Novel bi-specific immunotherapeutic against high-threat Gram-negative pathogens
Novel bi-specific immunotherapeutic against high-threat Gram-negative pathogens
批准号:
10337197
负责人:
David S Perlin
金额:
$114.2万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-02-21 至 2024-01-31
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
中文摘要
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。
英文摘要
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.
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会议论文
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