C. Garrett Rappazzo, Longping V. Tse, Chengzi I. Kaku, Daniel Wrapp, Mrunal Sakharkar, Deli Huang, Laura M. Deveau, Thomas J. Yockachonis, Andrew S. Herbert, Michael B. Battles, Cecilia M. O’Brien, Michael E. Brown, James C. Geoghegan, Jonathan Belk, Linghang Peng, Linlin Yang, Yixuan Hou, Trevor D. Scobey, Dennis R. Burton, David Nemazee, John M. Dye, James E. Voss, Bonwyn M. Gunn, Jason S. McLellan, Ralph S. Baric, Lisa E. Gralinski, Laura M. Walker.

Science 371, 823–829. DOI:10.1126/science.abf4830

January 21, 2021

The recurrent emergence of zoonotic coronaviruses, such as SARS-CoV and SARS-CoV-2, underscores the critical need for broadly effective therapeutic agents. In a pivotal study published in Science, Rappazzo et al. used a directed evolution approach to engineer three monoclonal antibodies (mAbs) originally isolated from the memory B cells of a survivor of the 2003 SARS-CoV outbreak. These parental antibodies exhibited modest neutralizing activity against a broad panel of SARS-like viruses (i.e., sarbecoviruses). Therefore, our aim was to engineer these broadly neutralizing antibodies (bnAbs) for improved neutralization potency against SARS-CoV-2 while maintaining or improving neutralization breadth and potency against other SARS-like viruses. One of these affinity-matured mAbs, designated ADG-2, exhibited strong binding activity to a large panel of sarbecovirus receptor binding domains in the spike (S) protein and neutralized representative epidemic sarbecoviruses with high potency, offering a promising avenue for the development of a pan-sarbecovirus prophylactic.

Mechanistic insights

Rappazzo and team further characterized the binding of ADG-2 and determined that ADG-2 binds a conserved epitope in the receptor-binding domain (RBD) of S protein, overlapping the human ACE2 (hACE2) receptor binding site, that is common across clade 1 sarbecoviruses, including SARS-CoV and SARS-CoV-2. Furthermore, it was confirmed that this mAb bound with high affinity (apparent KD = 0.24 to 1.12 nM) to every clade 1 sarbecovirus RBD that exhibited detectable hACE2 binding, supporting the high degree of ADG-2 epitope conservation among sarbecoviruses that can use hACE2 as a receptor. All of the affinity-matured mAbs demonstrated stronger neutralizing activity than their parental clones. The most-potent neutralizing variants (ADG-1, ADG-2, and ADG-3) had neutralization half-maximal inhibitory concentration (IC50) values as good or better than clinical SARS-CoV-2 neutralizing antibody controls. However, their binding affinities did not correlate with neutralization potency when compared to clinical-stage antibodies. This suggests that neutralization potency is more tightly linked to fine epitope specificity than binding affinity to the prefusion S protein. 

Through library-based screens and structural studies, the team evaluated the effect of known SARS-CoV-2 RBD variant mutations on mAb binding. For REGN10987 and REGN10933, the loss-of-binding variants partially overlapped with those observed in earlier in vitro neutralization escape studies, confirming that RBD displayed on yeast can assist with the prediction of antibody escape mutations. In contrast, ADG-2 bound to each of these variants and displayed broadly neutralizing activity. The evolutionary conservation of the ADG-2 epitope is likely directly linked to ACE2 binding and therefore represents a common vulnerability in sarbecoviruses that can be exploited for broad-spectrum neutralization.

Cell-based assays showed that ADG-2 could trigger multiple Fc-effector functions, including antibody-dependent natural killer (NK) cell activation and degranulation, antibody-dependent cellular phagocytosis by monocytes and neutrophils, and antibody-mediated complement deposition, with potency comparable to or greater than SARS-CoV-2 clinical antibodies.

Efficacy and therapeutic implications

Using immunocompetent mouse models of SARS-CoV and SARS-CoV-2 infection, the authors demonstrated that ADG-2 provides broad protection against zoonotic SARS-like viruses in both prophylactic and therapeutic settings. This study has identified a highly conserved epitope in clade 1 sarbecoviruses, reinforces the potential of targeting conserved viral epitopes to develop broad-spectrum antiviral therapies, such as mAbs and vaccines, and provides mechanistic insights for developing pan-SARS vaccines to elicit a broadly protective immune response. ADG-2’s efficacy against SARS-like viruses positions it as a strong candidate for further development in combating both current and future SARS-related coronavirus outbreaks. 

This antibody was subsequently optimized further by the team at Adimab for even greater potency and breadth of neutralization, including against the Omicron lineage of SARS-CoV-2, resulting in the clinical drug Pemivibart, which received an Emergency Use Authorization in March 2024, for pre-exposure prophylaxis against SARS-CoV-2 in immunocompromised individuals.

For more details, read the full article in Science.