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: 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
• 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

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.

疾病控制和预防中心估计，至少有200万人患病，2.3万人死亡 在美国，每年都是由抗菌素耐药性细菌引起的。革兰阴性(G-)病原菌 尤其令人担忧，因为它们每年造成约9.9万人死亡，医疗保健成本高达200亿美元。 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剂的耐药性(MDR)，突出了替代药物的必要性 预防耐多药G-感染的策略。此外，尽管MDR很少见，但它可能是一个严重的问题 G-选择剂，鉴于G-细菌中MDR决定簇的高度传播性，以及 选定的代理在环境中持续存在。因此，一种利用免疫学的广谱制剂 预防和治疗高危人群高危G-细菌感染的机制 将在满足这一需求方面拥有独特的优势。创新的CloudBreak™抗体药物 Cidara Treeutics开发的共轭化合物(ADC)平台是一种广谱G活性候选药物 这使用了一种全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)将保守的靶点结合在病原体上，而 通过效应器部分(EM)同时接触免疫系统的多个手臂。TM包括 一种与脂多糖(LPS)紧密结合并提供广谱G-覆盖的二聚体多肽 强大的内在抗菌活性。EM是人类的IgG1Fc，它集体激活补体 依赖细胞毒作用(CDC)、抗体依赖细胞介导的细胞毒作用(ADCC)和抗体依赖细胞毒作用 细胞吞噬作用，通过Fcγ受体的识别，从宿主中清除高威胁的G病原体 宿主细胞。这种创新的方法涉及到高效的细胞靶向和固有的细胞杀伤，催化了强大的 通过更有效地将病原体呈现给免疫组件以进行清除，从而实现免疫反应。CTC-026 是我们的主要ADC候选者，并显示出非常有前途的免疫预防和 治疗剂：广谱抗菌活性，既有内在的，也有免疫驱动的，急性安全性 啮齿动物对大肠杆菌败血症和鲍曼不动杆菌肺炎小鼠模型的体内疗效， 小鼠的血浆半衰期为67小时。进一步优化药效和频谱，深入评估 在这一应用中，提出了该铅的药理和毒理性质。首要目标是 这项提议的目的是在第三年确定一名合格的领先开发候选人和一种研究新药 (IND)候选人，在第5年年底前，满足以下标准：1)IV的可接受稳定性和溶解度 制剂，2)对临床分离的克雷伯氏菌、不动杆菌、 假单胞菌、大肠埃希氏菌和选择性图拉氏菌、鼠疫耶尔森菌和布鲁氏菌，3)MIC90 ≤1微米抗Mcr-1、Mcr-2和其他粘菌素耐药G-临床分离株，4)体内强大的预防 在感染前48-72小时的时间窗内对耐多药G-感染的疗效，以及强大的治疗效果 感染后≥3倍治疗窗优于标准护理，5)PK/PD参数支持 在人类中每周一次或更好的剂量，6)大鼠和食蟹猴GLP毒理学研究中的NOAEL 至少比临床目标剂量高五倍，以及7)GMP产品的可扩展合成。