mRNA Delivery of a Panel of Single-Domain Antibodies for Combinatorial Deciphering of Therapeutic Targets for Covid-19 Related Cytokine Release Syndrome

一组单域抗体的 mRNA 递送，用于组合破译 Covid-19 相关细胞因子释放综合征的治疗靶点

• 批准号: 10383635
• 负责人: Xiang Gao
• 金额: $ 29.91万
• 依托单位: ONCOTRAP, INC.
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-01 至 2023-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10383635
• 关键词: 2019-nCoV; Achievement; Acute Respiratory Distress Syndrome; Address; Affinity; Animal Model; Antibodies; Back; Bacterial Infections; Binding; Biological; Brazil; COVID-19; COVID-19 outbreak; COVID-19 patient; COVID-19 treatment; COVID-19 vaccine; Cause of Death; Clinical; Clinical Data; Clinical Trials; Combined Modality Therapy; Data; Development; Directed Molecular Evolution; Dose; Drops; Encapsulated; Ensure; Feedback; Fever; Formulation; Future; Granulocyte-Macrophage Colony-Stimulating Factor; Hepatocyte; Human; Immune Evasion; Immune System Diseases; In Vitro; Interferon Type II; Interleukin-1 beta; Interleukin-6; Intervention; Intravenous; Janus kinase; Lead; Libraries; Liver; Medical; Messenger RNA; Microfluidics; Middle East Respiratory Syndrome Coronavirus; Modality; Modeling; Molecular Evolution; Multiple Organ Failure; Mus; Mutation; Patients; Peripheral Blood Mononuclear Cell; Persons; Pharmacologic Substance; Phase; Phase III Clinical Trials; Process; Production; Proteins; Protocols documentation; Reaction; Reagent; Recovery; Research Personnel; Resolution; Resources; SARS coronavirus; SARS-CoV-2 B.1.1.7; SARS-CoV-2 B.1.351; SARS-CoV-2 immunity; SARS-CoV-2 variant; Severity of illness; Signal Transduction; Small Business Innovation Research Grant; Small Business Technology Transfer Research; Specificity; Surface; Symptoms; System; TNF gene; Technology; Testing; Time; Uncertainty; United States National Institutes of Health; Vaccines; Validation; Variant; Viral; Virus Diseases; Yeasts; chemokine; clinically relevant; combinatorial; cytokine; cytokine release syndrome; cytopenia; design; dosage; efficacy evaluation; experimental study; gene delivery system; improved; in vivo; inhibitor; inpatient service; lipid nanoparticle; mRNA delivery; mortality; mouse model; nanobodies; nanomolar; nanoparticle delivery; pandemic disease; phase 1 study; phase 2 study; pre-clinical; preclinical evaluation; primary endpoint; respiratory; screening; severe COVID-19; standard care; therapeutic target; therapeutically effective; tool; translational study; treatment strategy

Project Summary/Abstract Severe COVID-19 patients who develop acute respiratory distress syndrome (ARDS) and multiple organ failures share a hyperinflammatory cytokine/chemokine expression profile. This clinical observation resembles the cytokine release syndrome (CRS) which was the leading cause of mortality in patients infected with SARS-CoV and MERS-CoV. US FDA have fast-tracked dozens of clinical trials to evaluate the efficacy of cytokine blockade therapies in the management of COVID-19 associated CRS. However, recent data released from majority of the trials indicated that blockade of one cytokine or Janus Kinase only marginally benefited patients regarding recovery time, and yet barely improved the mortality rate compared with that of standard care. Therefore, it is urgently needed that a preclinical evaluation tool available to the medical researcher and pharmaceutical companies that could help them identify the most effective combinations of therapeutic targets in the treatment of CRS. We propose to construct a single domain antibody (sdAb) library that contains a panel of sdAbs against clinically-characterized, significantly elevated cytokines and chemokines associated with COVID- 19 CRS. This library could be harnessed as a tool to compare and contrast the potency of different cytokine/chemokine blockade therapy in a humanized PBMC engrafted CRS mouse model. Moreover, the library allows the testing of simultaneous blockade of multiple cytokine/chemokines as a combinatorial therapy for the treatment of CRS which is hypothesized to be resolution to the issue. To accomplish this in a prompt way, the modality of the library will be sdAb- encodings mRNA which is encapsulated in lipid nanoparticle (LNP) to avoid the hassle with the protein production and formulation. OncoTrap will leverage the expertise in in vitro antibody screening and molecular evolution platform, as well as the lipid nanoparticle-based gene delivery system, which will be achieved in three specific aims. Aim 1 is intended to screen the sdAbs against the designated cytokine or chemokine with each of them shows nanomolar or sub-nanomolar binding affinity toward its target. Aim 2 is intend to characterize the PK profiles of sdAbs when they are delivered in the form of mRNA by LNP in vivo. In Aim 3, two representative sdAbs in the library will be tested in human PBMC engrafted CRS mouse model as the proof of concept study. Achievement of NIH-STTR phase I study will prepare the library for large-scale and systemic screening in the phase II, where the most effective therapeutics target(s) in the treatment of CRS will be identified.

项目摘要/摘要 严重的COVID-19患者，患有急性呼吸窘迫综合征（ARD）和多器官失败共享 高炎性细胞因子/趋化因子表达谱。该临床观察类似于细胞因子的释放 综合征（CRS）是感染SARS-COV和MERS-COV的患者死亡率的主要原因。美国FDA 已经快速跟踪了数十项临床试验，以评估细胞因子封锁疗法在管理中的疗效 COVID-19相关CRS。但是，从大多数试验中发布的最新数据表明，封锁了一个 细胞因子或Janus激酶仅略微使患者受益于恢复时间，但几乎没有提高死亡率 与标准护理相比。因此，迫切需要使用临床前评估工具 可以帮助他们确定最有效组合的医学研究人员和制药公司 治疗CRS的治疗靶标。我们建议构建包含的单个域抗体（SDAB）库 针对临床特征化，细胞因子和趋化因子的临床表征显着升高的SDAB小组 19 crs。可以将该库作为比较和对比不同细胞因子/趋化因子的效力的工具 人源化PBMC植入CRS小鼠模型中的封锁治疗。此外，库允许测试 同时封锁多个细胞因子/趋化因子作为CRS治疗的组合疗法 假设是解决问题的方法。为了迅速完成此操作，库的方式将是SDAB- 封装在脂质纳米颗粒（LNP）中的编码mRNA，以避免因蛋白质产生和 配方。 Oncotrap还将利用体外抗体筛选和分子进化平台的专业知识 作为基于脂质纳米颗粒的基因递送系统，这将在三个特定目标中实现。目标1旨在 将SDAB筛选在指定的细胞因子或趋化因子上，每种都显示纳摩尔或亚纳米摩尔 对目标的绑定亲和力。 AIM 2旨在表征SDAB在交付中的PK配置文件 LNP体内的mRNA形式。在AIM 3中，库中的两个代表性SDAB将在植入的人类PBMC中进行测试 CRS鼠标模型作为概念研究证明。 NIH-STTR I期研究的成就将为图书馆做好准备 在II期中进行大规模和全身筛查，其中最有效的治疗靶标在治疗CRS中 将被确定。