The dual function monoclonal antibodies VIR-7831 and VIR-7832 demonstrate potent in vitro and in vivo activity against SARS-CoV-2

Abstract

VIR-7831 and VIR-7832 are dual action monoclonal antibodies (mAbs) targeting the spike glycoprotein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). VIR-7831 and VIR-7832 were derived from a parent antibody (S309) isolated from memory B cells of a 2003 severe acute respiratory syndrome coronavirus (SARS-CoV) survivor. Both mAbs contain an LS mutation in the Fc region to prolong serum half-life and potentially enhance distribution to the respiratory mucosa. In addition, VIR-7832 encodes an Fc GAALIE mutation that has been shown previously to evoke CD8+ T-cells in the context of an in vivo viral respiratory infection. VIR-7831 and VIR-7832 potently neutralize live wild-type SARS-CoV-2 in vitro as well as pseudotyped viruses encoding spike protein from the B.1.1.7, B.1.351 and P.1 variants. In addition, they retain activity against monoclonal antibody resistance mutations that confer reduced susceptibility to currently authorized mAbs. The VIR-7831/VIR-7832 epitope does not overlap with mutational sites in the current variants of concern and continues to be highly conserved among circulating sequences consistent with the high barrier to resistance observed in vitro. Furthermore, both mAbs can recruit effector mechanisms in vitro that may contribute to clinical efficacy via elimination of infected host cells. In vitro studies with these mAbs demonstrated no enhancement of infection. In a Syrian Golden hamster proof-of concept concept wildtype SARS-CoV-2 infection model, animals treated with VIR-7831 had less weight loss, and significantly decreased total viral load and infectious virus levels in the lung compared to a control mAb. Taken together, these data indicate that VIR-7831 and VIR-7832 are promising new agents in the fight against COVID-19.

Membrane lectins enhance SARS-CoV-2 infection and influence the neutralizing activity of different classes of antibodies

“…The auxiliary role of lectins in SARS-CoV-2 infection is in line with the known biology of these adhesion molecules that bind glycans characteristic of cellular membranes and pathogen surfaces to promote trans-infection 42 . Among the three auxiliary receptors, SIGLEC1 is of particular relevance because this receptor is prominently expressed in alveolar macrophages in association with viral RNA, thus supporting a model of trans-infection, tissue dissemination and the triggering of immune responses by myeloid cells, rather than a direct target for productive infection 43 . DC-SIGN and L-SIGN association with SARS-CoV-2 is also of relevance because of their interaction with blood endothelium and role in immune activation.…”

SARS-CoV-2 immune evasion by variant B.1.427/B.1.429

“…1) . Neutralization mediated by the casirivimab/imdevimab mAb cocktail (REGN10933 and REGN10987)( 14 , 15 ), which received an emergency use authorization in the US, and by VIR-7831 mAb( 10 , 38 ) (derivative of S309), which recently was shown to provide 85% protection against hospitalization and deaths in the COMET clinical trial, is unaffected by the L452R mutation. To address the role of B.1.427/B.1.429 L452R mutation in the neutralization escape from RBD-specific antibodies, we tested the binding of 35 RBD-specific mAbs to WT and L452R mutant RBD by biolayer interferometry ( Supplemental Fig.…”

“…Serum or plasma neutralizing activity is a correlate of protection against SARS-CoV-2 challenge in non-human primates( 39 , 40 ) and several monoclonal neutralizing Abs have demonstrated their ability to reduce viral burden as well as to decrease hospitalization and mortality in clinical trials( 10 , 14 , 15 , 22 , 38 , 41 ). The data presented here indicate that SARS-CoV-2 B.1.427/B.1.429 is associated with a reduction of sensitivity to plasma neutralizing Abs elicited by vaccination with two doses of Pfizer/BioNTech BNT162b2 or Moderna mRNA-1273 and by infection with the prototypic SARS-CoV-2 and the B.1.1.7 VOC.…”

Early Covid-19 Treatment With SARS-CoV-2 Neutralizing Antibody Sotrovimab

“…Consistent with this hypothesis, we subsequently demonstrated that, in vitro, sotrovimab retains activity against now widespread SARS-CoV-2 variants that were first identified in the United Kingdom (B.1.1.7), South Africa (B.1.351), Brazil (P.1), and California (B.1.427/B.1.429). 11,14,15 In contrast, many of the other monoclonal antibodies being developed for Covid-19 bind to the receptor-binding motif that engages the angiotensin-converting enzyme 2 (ACE2) receptor and is one of the most mutable and immunogenic regions of the virus; in some cases, these antibodies do not retain activity against the variants. [16][17][18][19] Sotrovimab contains a two-amino acid Fc modification (termed LS) to increase half-life and potentially improve bioavailability in the respiratory mucosa through enhanced engagement with the neonatal Fc receptor.…”

“…[20][21][22] Sotrovimab has demonstrated potent effector functions in vitro, which have the potential to result in immune-mediated viral clearance. 13,14 Here, we report the results from a preplanned interim analysis of the COvid-19 Monoclonal antibody Efficacy Trial-Intent to Care Early (COMET-ICE) study evaluating the efficacy and safety of treatment with sotrovimab in high-risk, ambulatory patients with mild/moderate Covid-19. The trial is currently closed for enrollment; data collection is ongoing.…”