Abstract
Although SARS-CoV-2-neutralizing antibodies are promising therapeutics against COVID-19, little is known about their mechanism(s) of action or effective dosing windows. We report the generation and development of SC31, a potent SARS-CoV-2 neutralizing antibody, isolated from a convalescent patient. Antibody-mediated neutralization occurs via an epitope within the receptor-binding domain of the SARS-CoV-2 Spike protein. SC31 exhibited potent anti-SARS-CoV-2 activities in multiple animal models. In SARS-CoV-2 infected K18-human ACE2 transgenic mice, treatment with SC31 greatly reduced viral loads and attenuated pro-inflammatory responses linked to the severity of COVID-19. Importantly, a comparison of the efficacies of SC31 and its Fc-null LALA variant revealed that the optimal therapeutic efficacy of SC31 requires Fc-mediated effector functions that promote IFNγ-driven anti-viral immune responses, in addition to its neutralization ability. A dose-dependent efficacy of SC31 was observed down to 5mg/kg when administered before viral-induced lung inflammatory responses. In addition, antibody-dependent enhancement was not observed even when infected mice were treated with SC31 at sub-therapeutic doses. In SARS-CoV-2-infected hamsters, SC31 treatment significantly prevented weight loss, reduced viral loads, and attenuated the histopathology of the lungs. In rhesus macaques, the therapeutic potential of SC31 was evidenced through the reduction of viral loads in both upper and lower respiratory tracts to undetectable levels. Together, the results of our preclinical studies demonstrated the therapeutic efficacy of SC31 in three different models and its potential as a COVID-19 therapeutic candidate.
Highlights
In December 2019, a cluster of human novel pneumonia cases, named COVID-19, emerged and rapidly spread globally [1, 2]
SARS-CoV-2 was found to bind to angiotensin-converting enzyme 2 (ACE2), the same cellular surface receptor used by SARS-CoV, via the receptor-binding domain (RBD) of the viral surface Spike protein (SP) [7]
SC31, a potent neutralizing antibody isolated from a convalescent patient, binds to a conserved region of RBD of the SARS-CoV-2 SP
Summary
In December 2019, a cluster of human novel pneumonia cases, named COVID-19, emerged and rapidly spread globally [1, 2]. The isolation of antibodies from the memory B cells of convalescent patients are fast becoming an attractive approach for the development of therapeutic antibodies Such antibodies have been found to be protective against coronavirus diseases, including SARS-CoV, in animal models [8, 9]. Antibodies that prevent viral SP from binding to ACE2 were highly potent at attenuating or abolishing SARS-CoV-2 infection [10, 11] While such antibodies are not routinely used clinically to treat coronavirus infections, antibodies derived from convalescent patients have been successfully used to treat other infectious diseases, including the highly lethal Ebola virus infection with protective efficacies superior to that of small molecule antivirals [12]. Therapeutic and prophylactic antibodies specific to SARS-CoV-2 possess great clinical potential as they provide a much-needed option for individuals who might respond poorly to vaccination
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