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

• 批准号: 10551227
• 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
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-21 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551227
• 关键词: Acinetobacter; Acinetobacter baumannii; Acinetobacter baumannii pneumonia; Acute; Address; Adverse effects; Anti-Bacterial Agents; Antibody-drug conjugates; Antimicrobial Resistance; Binding; Biological; 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; Escherichia coli drug resistance; Evaluation; Fc domain; Formulation; Francisella tularensis; Goals; Good Manufacturing Process; Gram-Negative Bacteria; Gram-Negative Bacterial Infections; 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; Modeling; Monkeys; Multi-Drug Resistance; Mus; Mutation; Nature; New Agents; New Jersey; Peptides; Phagocytosis; Pharmaceutical Preparations; Pharmacology; Pharmacology Study; Plasma; Property; Prophylactic treatment; Pseudomonas; Pseudomonas aeruginosa; Public Health; Qualifying; 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; cell killing; clinical efficacy; colistin resistance; dimer; drug candidate; drug metabolism; drug resistance development; drug synthesis; experimental study; high risk population; improved; in vivo; innovation; lead series; medical schools; meter; mouse model; neonatal Fc receptor; novel; pathogen; pathogenic bacteria; pharmacologic; prevent; programs; prophylactic; receptor; receptor binding; resistant strain; respiratory; safety study; screening; standard of care

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。 尤其值得关注，因为它们每年导致大约 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，尽管很少见，但 MDR 可能会成为一个严重的问题。 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。