Human Monoclonal Antibodies against Highly Conserved HR1 and HR2 Domains of the SARS-CoV Spike Protein Are More Broadly Neutralizing

Abstract

Immune sera from convalescent patients have been shown to be effective in the treatment of patients infected with Severe Acute Respiratory Syndrome Virus (SARS-CoV) making passive immune therapy with human monoclonal antibodies an attractive treatment strategy for SARS. Previously, using Xenomouse (Amgen British Columbia Inc), we produced a panel of neutralizing Human monoclonal antibodies (HmAbs) that could specifically bind to the ectodomain of the SARS-CoV spike (S) glycoprotein. Some of the HmAbs were S1 domain specific, while some were not. In this study, we describe non-S1 binding neutralizing HmAbs that can specifically bind to the conserved S2 domain of the S protein. However, unlike the S1 specific HmAbs, the S2 specific HmAbs can neutralize pseudotyped viruses expressing different S proteins containing receptor binding domain sequences of various clinical isolates. These data indicate that HmAbs which bind to conserved regions of the S protein are more suitable for conferring protection against a wide range of SARS-CoV variants and have implications for generating therapeutic antibodies or subunit vaccines against other enveloped viruses.

Tectonic conformational changes of a coronavirus spike glycoprotein promote membrane fusion

“…In the prefusion state, the yet unresolved HR2 C terminus of the fusion machinery would likely point in the opposite direction, compared with the postfusion conformation, corresponding to a 180°reorientation of the polypeptide chain with potential changes in secondary, tertiary, and quaternary structures. The large-scale nature of the predicted conformational changes in HR2 reinforces the idea that antibodies targeting this region will be neutralizing, in agreement with previous reports (46,47). For example, the 10G monoclonal antibody is known to inhibit MHV S-mediated cell-to-cell fusion and to block virus infectivity (47) upon binding to an epitope comprised within residues 1,212-1,226 that fold as an extended loop upstream of the HR2 C-terminal helix in the postfusion structure.…”

Heme Oxygenase-1-Expressing Dendritic Cells Promote Foxp3+ Regulatory T Cell Differentiation and Induce Less Severe Airway Inflammation in Murine Models

“…Blots were washed with TBST four times in-between steps. Primary antibodies in these experiments included those for HO-1 and β-actin (Millipore, Billerica, Mass., USA) [18, 19]. …”

Pseudomonas Aeruginosa : Arsenal of Resistance Mechanisms, Decades of Changing Resistance Profiles, and Future Antimicrobial Therapies

“…In addition to the progress being made in developing vaccines against P. aeruginosa, passive immunotherapeutics containing antipseudomonal monoclonal humanized antibodies are being developed for the treatment of pseudomonal infections. Humanized monoclonal antibodies and antiviral molecules have been successful in combating several viral infections [199][200][201]. Antivirulence therapeutic antibodies provide an additional strategy to overcome the complexity of P. aeruginosa infections.…”