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

Noy-Porat, Tal; Edri, Avishay; Alcalay, Ron; Makdasi, Efi; Gur, David; Aftalion, Moshe; Evgy, Yentl; Beth-Din, Adi; Levy, Yinon; Epstein, Eyal; Radinsky, Olga; Zauberman, Ayelet; Lazar, Shirley; Yitzhaki, Shmuel; Marcus, Hadar; Porgador, Angel; Rosenfeld, Ronit; Mazor, Ohad

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.