Recently, the Nankai university research team made up of Guo Yu, Zhang Hongkai and Rao Zihe together with Harbour BioMed have completed the preclinical studies of their jointly developed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) neutralizing antibodies. As the studies showed, the high-resolution X-ray crystallography structures unveiled three neutralizing antibodies (NAb) with novel binding epitopes, among which PR1077 scored high in the antiviral efficiency in an animal model. Taken together, these results will serve as important information in developing mAb-related therapeutic interventions for COVID-19.
On March 7, the research article“Structural basis for SARS-CoV-2 neutralizing antibodies with novel binding epitopes”was published online in PLOS Biology, a prestigious academic journal in the world.
Fig.1 Immunization and antibody isolation of H2L2 transgenic and BALB/c mice on a new antibody discovery platform
Primarily triggered by SARS-CoV-2, 2019 coronavirus disease (COVID-19) has now developed into an unprecedented threat to global public health. While SARS-CoV-2 NAbs have been proved to be a capable assistant in prevention and therapeutic interventions against the virus, the limited knowledge about other critical epitopes and immunogenic features in this field still hinders the development of new antibody-related therapeutics against COVID-19.
Fig.2 Test results of the activities of NAbs PR1077, PR953, and PR961
From the human NAb platform H2L2, the research team detected one human NAb, termed PR1077, and two humanized NAbs, including PR953 and PR961, all showing potent neutralizing activities at the sub-nM level. With this finding, they continued the research and discovered that the high-resolution X-ray crystallography structures revealed novel epitopes on the receptor-binding motif (RBM)for PR1077 and PR953, both of which directly competed with human angiotensin-converting enzyme2 (hACE2) for binding, and a novel non-blocking epitope on the neighboring site near RBM for PR961.
Fig.3 Complex structure of the three neutralizing antibodies with SARS-CoV-2, RBD-NAbs scFv: PR1077、PR953、PR961
Moreover, through the cooperation with another team led by Hu Zhihong and Wang Manli and from the Chinese Academy of Sciences located in Wuhan, the Nankai research team tested the antiviral efficiency of PR1077 in the Ad5-hACE2 transduction mouse model of COVID-19. The results showed that a single injection was able to provide effective protection against SARS-CoV-2 infection in both prophylactic and treatment groups.
Fig.4 Therapeutic effect of PR1077 in AdV-hACE2-transduced mice affected by SARS-CoV-2
Link: https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3001209
