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:
  • 金额:
    $ 107.68万
  • 依托单位:
  • 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

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,每年都有因耐药细菌造成的死亡。革兰氏阴性菌 (G-) 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 年。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 需要替代策略来预防 MDR G 感染。因此,一种利用免疫学的药物 预防高危人群感染药物敏感菌株和耐多药菌株的机制 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 Therapeutics 开发的缀合物 (ADC) 平台采用全新的基于免疫的技术 预防和治疗 G-感染的方法。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,同时与多个免疫臂结合 通过效应器部分(EM)的系统。 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 病原体通过免疫成分进行清除。 CTC-026 是我们的主要 ADC 候选药物,并已证明 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,小鼠血浆半衰期为 67 小时。进一步优化效能 并提出了该先导物的谱图和药理毒理特性的深入评价 在此应用程序中。该提案的总体目标是确定合格的先导开发候选人 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。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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David S Perlin其他文献

Worldwide emergence of fluconazole-resistant emCandida parapsilosis/em: current framework and future research roadmap
全球氟康唑耐药近平滑念珠菌的出现:当前框架和未来研究路线图
  • DOI:
    10.1016/s2666-5247(23)00067-8
  • 发表时间:
    2023-06-01
  • 期刊:
  • 影响因子:
    20.400
  • 作者:
    Farnaz Daneshnia;João N de Almeida Júnior;Macit Ilkit;Lisa Lombardi;Austin M Perry;Marilyn Gao;Clarissa J Nobile;Matthias Egger;David S Perlin;Bing Zhai;Tobias M Hohl;Toni Gabaldón;Arnaldo Lopes Colombo;Martin Hoenigl;Amir Arastehfar
  • 通讯作者:
    Amir Arastehfar

David S Perlin的其他文献

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{{ truncateString('David S Perlin', 18)}}的其他基金

Accelerated development of advanced leads against SARS-CoV-2 and other pandemic viruses
加速开发针对 SARS-CoV-2 和其他大流行病毒的先进先导药物
  • 批准号:
    10513922
  • 财政年份:
    2022
  • 资助金额:
    $ 107.68万
  • 项目类别:
Metropolitan AntiViral Drug Accelerator
大都会抗病毒药物加速器
  • 批准号:
    10513913
  • 财政年份:
    2022
  • 资助金额:
    $ 107.68万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10513914
  • 财政年份:
    2022
  • 资助金额:
    $ 107.68万
  • 项目类别:
Animal Model Core
动物模型核心
  • 批准号:
    10513920
  • 财政年份:
    2022
  • 资助金额:
    $ 107.68万
  • 项目类别:
A CETR-based partnership accelerator for rapid drug development targeting SARS-CoV-2 and pan-CoVs
基于 CETR 的合作加速器,用于针对 SARS-CoV-2 和泛冠状病毒的快速药物开发
  • 批准号:
    10187269
  • 财政年份:
    2020
  • 资助金额:
    $ 107.68万
  • 项目类别:
Center to develop innovative therapeutics to multidrug resistant high-threat bacterial agents
开发针对多重耐药高威胁细菌制剂的创新疗法的中心
  • 批准号:
    10394984
  • 财政年份:
    2019
  • 资助金额:
    $ 107.68万
  • 项目类别:
Critical Factors Influencing Echinocandin Resistance in Candidaglabrata
影响光滑念珠菌棘白菌素耐药性的关键因素
  • 批准号:
    10451830
  • 财政年份:
    2019
  • 资助金额:
    $ 107.68万
  • 项目类别:
Novel bi-specific immunoprophylactics against multi-drug resistant Gram-negative bacterial 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:
    9898899
  • 财政年份:
    2019
  • 资助金额:
    $ 107.68万
  • 项目类别:
Critical Factors Influencing Echinocandin Resistance in Candidaglabrata
影响光滑念珠菌棘白菌素耐药性的关键因素
  • 批准号:
    10215271
  • 财政年份:
    2019
  • 资助金额:
    $ 107.68万
  • 项目类别:
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
  • 财政年份:
    2019
  • 资助金额:
    $ 107.68万
  • 项目类别:

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用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
  • 批准号:
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