Pan-sarbecovirus prophylaxis with human anti-ACE2 monoclonal antibodies

Abstract

Human monoclonal antibodies (mAbs) that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein have been isolated from convalescent individuals and developed into therapeutics for SARS-CoV-2 infection. However, therapeutic mAbs for SARS-CoV-2 have been rendered obsolete by the emergence of mAb-resistant virus variants. Here we report the generation of a set of six human mAbs that bind the human angiotensin-converting enzyme-2 (hACE2) receptor, rather than the SARS-CoV-2 spike protein. We show that these antibodies block infection by all hACE2 binding sarbecoviruses tested, including SARS-CoV-2 ancestral, Delta and Omicron variants at concentrations of ~7–100 ng ml−1. These antibodies target an hACE2 epitope that binds to the SARS-CoV-2 spike, but they do not inhibit hACE2 enzymatic activity nor do they induce cell-surface depletion of hACE2. They have favourable pharmacology, protect hACE2 knock-in mice against SARS-CoV-2 infection and should present a high genetic barrier to the acquisition of resistance. These antibodies should be useful prophylactic and treatment agents against any current or future SARS-CoV-2 variants and might be useful to treat infection with any hACE2-binding sarbecoviruses that emerge in the future.

Synergistic Binding of SARS-CoV-2 to ACE2 and Gangliosides in Native Lipid Membranes

“…Similarly, we targeted the membrane ACE2 by blocking it in SMBs with monoclonal anti-ACE2 (Figure B-i). This type of targeting has been effective for blocking virus binding in cellular experiments. , We observed a significant drop in the virus coverage (saturated N accu. virus ) on MV+DOPC and MV+GD1a SMBs.…”

“…This type of targeting has been effective for blocking virus binding in cellular experiments. 41,42 We observed a significant drop in the virus coverage (saturated N accu. virus ) on MV+DOPC and MV+GD1a SMBs.…”

Giant Plasma Membrane Vesicles as Cellular‐Mimics for Probing SARS‐CoV‐2 Binding at Single Particle Level

“…Analytical studies of virus attachment require simple yet near-native systems that can mimic the complexity of host cells. In this work, we have [49] bound to ACE2 coupled with antibody Fab fragment (3.30 Å), [50] details in Figure S7. (G) Scheme of GPMV membrane composed of native membrane lipid-proteins and SARS-CoV-2 binds to the dimeric endogenous ACE2 present in the GPMV membrane.…”

RBD-based high affinity ACE2 antagonist limits SARS-CoV-2 replication in upper and lower airways

“…The benefits of an ACE2 antagonist could theoretically extend to other host-targeting approaches including anti-ACE2 antibodies (43,44) and ACE2 decoys that bind to RBD (45)(46)(47)(48)(49)(50)(51)(52)(53)(54)(55). It is noteworthy that chiropteran ACE2 functions as a host receptor for NeoCoV and PDF-2180, two merbecoviruses which have so far been restricted to transmission within bats (56).…”