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

Hansen et al., Science, 21 Aug 2020, 369:6506, 1010-1014, doi:10.1126/science.abd0827

Aug 2020

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Casirivimab/imdevimab

17th treatment shown to reduce risk in March 2021, now with p = 0.00036 from 31 studies, recognized in 45 countries. Efficacy is variant dependent.

Lower risk for hospitalization, progression, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine treatments.

5,100+ studies for 109 treatments. c19early.org

Study using humanized mice and blood samples from recovered COVID-19 patients to generate antibodies targeting multiple different regions of the critical receptor-binding domain (RBD) of the SARS-CoV-2 spike protein. The spike protein on the virus cell surface binds to the host cell and is required for infectivity. By blocking its interaction with the host cell, antibodies are able to neutralize the virus and block infection. Authors selected pairs of highly potent individual antibodies that simultaneously and non-competitively bind to the RBD. The multi-antibody approach is used to decrease the potential for the virus to escape.

Efficacy is variant dependent. In Vitro research suggests a lack of efficacy for many omicron variants1-7.

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1. Liu et al., Striking Antibody Evasion Manifested by the Omicron Variant of SARS-CoV-2, bioRxiv, doi:10.1101/2021.12.14.472719.biorxiv.org, doi.org.

2. Sheward et al., Variable loss of antibody potency against SARS-CoV-2 B.1.1.529 (Omicron), bioRxiv, doi:10.1101/2021.12.19.473354.biorxiv.org, doi.org.

3. VanBlargan et al., An infectious SARS-CoV-2 B.1.1.529 Omicron virus escapes neutralization by several therapeutic monoclonal antibodies, bioRxiv, doi:10.1101/2021.12.15.472828.biorxiv.org, doi.org.

4. Tatham et al., Lack of Ronapreve (REGN-CoV; casirivimab and imdevimab) virological efficacy against the SARS-CoV 2 Omicron variant (B.1.1.529) in K18-hACE2 mice, bioRxiv, doi:10.1101/2022.01.23.477397.biorxiv.org, doi.org.

5. Pochtovyi et al., In Vitro Efficacy of Antivirals and Monoclonal Antibodies against SARS-CoV-2 Omicron Lineages XBB.1.9.1, XBB.1.9.3, XBB.1.5, XBB.1.16, XBB.2.4, BQ.1.1.45, CH.1.1, and CL.1, Vaccines, doi:10.3390/vaccines11101533.mdpi.com, doi.org.

6. Haars et al., Prevalence of SARS-CoV-2 Omicron Sublineages and Spike Protein Mutations Conferring Resistance against Monoclonal Antibodies in a Swedish Cohort during 2022–2023, Microorganisms, doi:10.3390/microorganisms11102417.mdpi.com, doi.org.

7. Uraki et al., Antiviral efficacy against and replicative fitness of an XBB.1.9.1 clinical isolate, iScience, doi:10.1016/j.isci.2023.108147.sciencedirect.com, doi.org.

Hansen et al., 21 Aug 2020, peer-reviewed, 47 authors.

This Paper Casirivimab/i..All

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

Johanna Hansen, Alina Baum, Kristen E Pascal, Vincenzo Russo, Stephanie Giordano, Elzbieta Wloga, Benjamin O Fulton, Ying Yan, Katrina Koon, Krunal Patel, Kyung Min Chung, Aynur Hermann, Erica Ullman, Jonathan Cruz, Ashique Rafique, Tammy Huang, Jeanette Fairhurst, Christen Libertiny, Marine Malbec, Wen-Yi Lee, Richard Welsh, Glen Farr, Seth Pennington, Dipali Deshpande, Jemmie Cheng, Anke Watty, Pascal Bouffard, Robert Babb, Natasha Levenkova, Calvin Chen, Bojie Zhang, Annabel Romero Hernandez, Kei Saotome, Yi Zhou, Matthew Franklin, Sumathi Sivapalasingam, David Chien Lye, Stuart Weston, James Logue, Robert Haupt, Matthew Frieman, Gang Chen, William Olson, Andrew J Murphy, Neil Stahl, George D Yancopoulos, Christos A Kyratsous

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.

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.

References

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Baum, None, Science

Cao, None, Cell

Corti, None, Science

Dilillo, Palese, Wilson, Ravetch, None, J. Clin. Invest

Hansen, None, Science

Lan, None, Nature

Larkin, None, N. Engl. J. Med

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