Neutralizing human monoclonal antibodies to severe acute respiratory syndrome coronavirus: target, mechanism of action, and therapeutic potential

Abstract

The emergence of Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) led to a rapid response not only to contain the outbreak but also to identify possible therapeutic interventions, including the generation of human monoclonal antibodies (hmAbs). hmAbs may be used therapeutically without the drawbacks of chimeric or animal Abs. Several different methods have been used to generate SARS-CoV specific neutralizing hmAbs including the immunization of transgenic mice, cloning of small chain variable regions from naïve and convalescent patients, and the immortalization of convalescent B cells. Irrespective of the techniques used, the majority of hmAbs specifically reacted with the receptor binding domain (RBD) of the spike (S) protein and likely prevented receptor binding. However, several hmAbs that can bind to epitopes either within the RBD, located N terminal of the RBD or in the S2 domain, and neutralize the virus with or without inhibiting receptor binding have been identified. Therapeutic utility of hmAbs has been further elucidated through the identification of potential combinations of hmAbs that could neutralize viral variants including escape mutants selected using hmAbs. These results suggest that a cocktail of hmAbs that can bind to unique epitopes and have different mechanisms of action might be of clinical utility against SARS-CoV infection, and indicate that a similar approach may be applied to treat other viral infections.

Figure 1

Severe acute respiratory syndrome coronavirus (SARS‐CoV) spike protein and monoclonal antibody (mAb) epitopes. Depiction of various functional domains of SARS‐CoV S protein. Receptor binding domain (RBD), the minimum region responsible for binding angiotensin‐converting enzyme 2 (ACE2) 29; receptor binding motif (RBM), specific region contacting ACE2 27; fusion peptide (FP), HR1, and HR2 helical repeat domains involved in fusion 27, 37, 38. mAbs identified to react with indicated regions. *RBD specificity based on mutations identified in escape variants. **Influence of Y777D mutation identified in escape variants.

Figure 2

Alignment of representative severe acute respiratory syndrome coronavirus (SARS‐CoV) clinical isolates. The S protein sequences of 94 SARS‐CoV clinical isolates were aligned using Jelllyfish software. The changes within the S1 domain are depicted by representative isolates. The magnification highlights changes within the receptor binding domain. The box highlights amino acids that fall within the defined receptor binding motif.