Fc-independent neutralization of SARS-CoV-2 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. 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.

Current status of therapeutic monoclonal antibodies against SARS-CoV-2

“…Moreover, Fcmediated complement activation can exert a broad range of immunomodulatory functions, with activation of C1q resulting in antibody-mediated complement activation, and complement-dependent cytotoxicity. However, a recent study showed the diminished role of the Fc region in protecting against lethal SARS-CoV-2 infections in K18-hACE2 transgenic mice [42]. This study showed that potent NAbs do not rely on Fc effector functions to provide optimal protection when administered as therapy.…”