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200万种疾病和23,000
在美国,每年的死亡是由抗微生物剂抗性细菌引起的。革兰氏阴性(G-)
病原体尤其令人担忧,因为它们造成了大约99,000人死亡和200亿美元的医疗保健费用,
年更令人担忧的是,由于快速的感染,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多药耐药性(MDR)的出现,突出了
需要替代策略来预防MDR G-感染。因此,利用免疫学的试剂
预防高危人群感染药物敏感和MDR菌株的机制将
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)平台使用了一种全新的基于免疫的
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结合保守的
通过靶向部分(TM)靶向病原体,同时接合免疫系统的多个臂,
系统通过效应部分(EM)。TM由二聚体肽组成,所述二聚体肽紧密结合至
脂多糖(LPS),并赋予广谱G-覆盖与有效的内在抗微生物活性。
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依赖性细胞吞噬作用(ADCP),以清除MDR
G-通过宿主细胞上的Fcγ受体识别来自宿主的病原体。这种创新的方法,
具有固有细胞杀伤的有效细胞靶向通过更有效地呈现免疫应答来催化强有力的免疫应答。
病原体对免疫成分的清除。CTC-026是我们的主要ADC候选产品,
作为免疫预防剂具有非常有前途的特性:广谱抗菌活性,
内在和免疫驱动,啮齿类动物中的急性安全性,大肠杆菌脓毒症小鼠模型中的体内有效性
和鲍曼不动杆菌肺炎,以及在小鼠中的67小时血浆半衰期。进一步优化效价
和光谱和深入评价的药理学和毒理学性质的这种铅提出
在这个应用中。本提案的总体目标是确定合格的潜在客户开发候选人
在第3年,并在第5年结束时获得研究性新药(IND)候选药物,符合以下标准:1)
IV制剂的可接受稳定性和溶解度,2)对以下临床分离株(包括MDR)的MIC 90 ≤1 µM
克雷伯菌属、不动杆菌属、假单胞菌属和大肠埃希菌属。3)对MCR-1、MCR-2和其他粘菌素的MIC 90 ≤1 µM-
耐药G-临床分离株,4)在时间窗内对MDR G-感染的稳健体内预防功效
感染前48- 72小时,5)PK/PD参数,以支持每周一次或更好的人体给药,6)NOAEL
在大鼠和食蟹猴的GLP毒理学研究中,
剂量,和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)
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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:
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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