Previous studies during the SARS-CoV outbreak have identified Spike-specific neutralizing antibodies in the serum of convalescent patients, and have shown that most of them target the ACE2 receptor-binding domain (RBD) [1]. Thus, Spike RBD is a privileged candidate for vaccination and treatment strategies in the context of COVID-19.

One strategy is to study the potential cross-reactivity of SARS-CoV neutralizing antibodies with the SARS-CoV-2.
The anti-Spike RBD clone CR3022 is a SARS-CoV neutralizing antibody that was obtained from the screening of an antibody-phage library and converted to a human IgG1 format [2]. SARS-CoV-2 and SARS-CoV Spike RBD share 73% identity [3]. Modeling and in vitro studies have shown that CR3022 is also binding to SARS-CoV-2 RBD [4]. This cross-reactivity is explained by the 86% shared amino acid identity between the CR3022 epitopes from the two viruses [4]. Importantly, CR3022 does not interfere with the ACE2 binding motif [2-5]. Thus, CR3022 could be used alone or in combination with other antibodies or soluble ACE2 to maximize the neutralization of SARS-CoV-2 (Wuhan-Hu-1, D614) and mutant isolates [6].

Structural studies have led to a binding model where:

the CR3022 epitope in RBD does not overlap with the ACE2 receptor binding motif [2-5]
the CR3022 epitopes in SARS-CoV and SARS-CoV-2 RBD share 24 residues out of 28 (86% identity in amino acids) [4]
Spike trimers stochastically exhibit their RBD in a “down” or “up” state [7, 8]
the CR3022 antibody only accesses its epitope when at least two RBDs are in the “up” conformation and slightly-rotated [4, 5]
CR3022 does not sterically prevent ACE2 binding to RBD [4, 5]

To this date, there are discrepancies among studies addressing the CR3022 neutralization activity and underlying mechanisms.
Yuan et al. used a microneutralization assay to show that CR3022 can neutralize SARS-CoV, but not SARS-CoV-2 [4]. On the contrary, Huo et al, showed that CR3022 does neutralize SARS-CoV-2, and their experimental data suggest that neutralization occurs by the destruction of the Spike protein in its prefusion conformation [5].

References

1. Jiang S. et al. 2020. Neutralizing antibodies against SARS-CoV-2 and other human coronaviruses. Trends Immunol. 41 (5):355-359.
2. Ter Muelen J.et al., 2006. Human monoclonal antibody combination against SARS coronavirus: synergy and coverage of escape mutants. PLos Med. 3(7):e237.
3. Tian X. et al., 2020. Potent binding of 2019 novel coronavirus spike protein by a SARS coronavirus-specific human monoclonal antibody. Emerging Microbes & Infections. 9(1):382-385.
4. Yuan M. et al., 2020. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV. Science. DOI: 10.1126/science.abb7269.
5. Huo J. et al., 2020. Neutralization of SARS-CoV-2 by destruction of the prefusion Spike. bioRxiv. DOI:10.1101/2020.05.05.079202.
6. Korber B. et al., 2020. Spike mutation pipeline reveals the emergence of a more transmissible form of SARS-CoV-2. bioRxiv. DOI:10.1101/2020.04.29.069054.
7. Walls A.C. et al., 2020. Structure, function, and antigenicity of the SARS-CoV-2 Spike glycoprotein. Cell. 181(2):281-292.e6.
8. Wrapp D. et al., 2020. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science. 367:1260-1263.

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