Genetic barrier to resistance: a critical parameter for efficacy of neutralizing monoclonal antibodies against SARS-CoV-2 in a nonhuman primate model

Stahl-Hennig C, Peter AS, Cordsmeier A, Stolte-Leeb N, Vestweber R, Socher E, Merida SA, Sauermann U, Bleyer M, Fraedrich K, Grunwald T, Winkler T, Enßer A, Jäck HM, Überla K (2024)

Publication Type: Journal article

Publication year: 2024

Journal

DOI: 10.1128/jvi.00628-24

Abstract

The potency of antibody neutralization in cell culture has been used as the key criterion for selection of antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) for clinical development. As other aspects may also influence the degree of protection in vivo, we compared the efficacy of two neutralizing monoclonal antibodies (TRES6 and 4C12) targeting different epitopes of the receptor binding domain (RBD) of SARS-CoV-2 in a prophylactic setting in rhesus monkeys. All four animals treated with TRES6 had reduced viral loads in the upper respiratory tract 2 days after naso-oropharyngeal challenge with the Alpha SARS-CoV-2 variant. Starting 2 days after challenge, mutations conferring resistance to TRES6 were dominant in two of the rhesus monkeys, with both animals failing to maintain reduced viral loads. Consistent with its lower serum neutralization titer at the day of challenge, prophylaxis with 4C12 tended to suppress viral load at day 2 less efficiently than TRES6. However, a week after challenge, mean viral loads in the lower respiratory tract in 4C12-treated animals were lower than in the TRES6 group and no mutations conferring resistance to 4C12 could be detected in viral isolates from nasal or throat swabs. Thus, genetic barrier to resistance seems to be a critical parameter for the efficacy of prophylaxis with monoclonal antibodies against SARS-CoV-2. Furthermore, comparison of antibody concentrations in respiratory secretions to those in serum shows reduced distribution of the 4C12 antibody into respiratory secretions and a delay in the appearance of antibodies in bronchoalveolar lavage fluid compared to their appearance in secretions of the upper respiratory tract.

Authors with CRIS profile

Involved external institutions

Deutsches Primatenzentrum (DPZ), Leibniz-Institut für Primatenforschung Germany (DE) Fraunhofer-Institut für Zelltherapie und Immunologie (IZI) Germany (DE)

How to cite

APA:

Stahl-Hennig, C., Peter, A.S., Cordsmeier, A., Stolte-Leeb, N., Vestweber, R., Socher, E.,... Überla, K. (2024). Genetic barrier to resistance: a critical parameter for efficacy of neutralizing monoclonal antibodies against SARS-CoV-2 in a nonhuman primate model. Journal of Virology. https://doi.org/10.1128/jvi.00628-24

MLA:

Stahl-Hennig, Christiane, et al. "Genetic barrier to resistance: a critical parameter for efficacy of neutralizing monoclonal antibodies against SARS-CoV-2 in a nonhuman primate model." Journal of Virology (2024).

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