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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.

SUBMITTER: Elshabrawy HA

PROVIDER: S-EPMC3503966 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:IntroductionThe last 12 years have seen remarkable progress in the isolation and characterization of at least five different epitope classes of HIV-specific broadly neutralizing antibodies (bnAbs). Detailed analyses of these bnAb lineages, maturation pathways and epitopes have created new opportunities for vaccine development. In addition, interest exists in passive administration of monoclonal antibodies as a viable option for HIV prevention.DiscussionRecently, two antibody-mediated prevention (AMP) trials of a passively administered monoclonal antibody targeting the HIV envelope CD4 binding site, called VRC01, provided proof-of-concept that monoclonal antibody infusion could offer protection against HIV acquisition. While the trials failed to show overall protection against HIV acquisition, sub-analyses revealed that VRC01 infusion provided a 75% prevention efficacy against HIV strains that were susceptible to the antibody. The study also demonstrated that in vitro neutralizing activity, measured by the TZM-bl/pseudovirus assay, was able to predict HIV prevention efficacy in humans. In addition, the AMP trials defined a threshold protective concentration, or neutralization titer, for the VRC01 class of bnAbs, explaining the observed low overall efficacy and serving as a benchmark for the clinical testing of new bnAbs, bnAb cocktails and neutralizing antibody-inducing vaccines. Newer bnAbs that exhibit greater potency and breadth of neutralization in vitro than VRC01 are available for clinical testing. Combinations of best-in-class bnAbs with complementary magnitude, breadth and extent of complete neutralization are predicted to far exceed the prevention efficacy of VRC01. Some engineered bi- and trispecific mAbs exhibit similar desirable neutralizing activity and afford advantages for manufacturing and delivery. Modifications that prolong the serum half-life and improve genital tissue persistence offer additional advantages.ConclusionsIterative phase 1 trials are acquiring safety and pharmacokinetic data on dual and triple bnAbs and bi- and trispecific antibodies in preparation for future AMP studies that seek to translate findings from the VRC01 efficacy trials and achieve acceptable levels of overall prevention efficacy.

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Human monoclonal antibodies against highly conserved HR1 and HR2 domains of the SARS-CoV spike protein are more broadly neutralizing.

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