Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the ongoing coronavirus disease 2019 (COVID-19) pandemic, which has resulted in ~1,119,431 deaths. There is currently no approved vaccines or therapeutics for treating COVID-19. The SARS-CoV-2 Spike protein promotes entry into host cells and is considered a key therapeutic target by many researchers. Here we describe the identification of several monoclonal antibodies that target the SARS-CoV-2 Spike protein. One human antibody, CA521 LALA , demonstrated neutralization potential by immunizing human antibody transgenic mice. CA521 LALA showed potent SARS-CoV-2-specific neutralization activity against SARS-CoV-2 pseudovirus and authentic SARS-CoV-2 infection in vitro . The LALA mutation introduced to CA521 abrogates the binding with Fc receptors or complement receptors reducing antibody-dependent enhancement seen with anti-SARS-CoV antibodies. CA521 LALA also demonstrated having a long half-life of 9.5 days in mice and 9.3 days in rhesus monkeys. CA521 LALA inhibited SARS-CoV-2 infection in SARS-CoV-2 susceptible mice at a therapeutic setting with the virus titer of the lung reduced by 4.5 logs. Structural analysis by cryo-EM revealed that CA521 LALA recognizes an epitope overlapping with angiotensin converting enzyme 2 (ACE2)-binding sites in SARS-CoV-2 receptor binding domain (RBD) in the Spike protein. CA521 LALA blocks the interaction by binding all three RBDs of one SARS CoV-2 spike trimer simultaneously. These results demonstrate the importance for antibody-based therapeutic interventions in the treatment of COVID-19 and identifies CA521 LALA a promising antibody that reacts with SARS-CoV-2 Spike protein to strongly neutralize its activity.
Structure and function analysis of a potent human neutralizing antibody CA521LALA against SARS-CoV-2