Fc-independent neutralization of SARS-CoV-2 by recombinant human monoclonal antibodies

Noy-Porat, T.; Edri, A.; Alcalay, R.; Makdasi, E.; Gur, D.; Aftalion, M.; Evgy, Y.; Beth-Din, A.; Levy, Y.; Epstein, E.; Radinsky, O.; Zauberman, A.; Lazar, S.; Yitzhaki, S.; Marcus, H.; Porgador, A.; Rosenfeld, R.; Mazor, O.

doi:10.1101/2021.05.15.443978

bioRxiv · 10.1101/2021.05.15.443978

Fc-independent neutralization of SARS-CoV-2 by recombinant human monoclonal antibodies

Noy-Porat, T.·Edri, A.·Alcalay, R.·Makdasi, E.·Gur, D.·Aftalion, M.·Evgy, Y.·Beth-Din, A.·Levy, Y.·Epstein, E.·Radinsky, O.·Zauberman, A.·Lazar, S.·Yitzhaki, S.·Marcus, H.·Porgador, A.·Rosenfeld, R.·Mazor, O.

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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. Delineating the role this process plays in antibody-mediated protection will have a great impact on the design of such therapeutics. Here, the Fc of two highly potent SARS-CoV-2 neutralizing human monoclonal antibodies, targeting distinct domains of the spike, was engineered to abrogate their Fc-dependent functions. The protective activity of these antibodies was tested against lethal SARS-CoV-2 infections in K18-hACE2 transgenic mice, both before or two days post-exposure in comparison to their original, Fc-active antibodies. Antibody treatment with both Fc-variants similarly rescued the mice from death, reduced viral load and prevented signs of morbidity. In addition, surviving animals developed a significant endogenous immune response towards the virus. Taken together, this work provides important insight regarding the contribution of Fc-effector functions in antibody-mediated protection, which should aid in future design of effective antibody-based therapies.

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Noy-Porat, T., Edri, A., Alcalay, R., Makdasi, E., Gur, D., Aftalion, M., Evgy, Y., Beth-Din, A., Levy, Y., Epstein, E., Radinsky, O., Zauberman, A., Lazar, S., Yitzhaki, S., Marcus, H., Porgador, A., Rosenfeld, R., Mazor, O.. 2021-05-15. Fc-independent neutralization of SARS-CoV-2 by recombinant human monoclonal antibodies. https://doi.org/10.1101/2021.05.15.443978

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