The Fc-mediated effector functions of a potent SARS-CoV-2 neutralizing antibody, SC31, isolated from an early convalescent COVID-19 patient, are essential for the optimal therapeutic efficacy of the antibody

Abstract

SARS-CoV-2-neutralizing antibodies are promising therapeutics for COVID-19. However, little is known about the mechanisms of action of these antibodies or their effective dosing windows. We report the discovery and development of SC31, a potent SARS-CoV-2 neutralizing IgG1 antibody, originally isolated from a convalescent patient at day 27 after the onset of symptoms. Neutralization occurs via a binding epitope that maps within the ACE2 interface of the SARS-CoV-2 Spike protein, conserved across all common circulating SARS-CoV-2 mutants. In SARS-CoV-2 infected K18-human ACE2 transgenic mice, SC31 demonstrated potent survival benefit by dramatically reducing viral load concomitant with attenuated pro-inflammatory responses linked to severe systemic disease, such as IL-6. Comparison with a Fc-null LALA variant of SC31 demonstrated that optimal therapeutic efficacy of SC31 requires intact Fc-mediated effector functions that can further induce an IFNγ-driven anti-viral immune response. Dose-dependent efficacy for SC31 was observed down to 5mg/kg when dosed before the activation of lung inflammatory responses. Importantly, despite FcγR binding, no evidence of antibody dependent enhancement was observed with the Fc-competent SC31 even at sub-therapeutic doses. Therapeutic efficacy was confirmed in SARS-CoV-2-infected hamsters, where SC31 again significantly reduced viral load, decreased lung lesions and inhibited progression to severe disease manifestations. This study underlines the potential for significant COVID-19 patient benefit for the SC31 antibody that justifies rapid advancement to the clinic, as well as highlighting the importance of appropriate mechanistic and functional studies during development.

Longitudinal analysis of humoral immunity against SARS-CoV-2 Spike in convalescent individuals up to 8 months post-symptom onset

“…Fc-mediated effector functions of antibodies can contribute to the efficacy of immune response against SARS-CoV-2. Recent studies have examined Fc-mediated effector functions of antibodies elicited upon SARS-CoV-2 infection (19, 32). Both the presence of IgG and their Fc-mediated effector activities have been linked to reduced severity of disease (21).…”

“…Antibodies capable of mediating Fc-dependant functions, such as antibody-dependent phagocytosis and ADCC, have been isolated from convalescent donors (35). Importantly, Fc-mediated effector activity was shown to protect from SARS-CoV-2 infection in adapted mice and hamster models (9, 19, 32). Thus, our observations of the persistence of ADCC responses in convalescent plasma up to 8 months PSO suggest that Fc-mediated effector functions could play a vital role in protection from reinfection.…”

Neutralization of viruses with European, South African, and United States SARS-CoV-2 variant spike proteins by convalescent sera and BNT162b2 mRNA vaccine-elicited antibodies

“…The B.1.1.7 lineage is defined by 23 mutations of which 8 are located in S (Δ69-70, Y144Del, N501Y, A570D, P681H, T716I, S982A and D1118H). N501Y is one of six contact residues with ACE2 8 and has been shown to increase affinity for ACE2 9 . The Δ69-70, which was found in multiple independent lineages, increases viral infectivity and leads to immunoevasion in immunocompromised patients 10 .…”

Decreased neutralization of SARS-CoV-2 global variants by therapeutic anti-spike protein monoclonal antibodies

“…The B.1.1.7 lineage (VOC-202012/01) variant identified in patients in the United Kingdom 10–12 encodes a spike protein with 8 mutations in addition to D614G (Δ69-70, Y144Del, N501Y, A570D, P681H, T716I, S982A and D1118H). N501Y is one of six ACE2 contact residues and has been shown to increase affinity for ACE2 13 by hydrogen bonding with ACE2 Y41 14 ; the Δ69-70 deletion in the N-terminal domain is found in multiple independent lineages 15 ; and P681H lies adjacent to the furin cleavage site suggesting a role in spike protein processing. The B.1.351 lineage variant identified in patients in South Africa rapidly became the predominant circulating genotype 16 .…”