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.

项目摘要当前，系统地管理固体ACE2作为病毒诱饵测试以防止 COVID-19患者的SARS-COV-2细胞进入。但是，这种固体ACE2蛋白的短半衰期和肺中的生物利用度有限，尤其是在SARS-COV-2进入的目标部位，即鼻和肺II型肺泡细胞。为了克服这个问题，我们开发了 AGT001，一种新型的固体人ACE2（ACE2 1-618），并与专辑绑定融合域（ABD）。这种蛋白质，我们称为Agt001的蛋白质半衰期增加体内长期ACE2活性。最近，我们引入了一个十二肽（DDC）图案 AGT001，导致二聚化。我们称为Agt002和在此重新提取申请中使用的建议具有增加的约束性亲和力的20-30倍与AGT001相比，SARS-COV-2。我们将使用鼻内交付Agt002进行这些特性的优势可有效增加呼吸道腔表面 ACE2活性的浓度并增加了其作为诱饵的能力，以拦截SARS- COV-2从结合其主要接收器，膜结合的FL-ACE2。此外，AGT002 将补充ACE2酶活性可能会减少相关的炎症过程血管紧张素II和DES-ARG9肌激肽过量，ACE2驱动降解的底物。即使在SARS-COV-2疫苗接种时代，商业上市的AGT002也有益于由于免疫抑制与移植和透析患者一样。此外，AGT002还可以使用对于新的SARS-COV-2变体，可以逃脱疫苗或其他未来的冠状病毒 fl-ace2作为主接收器。这是该程序的目的是1）测试概念证明允许小鼠模型（K18-HACE2）中肺部传递AGT002的功效，2）评估 AGT002的气溶胶开发潜力，以及3）评估AGT002的最初安全性和野生型小鼠的药代动力学特征。我们已经组建了一流的专家团队促进该项目的性能包括1）1）AGT002的共同发明者 2）芝加哥大学的最先进的BSL-3设施能够感染宽松的小鼠使用SARS-COV-2并测试AGT002和3）气溶胶，毒理学和药代动力学的效率 Lovelace生物医学的专业知识。该计划的结果将是追求的决策门调查新药（IND）应用。如果成功，我们将通过传统的化学制造和控制（CMC），GLP毒理学，IND应用以及人力安全和概念证明利用II期SBIR和/或传统融资。