Studies in humanized mice and convalescent humans yield a SARS-CoV-2 antibody cocktail

By J. Hansen, A. Baum, Kristen E. Pascal, Vincenzo Russo, Stephanie Giordano, Elzbieta Wloga, Benjamin O. Fulton, Ying Yan, Katrina Koon, Krunal Patel and 37 more. 2020

1,225 citations recorded by the source corpus.

An antibody cocktail against SARS-CoV-2 There is an urgent focus on antibodies that target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral spike and prevent the virus from entering host cells. Hansen et al. generated a large panel of antibodies against the spike protein from humanized mice and recovered patients. From this panel, they identified several neutralizing antibodies, including pairs that do not compete for binding to the receptor binding domain. Baum et al. focused in on four of these antibodies. All four are effective against known spike variants. However, by growing a pseudovirus that expresses the spike in the presence of individual antibodies, the authors were able to select for spike mutants resistant to that antibody. In contrast, escape mutants are not selected when pseudovirus is grown in the presence of pairs of antibodies that either do not compete or only partially compete for binding to the RBD. Such a pair might be used in a therapeutic antibody cocktail. Science, this issue p. 1010, p. 1014 A noncompeting antibody cocktail to SARS-CoV-2 spike protein safeguards against the ability of virus mutations to lead to antibody resistance. Neutralizing antibodies have become an important tool in treating infectious diseases. Recently, two separate approaches yielded successful antibody treatments for Ebola—one from genetically humanized mice and the other from a human survivor. Here, we describe parallel efforts using both humanized mice and convalescent patients to generate antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, which yielded a large collection of fully human antibodies that were characterized for binding, neutralization, and three-dimensional structure. On the basis of these criteria, we selected pairs of highly potent individual antibodies that simultaneously bind the receptor binding domain of the spike protein, thereby providing ideal partners for a therapeutic antibody cocktail that aims to decrease the potential for virus escape mutants that might arise in response to selective pressure from a single-antibody treatment.

Subfields: Infectious Diseases, Molecular Biology

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Citations in the corpus

SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies (2021, neutral): “Proteinmodels are based on PDB: 6XDG (Hansen et al., 2020) or PDB: 7L3N (Jones et al.”
Comprehensive mapping of mutations to the SARS-CoV-2 receptor-binding domain that affect recognition by polyclonal human serum antibodies (2021, background): “Dilution series of the “synthetic” sera comprised of the anti-RBD antibody rREGN10987 (Hansen et al., 2020) or anti-NTD antibody 4A8 (Chi et al.”
CoV-AbDab: the Coronavirus Antibody Database (2020, background): “Researchers can use CoV-AbDab to yield new insights, including deriving crucial sequence/structural patterns that distinguish neutralising from nonneutralising SARS-CoV-2 binders (Iwasaki and Yang (2020)), or deducing independent neutralising epitopes exploitable by combination therapies (Hansen et ”
Nanobody cocktails potently neutralize SARS-CoV-2 D614G N501Y variant and protect mice (2021, neutral): “2 C ) (47).”
Neutralizing and protective human monoclonal antibodies recognizing the N-terminal domain of the SARS-CoV-2 spike protein (2021, neutral): “These studies also defined inhibition of S trimer binding to the cellular receptor ACE2 as a principal mechanism of action of RBD-targeting antibodiesagainstSARS-CoV-2andshowedprotection inanimals against infection and disease by this class of mAbs (Baum et al., 2020a; Hansen et al., 2020; Hassan et”
Escape from neutralizing antibodies by SARS-CoV-2 spike protein variants (2020, background): “As these antibodies are used clinically (17, 28), in therapeutic and prophylactic modes, it will be important to identify resistance mutations and monitor their prevalence in a way that is analogous to antiviral and antibiotic resistance monitoring in other infectious diseases.”