠和食蟹猴的 GLP 毒理学研究中的结果比临床目标至少高出五倍剂量，以及 7) 可扩展的 GMP 产品合成。