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
- 来源:
- 关键词:AcinetobacterAcinetobacter baumanniiAcinetobacter baumannii pneumoniaAcuteAddressAdverse effectsAnti-Bacterial AgentsAntibodiesAntibody-drug conjugatesAntimicrobial ResistanceBacteriaBindingCardiovascular systemCellsCenters for Disease Control and Prevention (U.S.)Cessation of lifeClinicalColistinCollaborationsColony-forming unitsComplement-Dependent CytotoxicityDevelopmentDoseDose FractionationDrug KineticsDrug resistanceEnterobacterEscherichia coliEvaluationFc domainFormulationGoalsHalf-LifeHealth Care CostsHealth systemHourHumanIgG1ImmuneImmune responseImmune systemImmunologicsIn VitroInfectionInfection preventionInvestigational DrugsKidneyKlebsiellaKlebsiella pneumoniaeLeadLifeLipopolysaccharidesLung infectionsMacaca fascicularisMalignant NeoplasmsMediatingMethodsMicrobiologyModelingMonkeysMulti-Drug ResistanceMusMutationNew AgentsNew JerseyPeptidesPhagocytosisPharmaceutical PreparationsPharmacologyPharmacology StudyPharmacology and ToxicologyPlasmaPropertyPseudomonasPseudomonas aeruginosaPublic HealthRattusResearch InstituteResistanceRodentSafetySepsisSepticemiaSolubilitySystemic infectionTherapeuticTherapeutic UsesTimeTissuesToxicokineticsToxicologyUnited StatesUniversitiesValidationWhole BloodWorkantibody-dependent cell cytotoxicityantimicrobialantimicrobial drugarmbacterial resistancebasecell killingclinical efficacycolistin resistancedimerdrug candidatedrug metabolismdrug synthesisexperimental studyhigh risk populationimprovedin vivoinnovationlead seriesmedical schoolsmouse modelneonatal Fc receptornovelpathogenpathogenic bacteriapreventprogramsprophylacticpublic health researchreceptorreceptor bindingresistant strainrespiratorysafety studyscreening
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.
疾病控制和预防中心(CDC)估计,至少有200万人患病,23000人
在美国,每年的死亡都是由抗菌素耐药性细菌造成的。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
年。更令人担忧的是,G感染的治疗选择越来越有限,因为
对现有和新批准的抗菌剂出现多药耐药(MDR),突出了
需要采取替代战略来预防耐多药G-感染。因此,一种利用免疫学
预防药物敏感和耐多药菌株感染高危人群的机制将
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)平台使用了一种全新的基于免疫的
预防和治疗G感染的方法。类似于成功的癌症双特异性药物,ADC结合保守
通过靶向部分(TM)靶向病原体,同时接触免疫的多个手臂
系统通过效应器部分(EM)。TM是由一种二聚体多肽组成的,它与
脂多糖(LPS),并赋予广谱G-覆盖,具有强大的内在抗菌活性。
EM是一种人IgG1Fc,它能集体激活补体依赖性细胞毒(CDC)抗体
(AB)依赖细胞介导的细胞毒性(ADCC)和抗体依赖的细胞吞噬(ADCP)以清除MDR
来自宿主的G-病原体,通过宿主细胞上的Fcγ受体识别。
高效的细胞靶向与固有的细胞杀伤通过更有效地呈递
病原体对免疫成分进行清除。CTC-026是我们的主要ADC候选者,并已展示
作为免疫预防药物的极具前景的特性:广谱抗菌活性,即
本征和免疫驱动,对啮齿动物的急性安全性,在小鼠模型中对大肠杆菌败血症的体内疗效
鲍曼不动杆菌肺炎,以及小鼠67小时的血浆半衰期。进一步优化效能
并对该铅的药理和毒理性质进行了波谱和深入评价。
在此应用程序中。这项提议的首要目标是确定一位合格的领导发展候选人
在第三年,并在第五年年底之前成为研究用新药(IND)候选药物,满足以下标准:1)
IV制剂的可接受的稳定性和溶解性,2)MIC90≤1µM对临床分离株(包括mdr)的抗药性
克雷伯氏菌、不动杆菌、假单胞菌和大肠埃希菌,3)MIC90对Mcr-1、Mcr-2和其他粘菌素的≤为1µM。
耐药G-临床分离株,4)在一个时间窗口内对MDR G-感染的体内强大预防效果
感染前48-72小时,5)PK/PD参数以支持人类每周一次或更好的剂量,6)无AEL
在对大鼠和食蟹猴的GLP毒理学研究中,至少是目标临床试验的五倍
剂量,以及7)GMP产品的可扩展合成。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
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
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
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:
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:
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:
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:
相似海外基金
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
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:
MR/Y008693/1 - 财政年份:2024
- 资助金额:
$ 107.68万 - 项目类别:
Research Grant
Generative machine learning for narrow spectrum antibiotic discovery against Acinetobacter baumannii
生成机器学习用于发现针对鲍曼不动杆菌的窄谱抗生素
- 批准号:
477936 - 财政年份:2023
- 资助金额:
$ 107.68万 - 项目类别:
Operating Grants
Conserved structural dynamics of outer-membrane channels in Acinetobacter baumannii as potential drug targets
鲍曼不动杆菌外膜通道的保守结构动力学作为潜在的药物靶点
- 批准号:
494854 - 财政年份:2023
- 资助金额:
$ 107.68万 - 项目类别:
Operating Grants
Defining key players at the host-pathogen interface during Acinetobacter baumannii infection
定义鲍曼不动杆菌感染期间宿主-病原体界面的关键参与者
- 批准号:
488684 - 财政年份:2023
- 资助金额:
$ 107.68万 - 项目类别:
Operating Grants
Study of clinically over-expressed and chimeric RND multidrug efflux pumps from Acinetobacter baumannii and Pseudomonas aeruginosa
鲍曼不动杆菌和铜绿假单胞菌临床过表达和嵌合 RND 多药外排泵的研究
- 批准号:
23K14346 - 财政年份:2023
- 资助金额:
$ 107.68万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Biomimetic Macrophage Membrane-Coated Nanosponges: A Novel Therapeutic for Multidrug-Resistant Pseudomonas aeruginosa and Acinetobacter baumannii Hospital-Associated Pneumonia
仿生巨噬细胞膜包被的纳米海绵:一种治疗多重耐药铜绿假单胞菌和鲍曼不动杆菌医院相关肺炎的新疗法
- 批准号:
10674406 - 财政年份:2023
- 资助金额:
$ 107.68万 - 项目类别:
Using strain history to improve prediction of the evolution of antimicrobial resistance in Acinetobacter baumannii
利用菌株历史改进对鲍曼不动杆菌抗菌药物耐药性演变的预测
- 批准号:
10677362 - 财政年份:2023
- 资助金额:
$ 107.68万 - 项目类别:
Inhibitors of adaptive efflux mediated resistance in Acinetobacter baumannii
鲍曼不动杆菌适应性外排介导的耐药性抑制剂
- 批准号:
10625029 - 财政年份:2023
- 资助金额:
$ 107.68万 - 项目类别:
Identifying niche specific adaptations in Acinetobacter baumannii
鉴定鲍曼不动杆菌的生态位特异性适应
- 批准号:
10596620 - 财政年份:2022
- 资助金额:
$ 107.68万 - 项目类别:
Identifying niche specific adaptations in Acinetobacter baumannii
鉴定鲍曼不动杆菌的生态位特异性适应
- 批准号:
10449699 - 财政年份:2022
- 资助金额:
$ 107.68万 - 项目类别: