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Fc-Independent Protection from SARS-CoV-2 Infection by Recombinant Human Monoclonal Antibodies.

ABSTRACT: The use of passively-administered neutralizing antibodies is a promising approach for the prevention and treatment of SARS-CoV-2 infection. Antibody-mediated protection may involve immune system recruitment through Fc-dependent activation of effector cells and the complement system. However, the role of Fc-mediated functions in the efficacious in-vivo neutralization of SARS-CoV-2 is not yet clear, and it is of high importance to delineate the role this process plays in antibody-mediated protection. Toward this aim, we have chosen two highly potent SARS-CoV-2 neutralizing human monoclonal antibodies, MD65 and BLN1 that target distinct domains of the spike (RBD and NTD, respectively). The Fc of these antibodies was engineered to include the triple mutation N297G/S298G/T299A that eliminates glycosylation and the binding to FcγR and to the complement system activator C1q. As expected, the virus neutralization activity (in-vitro) of the engineered antibodies was retained. To study the role of Fc-mediated functions, the protective activity of these antibodies was tested against lethal SARS-CoV-2 infection of K18-hACE2 transgenic mice, when treatment was initiated either before or two days post-exposure. Antibody treatment with both Fc-variants similarly rescued the mice from death reduced viral load and prevented signs of morbidity. Taken together, this work provides important insight regarding the contribution of Fc-effector functions in MD65 and BLN1 antibody-mediated protection, which should aid in the future design of effective antibody-based therapies.

SUBMITTER: Noy-Porat T

PROVIDER: S-EPMC8628512 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main target for neutralizing antibodies. These antibodies can be elicited through immunization or passively transferred as therapeutics in the form of convalescent-phase sera or monoclonal antibodies (MAbs). Potently neutralizing antibodies are expected to confer protection; however, it is unclear whether weakly neutralizing antibodies contribute to protection. Also, their mechanism of action in vivo is incompletely understood. Here, we demonstrate that 2B04, an antibody with an ultrapotent neutralizing activity (50% inhibitory concentration [IC50] of 0.04 μg/ml), protects hamsters against SARS-CoV-2 in a prophylactic and therapeutic infection model. Protection is associated with reduced weight loss and viral loads in nasal turbinates and lungs after challenge. MAb 2B04 also blocked aerosol transmission of the virus to naive contacts. We next examined three additional MAbs (2C02, 2C03, and 2E06), recognizing distinct epitopes within the receptor binding domain of spike protein that possess either minimal (2C02 and 2E06, IC50 > 20 μg/ml) or weak (2C03, IC50 of 5 μg/ml) virus neutralization capacity in vitro. Only 2C03 protected Syrian hamsters from weight loss and reduced lung viral load after SARS-CoV-2 infection. Finally, we demonstrated that Fc-Fc receptor interactions were not required for protection when 2B04 and 2C03 were administered prophylactically. These findings inform the mechanism of protection and support the rational development of antibody-mediated protection against SARS-CoV-2 infections. IMPORTANCE The ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by SARS-CoV-2, has resulted in the loss of millions of lives. Safe and effective vaccines are considered the ultimate remedy for the global social and economic disruption caused by the pandemic. However, a thorough understanding of the immune correlates of protection against this virus is lacking. Here, we characterized four different monoclonal antibodies and evaluated their ability to prevent or treat SARS-CoV-2 infection in Syrian hamsters. These antibodies varied in their ability to neutralize the virus in vitro. Prophylactic administration of potent and weakly neutralizing antibodies protected against SARS-CoV-2 infection, and this effect was Fc receptor independent. The potent neutralizing antibody also had therapeutic efficacy and eliminated onward aerosol transmission. In contrast, minimally neutralizing antibodies provided no protection against infection with SARS-CoV-2 in Syrian hamsters. Combined, these studies highlight the significance of weakly neutralizing antibodies in the protection against SARS-CoV-2 infection and associated disease.

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Fc-Independent Protection from SARS-CoV-2 Infection by Recombinant Human Monoclonal Antibodies.

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