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

• 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
• 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

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.

疾病控制与预防中心（CDC）估计，至少有200万疾病和23,000个疾病 每年死亡是由美国抗菌细菌引起的。革兰氏阴性（g-） 病原体特别关注，因为它们约占99,000人死亡和20B美元的医疗保健费用 年。由于迅速，更多令人震惊的G型治疗选择变得越来越限制 多药耐药性（MDR）的现有和新认可的抗微生物剂的出现，强调了 需要采取替代策略来防止MDR G感染。那是一种利用免疫学的代理 防止因药物敏感和MDR菌株感染的高风险种群感染的机制 在满足这一需求方面具有独特的优势。创新的CloudBreak™抗体药物 Cidara Therapeutics开发的共轭（ADCS）平台使用了基本的基于免疫的新的 预防和治疗G感染的方法。与成功的癌症双特异性药物相似，ADC结合构成 通过靶向部分（TM）靶向病原体，同时与免疫的多个臂相关 通过效应子部分（EM）进行系统。 TM由一个二聚体的胡椒组成，该胡椒紧密结合到 脂多糖（LPS）并承认具有潜在的内在抗菌活性的广泛频谱G覆盖。 EM是人类IgG1 FC，该FC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 通过Fcγ受体在宿主细胞上识别的宿主的G-病原体。！这种创新方法涉及 固有细胞杀死的有效细胞靶向通过更有效地呈现促进可靠的免疫反应 免疫成分的病原体清除。 CTC-026是我们的主要ADC候选人，已证明 作为免疫原子剂的高度有希望的特性：广泛的抗菌活性 啮齿动物的固有和免疫驱动的急性安全性，在大肠杆菌败血症的小鼠模型中体内效率 小鼠和小鼠的鲍曼尼杆菌肺炎和67小时的血浆半衰期。进一步优化效力 提出了该铅的药物和毒理学特性的光谱和深入评估 在此应用程序中。该提案的总体目标是确定合格的铅开发候选人 在第3年和一个调查新药（IND）候选人到第5年底，符合以下标准：1） IV公式的可接受稳定性和溶解度，2）MIC90S≤1µM针对临床分离株（包括MDR）的MIC 90≤1µm Klebsiella，acinetobacter，Pseudomonas和E. coli，3）MIC90S≤1µM，对MCR-1，MCR-2和其他colistin- 抗性G-临床分离株，4）在时间窗口中针对MDR G感染的体内预防效率的鲁棒 感染前的48-72H，5）PK/PD参数每周一次或更高的给药，6）Noael 在GLP毒理学研究中，在大鼠和cernomolgus猴子中至少比靶向临床高五倍 剂量和7）与GMP产品的可扩展合成。