Lung delivery of novel ACE2 variants for COVID-19

针对 COVID-19 的新型 ACE2 变体的肺部输送

• 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
• 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

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 目前，全身给予可溶性天然ACE 2作为病毒诱饵进行了测试，以预防 COVID-19患者中的SARS-CoV-2细胞进入。然而，这种可溶性ACE 2蛋白具有短的 在肺中的半衰期和有限的生物利用度，特别是在SARS-CoV-2进入的靶位点， 即鼻和肺的II型肺泡细胞。为了解决这个问题，我们开发了 AGT 001，一种新的可溶性人ACE 2（ACE 2 1-618）变体，并与白蛋白结合蛋白融合 结构域（ABD）。我们称之为AGT 001的这种蛋白质具有增加的蛋白质半衰期， 体内ACE 2活性延长。最近，我们引入了十二肽（DDC）基序， AGT 001，导致二聚化。我们将得到的蛋白质命名为AGT 002， 建议在此重新提交申请中使用具有20-30倍的结合亲和力， SARS-CoV-2与AGT 001相比。我们将使用AGT 002的鼻内递送， 这些特性的优点是有效地增加呼吸道管腔表面 浓度的ACE 2活性，并增加其作为诱饵拦截SARS的能力- CoV-2与其主要受体膜结合的FL-ACE 2结合。此外，AGT 002 将补充ACE 2酶活性，可能减少相关的炎症过程 血管紧张素II和des-Arg 9缓激肽过量，ACE 2驱动降解的底物。 即使在SARS-CoV-2疫苗接种的时代，商业销售的AGT 002 可能是未接种疫苗和/或疫苗接种难治性COVID-19患者， 免疫抑制，如移植和透析患者。AGT 002，此外， 对于新的SARS-CoV-2变种，逃避疫苗或其他未来的冠状病毒， FL-ACE 2为主要受体。因此，该计划的目标是1）测试概念证明 肺递送AGT 002在许可小鼠模型（k18-hACE 2）中的功效，2）评估 AGT 002的气雾剂开发潜力，以及3）评估AGT 002的初始安全性， 在野生型小鼠中的药代动力学曲线。我们组建了一流的专家团队， 促进项目的执行，包括1）西北大学AGT 002的共同发明人， 2)芝加哥大学的最先进的BSL-3设施能够感染许可小鼠 与SARS-CoV-2的接触，并测试AGT 002的有效性; 3）气雾剂、毒理学和药代动力学 Lovelace生物医学的专业知识该计划的结果将是一个决策门， 研究性新药（IND）申请如果成功，我们将把AGT 002 传统化学品生产和控制（CMC）、GLP毒理学、IND申请，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。