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，23,000人死亡， 在美国，每年都有由耐药性细菌引起的。革兰氏阴性（G-）病原体 尤其令人担忧，因为它们每年造成约99，000人死亡和200亿美元的医疗费用。 由于多种药物的快速出现，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），强调了替代药物的必要性 预防MDR G感染的策略。此外，虽然它很罕见，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， 选定的代理在环境中持续存在。因此，利用免疫学的广谱剂 预防和治疗高危人群中高威胁G-细菌感染的机制 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开发的缀合物（ADC）平台是一种广谱G活性候选药物 它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 对于癌症双特异性试剂，ADC通过靶向部分（TM）结合病原体上的保守靶标， 通过效应部分（EM）同时接合免疫系统的多个臂。TM由 紧密结合脂多糖（LPS）并赋予广谱G-覆盖的二聚肽， 有效的内在抗菌活性。EM是人IgG 1 Fc，其共同激活补体 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依赖性细胞毒性（CDC）。 细胞吞噬作用（ADCP），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有效的细胞靶向与固有的细胞杀伤催化了一个强大的 通过更有效地将病原体呈递给免疫组分以进行清除来增强免疫应答。公司简介 是我们领先的ADC候选药物，已证明其作为免疫预防剂具有非常有前途的特性， 治疗剂：具有内在和免疫驱动的广谱抗菌活性， 啮齿类动物，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， 和67小时的血浆半衰期。进一步优化效价和光谱，深入评价 在本申请中提出了该铅的药理学和毒理学性质。总体目标 该提案的一个目的是在第3年确定合格的先导开发候选药物， (IND)在第5年结束时，候选人符合这些标准：1）IV的可接受的稳定性和溶解度 制剂，2）对克雷伯菌属、不动杆菌属、 假单胞菌属、E.大肠杆菌和选择性病原体土拉热弗朗西斯菌、鼠疫耶尔森菌和布鲁氏菌，3）MIC 90 对MCR-1、MCR-2和其他粘菌素耐药G-临床分离株≤1 µM，4）稳健的体内预防性 在感染前48- 72小时的时间窗内对MDR G-感染的有效性，以及有效的治疗效果 优于标准治疗，感染后治疗窗≥3倍，5）PK/PD参数支持 每周一次或更佳剂量，6）大鼠和食蟹猴GLP毒理学研究中的NOAEL 比目标临床剂量高至少五倍，和7）可放大合成为GMP产品。