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
基本信息
- 批准号:10337197
- 负责人:
- 金额:$ 114.2万
- 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:2019-02-21 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcinetobacterAcinetobacter baumanniiAcinetobacter baumannii pneumoniaAcuteAddressAdverse effectsAnti-Bacterial AgentsAntibodiesAntibody-drug conjugatesAntimicrobial ResistanceBacteriaBacterial InfectionsBindingBrucellaCardiovascular systemCellsCenters for Disease Control and Prevention (U.S.)Cessation of lifeClinicalColistinCollaborationsColony-forming unitsComplement-Dependent CytotoxicityDevelopmentDoseDose FractionationDrug KineticsDrug resistanceEnterobacterEnvironmentEscherichia coliEvaluationFc domainFormulationFrancisella tularensisGoalsHalf-LifeHealth Care CostsHealth systemHourHumanIgG1ImmuneImmune responseImmune systemImmunologicsImmunotherapeutic agentIn VitroInfectionInfection preventionInvestigational DrugsKidneyKlebsiellaKlebsiella pneumoniaeLeadLifeLipopolysaccharidesLung infectionsMacaca fascicularisMalignant NeoplasmsMediatingMethodsMicrobiologyModelingMonkeysMulti-Drug ResistanceMusMutationNatureNew AgentsNew JerseyPeptidesPhagocytosisPharmaceutical PreparationsPharmacologyPharmacology StudyPharmacology and ToxicologyPlasmaPropertyProphylactic treatmentPseudomonasPseudomonas aeruginosaPublic HealthRattusResistanceRodentSafetySepsisSepticemiaSolubilitySystemic infectionTherapeuticTherapeutic AgentsTimeTissuesToxicokineticsToxicologyTreatment EfficacyUnited StatesUniversitiesValidationWhole BloodWorkYersinia pestisantibody-dependent cell cytotoxicityantimicrobialantimicrobial drugarmbacterial resistancebasecell killingclinical efficacycolistin resistancedimerdrug candidatedrug metabolismdrug synthesisexperimental studyhigh risk populationimprovedin vivoinnovationlead seriesmedical schoolsmouse modelneonatal Fc receptornovelpathogenpathogenic bacteriapreventprogramsprophylacticreceptorreceptor bindingresistant strainrespiratorysafety studyscreeningstandard of care
项目摘要
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.
美国疾病控制与预防中心估计,至少有 200 万人患病,23,000 人死亡
在美国,每年都是由耐药细菌引起的。革兰氏阴性 (G-) 病原体
特别值得关注,因为它们每年造成大约 99,000 人死亡,并造成 20B 美元的医疗费用。
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药物的耐药性(MDR),强调需要替代品
预防MDR G-感染的策略。此外,虽然很少见,但 MDR 可能会成为一个严重的问题
鉴于 G- 细菌中 MDR 决定簇的高度传播性以及以下事实,G- 选择药剂
选择的代理持续存在于环境中。因此,一种利用免疫学的广谱药物
预防和治疗高危人群高威胁 G 细菌感染的机制
在满足这一需求方面将拥有独特的优势。创新的 Cloudbreak™ 抗体药物
Cidara Therapeutics 开发的缀合物 (ADC) 平台是一种广谱 G 活性候选药物
它使用一种全新的基于免疫的方法来预防和治疗 G-感染。类似成功
癌症双特异性药物,ADC 通过靶向部分 (TM) 结合病原体上的保守靶点,同时
通过效应器部分 (EM) 同时参与免疫系统的多个臂。 TM包括
与脂多糖 (LPS) 紧密结合并赋予广谱 G 覆盖的二聚肽
强大的内在抗菌活性。 EM 是人类 IgG1 Fc,可共同激活补体
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) 通过 Fcγ 受体的识别从宿主中清除高威胁 G-病原体
宿主细胞。这种创新方法涉及有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成分进行清除来产生免疫反应。 CTC-026
是我们的主要 ADC 候选药物,并已表现出作为免疫预防和治疗药物的非常有前景的特性。
治疗剂:具有内在和免疫驱动的广谱抗菌活性,具有极高的安全性
啮齿类动物,在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,
小鼠体内的血浆半衰期为 67 小时。效价和谱图的进一步优化和深入评价
本申请提出了该先导化合物的药理学和毒理学特性。总体目标
该提案的目的是在第 3 年确定合格的先导开发候选药物和研究性新药
(IND) 候选者在第 5 年末满足以下标准:1) IV 可接受的稳定性和溶解度
配方,2) 针对克雷伯菌属、不动杆菌属、不动杆菌临床分离株(包括 MDR)的 MIC90 ≤ 1 µM
假单胞菌、大肠杆菌和选择土拉弗朗西斯菌、鼠疫耶尔森氏菌和布鲁氏菌种,3) MIC90
针对 MCR-1、MCR-2 和其他粘菌素耐药性 G 临床分离株≤1 µM,4) 强大的体内预防作用
在感染前48-72小时的时间窗口内对MDR G-感染有效,并且具有强大的治疗效果
优于标准护理,感染后治疗窗≥3倍,5) PK/PD参数支持
每周一次或在人类中更好的给药剂量,6) 在大鼠和食蟹猴中进行的 GLP 毒理学研究中的 NOAEL
比目标临床剂量至少高出五倍,以及 7) 可扩展合成 GMP 产品。
项目成果
期刊论文数量(0)
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:
$ 114.2万 - 项目类别:
A CETR-based partnership accelerator for rapid drug development targeting SARS-CoV-2 and pan-CoVs
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- 批准号:
10187269 - 财政年份:2020
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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:
$ 114.2万 - 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:
$ 114.2万 - 项目类别:
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
- 批准号:
10380759 - 财政年份:2019
- 资助金额:
$ 114.2万 - 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:
$ 114.2万 - 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:
$ 114.2万 - 项目类别:
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