Development and characterization of engineered therapeutic antibodies against SARS-CoV-2

针对 SARS-CoV-2 的工程化治疗抗体的开发和表征

• 批准号: 10865147
• 负责人: Gaya K. Amarasinghe
• 金额: $ 38.88万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10865147
• 关键词: 2019-nCoV; ACE2; Address; Animal Model; Animals; Antibodies; Antibody Therapy; Binding; Biological Assay; Biophysics; COVID-19; COVID-19 pandemic; Cessation of life; Characteristics; China; Chiroptera; Collaborations; Development; Diamond; Disease; Dose; Drug Combinations; Engineering; Epitopes; Geometry; Glycoproteins; Health; Healthcare Systems; Human; Immunoglobulin G; Immunologics; In Vitro; Incidence; Incubated; Individual; Infection; Infrastructure; Integration Host Factors; Lentivirus; Lightning; Lung; Mammals; Marketing; Methods; Middle East Respiratory Syndrome Coronavirus; Persons; Phage Display; Pharmaceutical Preparations; Protein Engineering; Proteins; RNA Viruses; Race; Reporting; Research; Research Personnel; Resistance; Respiratory Disease; SARS coronavirus; SARS-CoV-2 antibody; SARS-CoV-2 inhibitor; SARS-CoV-2 pathogenesis; Series; Speed; System; Technology; Testing; Therapeutic antibodies; Time; United States; Vaccines; Validation; Vesicular stomatitis Indiana virus; Viral; Virion; Virus; Virus Diseases; Virus Replication; Work; Writing; antibody engineering; betacoronavirus; convalescent plasma; current pandemic; early phase clinical trial; experience; in vivo; indexing; innovation; lead candidate; mouse model; mutant; neutralizing antibody; pandemic disease; physical property; potency testing; pre-clinical; receptor; receptor binding; resistance mutation; standard of care; synergism; therapeutic candidate; transmission process

Project Summary/Abstract This R01 entitled, “Development and characterization of engineered therapeutic antibodies against SARS-CoV- 2”, builds on our project infrastructure, expertise, and experience in characterizing viral-host factor interactions in negative strand RNA viruses. Since originating in China, SARS-CoV-2 has since rapidly spread and is now a global pandemic. Significant concerns are that humans are immunologically naïve, and there are no available therapies. In the US, the disease has already overwhelmed the healthcare system in some states and have a serious knock-on effect in exacerbating the standard of care for other diseases. At the time of writing, nearly 5 million cases and >160,000 deaths have been attributed to COVID-19. The virus replicates in the lungs and causes a severe respiratory disease, COVID-19, which is fatal in >2% of cases. Neutralizing antibodies (nAbs) generated by natural infection or vaccines is known to control many infections and early studies in the current COVID-19 pandemic, including studies to test convalescent plasma treatments, are promising. These studies highlight the potential significance of nAb-based therapy. While IgG format of nAbs have long been the most extensively used format, early studies, including our own suggest that additional multivalent formats of nAbs may be more effective. This provides an innovative method to develop nAbs while acquiring potential benefits from effective neutralization at lower doses and lower likelihood of the emergence of resistance mutants. SARS-CoV- 2 is a single stranded, non-segmented, enveloped RNA virus. Viral infection requires interaction of the spike glycoprotein receptor binding domain (RBD) to the host receptor ACE2. Here, we will build on newly developed and established approaches that have been optimized through our work other systems to generate antibodies targeting spike and spike RBD using phage display technology and characterize their physical properties. We will engineer antibodies with increased valency and test for potency in in vitro neutralization assays and in vivo efficacy in a mouse model. At the completion, we expect to provide innovative and unique multivalent nAb leads with unique characteristics that will rival the best in class IgG drugs.

项目总结/文摘