Lung delivery of novel ACE2 variants for COVID-19

针对 COVID-19 的新型 ACE2 变体的肺部输送

基本信息

批准号：
10483042
负责人：
Jack Henkin
金额：
$ 29.98万
依托单位：
ANGIOTENSIN THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10483042
关键词：
2019-nCoV ACE2 Acute Lung Injury Aerosols Affinity Albumins Angiotensin II Angiotensins Binding Biological Assay Biological Availability Bradykinin COVID-19 COVID-19 patient COVID-19 risk COVID-19 test COVID-19 treatment COVID-19 vaccination Cell membrane Cells Chemicals Chicago Chimeric Proteins Clinic Clinical Clinical Research Coronavirus Data Development Dialysis patients Dimerization Disease Dose Drug Kinetics Early Intervention Enzymes Excipients Formulation Funding Future Half-Life Histopathology Human Immunocompromised Host Immunosuppression In Vitro Inflammatory Inhalation Inhalation Therapy Intercept Intranasal Administration Investigational Drugs Investigational New Drug Application Legal patent Length Liquid substance Lung Lung retention Membrane Methods Mus Nebulizer Nose Outcome Output Particle Size Performance Persons Phase Phase I/II Clinical Trial Plasma Cells Preparation Prevention Procedures Process Production Property Proteins Publishing Readiness Recombinants Refractory Research Personnel Respiratory System SARS-CoV-2 exposure SARS-CoV-2 infection SARS-CoV-2 variant Safety Site Small Business Innovation Research Grant Surface Symptoms System Technology Testing Therapeutic Therapeutic Intervention Time Toxicology Translations Transplant Recipients Treatment Efficacy Universities Vaccination Vaccines Variant Viral Western Blotting Wild Type Mouse alveolar type II cell aqueous base biosafety level 3 facility clinical trial readiness efficacy evaluation efficacy testing experimental study in vivo interest lung injury mouse model novel novel coronavirus phase 1 study pre-clinical prevent programs receptor receptor binding respiratory scale up stem unvaccinated

项目摘要

Project Summary Systemically administered soluble native ACE2 is currently tested as a viral decoy to prevent SARS-CoV-2 cell entry in COVID-19 patients. This soluble ACE2 protein, however, has a short half-life and limited bioavailability in the lung, especially at the target sites for SARS-CoV-2 entry, namely nasal and pulmonary type II alveolar cells. To overcome this problem, we developed AGT001, a novel variant of soluble human ACE2 (ACE2 1-618) and fused with an albumin binding domain (ABD). This protein, that we termed AGT001 has an increased protein half-life and prolonged ACE2 activity in vivo. More recently, we introduced a dodecapeptide (DDC) motif to AGT001, that leads to dimerization. The resulting protein that we have termed AGT002 and propose to use in this resubmission application has 20-30 times increased binding affinity for SARS-CoV-2 as compared to AGT001. We will use intranasal delivery of AGT002 to take advantage of these properties to effectively increase respiratory tract luminal surface concentrations of ACE2 activity and increase its capacity to act as a decoy to intercept SARS- CoV-2 from binding to its main receptor, the membrane-bound FL-ACE2. In addition, AGT002 will supplement ACE2 enzymatic activity potentially reducing inflammatory processes associated with excess of Angiotensin II and des-Arg9 Bradykinin, substrates of ACE2 driven degradation. Even in an era of SARS-CoV-2 vaccinations benefactors of a commercially marketed AGT002 could be unvaccinated and/or vaccination refractory COVID-19 patients owing to immunosuppression as in transplant and dialysis patients. AGT002, moreover, would be available for new SARS-CoV-2 variants that escape the vaccine or other future coronavirus that also use FL-ACE2 as main receptor. Thus, the objective of this program is to 1) test proof of concept efficacy of pulmonary-delivered AGT002 in a permissive mouse model (k18-hACE2), 2) assess AGT002’s aerosol development potential, and 3) assess AGT002’s initial safety and pharmacokinetic profile in wild-type mice. We have assembled a first-class team of experts to facilitate the performance of the project to include the 1) co-inventors of AGT002 at Northwestern, 2) state of the art BSL-3 facility at the University of Chicago to be able to infect permissive mice with SARS-CoV-2 and test the efficacy of AGT002 and 3) aerosol, toxicology and pharmacokinetic expertise at Lovelace Biomedical. The results of this program will be a decision gate for pursuing an Investigational New Drug (IND) application. If successful, we will move AGT002 through traditional chemical manufacturing and controls (CMC), GLP toxicology, IND application, and human safety and proof of concept studies utilizing the Phase II SBIR and/or traditional financing.

项目概要目前正在测试全身施用可溶性天然 ACE2 作为病毒诱饵以预防然而，这种可溶性 ACE2 蛋白在 SARS-CoV-2 细胞中进入 COVID-19 患者体内的时间很短。肺部的半衰期和有限的生物利用度，特别是在 SARS-CoV-2 进入的目标位点，为了克服这个问题，我们开发了鼻和肺 II 型肺泡细胞。 AGT001，可溶性人 ACE2 (ACE2 1-618) 的新型变体，与白蛋白结合融合这种蛋白质，我们称为 AGT001，具有延长的蛋白质半衰期和最近，我们引入了十二肽（DDC）基序来延长 ACE2 的体内活性。 AGT001，导致二聚化，所得蛋白质我们称为 AGT002 和建议在此重新提交申请中使用，其结合亲和力增加 20-30 倍与 AGT001 相比，我们将使用鼻内递送 AGT002 来服用 SARS-CoV-2。利用这些特性有效增加呼吸道管腔表面积 ACE2 活性浓度并增加其作为拦截 SARS 诱饵的能力 CoV-2 与其主要受体（膜结合的 FL-ACE2）结合。将补充 ACE2 酶活性，有可能减少相关的炎症过程过量的血管紧张素 II 和 des-Arg9 缓激肽（ACE2 的底物）驱动降解。即使在 SARS-CoV-2 疫苗接种时代，商业销售的 AGT002 的捐助者可能是未接种疫苗和/或疫苗接种难治的 COVID-19 患者，因为此外，还可以使用 AGT002 来治疗移植和透析患者。寻找逃避疫苗的新 SARS-CoV-2 变种或其他也使用疫苗的未来冠状病毒 FL-ACE2 作为主要受体因此，该计划的目标是 1) 测试概念验证。评估经肺输送的 AGT002 在许可小鼠模型 (k18-hACE2) 中的功效，2) AGT002 的气溶胶开发潜力，以及 3) 评估 AGT002 的初始安全性和我们组建了一流的专家团队来研究野生型小鼠的药代动力学特征。促进项目的实施，包括 1) 西北大学 AGT002 的共同发明人， 2) 芝加哥大学最先进的 BSL-3 设施能够感染允许的小鼠 SARS-CoV-2 并测试 AGT002 和 3) 气雾剂、毒理学和药代动力学的功效 Lovelace Biomedical 的专业知识将成为追求该计划的决策门。研究性新药 (IND) 申请如果成功，我们将通过 AGT002。传统化学品制造和控制 (CMC)、GLP 毒理学、IND 应用以及利用第二阶段 SBIR 和/或传统融资进行人类安全和概念验证研究。