A newly identified novel coronavirus (SARS-CoV-2) is causing pneumonia-associated respiratory syndrome across the world. Epidemiology, genomics, and pathogenesis of the SARS-CoV-2 show high homology with that of SARS-CoV. Current efforts are focusing on development of specific antiviral drugs. Therapeutic neutralizing antibodies (NAbs) against SARS-CoV-2 will be greatly important therapeutic agents for the treatment of coronavirus disease 2019 (COVID-19). Herein, the host immune responses against SARS-CoV discussed in this review provide implications for developing NAbs and understanding clinical interventions against SARS-CoV-2. Further, we describe the benefits, challenges and considerations of NAbs against SARS-CoV-2. Although many challenges exist, NAbs still offer a therapeutic option to control the current pandemic and the possible re-emergence of the virus in the future, and their development therefore remains a high priority
Perspectives on the development of neutralizing antibodies against SARS-CoV-2
The simplest and most direct approach to combating SARS-CoV-2 during the outbreak would be to use plasma from the convalescent patients. Polyclonal NAbs could be induced in some convalescent patients and will be effective in treating SARS-CoV-2. These NAbs can provide passive immune responses to viral infection. Indeed, both SARS and Ebola patients received the treatment of convalescent plasma. However, the outcomes of passive plasma therapy are unpredictable due to variability of sera in different patients.
Development of NAbs against SARS-CoV-2 is a relatively rapid approach to obtain the standardized agents that control re-emergence of COVID-19. The SARS-CoV-2 S protein is likely important target for developing NAbs to block binding and fusion of SARS-CoV-2. SARS-CoV-2 seems to use the same cell entry receptor, ACE2, as the SARS-CoV because ACE2 shows binding to RBD of both SARS-CoV and SARS-CoV-2. However, a recent study demonstrates that SARS-CoV-2 S protein binds ACE2 with higher affinity than SARS-CoV (10- to 20-folder), suggesting its recognition to ACE2 could be different with SARS-CoV. Although SARS-CoV-2 shows the high homology with SARS-CoV, antibody cross-reactivity is limited between the two virus S proteins. Several published SARS-CoV NAbs do not have appreciable binding to SARS-CoV-2 S protein. A recent study shows that a SARS-CoV antibody, CR3022, binds to SARS-CoV-2 RBD, but its neutralization capability is uncertain. Cocktail of NAbs has showed the stronger neutralization than alone in treatment of both Ebola and SARS viruses. This finding suggests that a cocktail antibody approach for SARS-CoV-2 could be undertaken. Therefore, it will be very meaningful to generate NAbs targeting different epitopes on SARS-CoV-2. Combination of several potent NAbs could decrease the probability for escape virus isolates with decreased sensitivity to neutralization.
Computational simulation of antibody-antigen complexes has been used to guide the design of therapeutic antibodies 54-56. Numbers of antibody structures (currently around 2,000 depositions) are available in the Protein Data Bank [PDB]. Based on these PDB data, the comparative model of an antibody onto the viral surface antigen can be predicted. The key residues between RBD and NAbs can be identified to provide important implications for the vaccines against SARS-CoV-2. The key residues of interface between an antibody and the antigen can be optimized to produce high affinity 57. Several recent computer docking models have been used to predict the interaction between S protein and human ACE2 10 or antibodies 52. The studies revealed the important discovery that SARS-CoV-specific CR3022 antibody could cross-react to SARS-CoV-2.
The availability of therapeutic NAbs against SARS-CoV-2 will offer benefits for the control of the current pandemic and the possible re-emergence of the virus in the future, and their development therefore remains a high priority. The efforts of NAb development will surely be an area of intense research in the coming months and even years. Currently, several strategies are used in the clinic or under development, such as viral-targeting therapeutics and host-targeting agents (such as interferons, glucocorticoids) for the treatment of COVID-19. As compared with these therapeutic strategies, NAbs appear to be more specific for virions. Understanding of action mechanisms of NAbs may provide valuable implications for the rapid development of antibody therapy and vaccine for SARS-CoV-2. However, the development of NAb-based therapeutics is a time-consuming and laborious process. To date, no NAb agents for either SARS-CoV or (Middle East Respiratory Syndrome Coronavirus) MERS-CoV are available in the market. Meanwhile, a note of caution is that the effect of antibody immune response in protecting against pulmonary pathogenesis of SARS-CoV is controversial 31. Some patients who died of SARS showed the strong NAb responses and pulmonary proinflammatory accumulation, suggesting NAbs could be associated with fatal acute lung injury. Therefore, it is important to take insight into humoral and cellular responses of SARS-CoV-2 when antiviral immunotherapy is developed.
Reference & Source information: https://europepmc.org/
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