tetano
Editor, Senior Moderator
Nat Chem Biol
. 2022 Sep 8.
doi: 10.1038/s41589-022-01140-1. Online ahead of print.
Converting non-neutralizing SARS-CoV-2 antibodies into broad-spectrum inhibitors
Payton A-B Weidenbacher[SUP] 1 2 [/SUP], Eric Waltari[SUP] 3 [/SUP], Izumi de Los Rios Kobara[SUP] 4 [/SUP], Benjamin N Bell[SUP] 1 5 [/SUP], Mary Kate Morris[SUP] 6 [/SUP], Ya-Chen Cheng[SUP] 1 7 [/SUP], Carl Hanson[SUP] 6 [/SUP], John E Pak[SUP] 3 [/SUP], Peter S Kim[SUP] 8 9 10 [/SUP]
Affiliations
Abstract
Omicron and its subvariants have rendered most authorized monoclonal antibody-based treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ineffective, highlighting the need for biologics capable of overcoming SARS-CoV-2 evolution. These mostly ineffective antibodies target variable epitopes. Here we describe broad-spectrum SARS-CoV-2 inhibitors developed by tethering the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), to known non-neutralizing antibodies that target highly conserved epitopes in the viral spike protein. These inhibitors, called receptor-blocking conserved non-neutralizing antibodies (ReconnAbs), potently neutralize all SARS-CoV-2 variants of concern (VOCs), including Omicron. Neutralization potency is lost when the linker joining the binding and inhibitory ReconnAb components is severed. In addition, a bi-functional ReconnAb, made by linking ACE2 to a bi-specific antibody targeting two non-overlapping conserved epitopes, defined here, shows sub-nanomolar neutralizing activity against all VOCs, including Omicron and BA.2. Given their conserved targets and modular nature, ReconnAbs have the potential to act as broad-spectrum therapeutics against SARS-CoV-2 and other emerging pandemic diseases.
. 2022 Sep 8.
doi: 10.1038/s41589-022-01140-1. Online ahead of print.
Converting non-neutralizing SARS-CoV-2 antibodies into broad-spectrum inhibitors
Payton A-B Weidenbacher[SUP] 1 2 [/SUP], Eric Waltari[SUP] 3 [/SUP], Izumi de Los Rios Kobara[SUP] 4 [/SUP], Benjamin N Bell[SUP] 1 5 [/SUP], Mary Kate Morris[SUP] 6 [/SUP], Ya-Chen Cheng[SUP] 1 7 [/SUP], Carl Hanson[SUP] 6 [/SUP], John E Pak[SUP] 3 [/SUP], Peter S Kim[SUP] 8 9 10 [/SUP]
Affiliations
- PMID: 36076082
- DOI: 10.1038/s41589-022-01140-1
Abstract
Omicron and its subvariants have rendered most authorized monoclonal antibody-based treatments for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) ineffective, highlighting the need for biologics capable of overcoming SARS-CoV-2 evolution. These mostly ineffective antibodies target variable epitopes. Here we describe broad-spectrum SARS-CoV-2 inhibitors developed by tethering the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), to known non-neutralizing antibodies that target highly conserved epitopes in the viral spike protein. These inhibitors, called receptor-blocking conserved non-neutralizing antibodies (ReconnAbs), potently neutralize all SARS-CoV-2 variants of concern (VOCs), including Omicron. Neutralization potency is lost when the linker joining the binding and inhibitory ReconnAb components is severed. In addition, a bi-functional ReconnAb, made by linking ACE2 to a bi-specific antibody targeting two non-overlapping conserved epitopes, defined here, shows sub-nanomolar neutralizing activity against all VOCs, including Omicron and BA.2. Given their conserved targets and modular nature, ReconnAbs have the potential to act as broad-spectrum therapeutics against SARS-CoV-2 and other emerging pandemic diseases.