Development of neutralizing nanobodies against SARS-CoV-2

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

During the pandemic, Dr Ho has evaluated the challenges for developing antibody therapeutics targeting SARS-Cov-2 and wrote a review/perspective article [Ho Antibody Therapeutics 2020; PMID: 32566896]. SARS-CoV-2 gains entry to human cells through its spike (S) protein binding to angiotensin-converting enzyme 2 (ACE2). Therefore, the S protein is the primary target for neutralizing antibodies. A cocktail strategy combining two (or more) antibodies that recognize different parts of the viral surface that interact with human cells might be the most effective. In FY2021, the Ho lab using phage display technology has identified a panel of camel nanobodies that might recognize diverse conformations of the RBD. Some might bind an open conformation of the RBD, which might block the interaction with the ACE2 on human cell, while others might bind a close conformation, which might lock its conformation in the off state. Epitope mapping of these nanobodies on the viral spike protein reveals two distinct binding epitopes, one is directly involved in the ACE2 binding and the other is conserved between SARS-CoV-2 and SARS-CoV. The top candidates that recognize these two distinct epitopes shows potent neutralization activities against SARS-CoV-2 variants B.1.1.7 and B.1.351. The 2-in-1 cocktail treatment with these two groups of nanobodies shows potent protection against the B.1.351 variant in mice, suggesting promising therapeutic potential to prevent and treat COVID-19. Ongoing studies will establish our nanobodies as a new family of anti-viral drugs for treating COVID-19 and potentially future coronavirus infections in humans. We are actively searching for industry partners to clinically develop our novel nanobodies targeting SARS-CoV-2 for treating COVID-19 pandemic.