Pan-coronavirus neutralizing S2 human monoclonal antibodies and utility of direct respiratory administration as combination therapy with S1 antibodies against SARS-CoV-2

Abstract

Abstract To determine if pan-coronavirus neutralizing antibodies are induced by SARS-CoV-2 infection, human monoclonal antibodies (mAb) targeting the highly conserved S2 domain of the Spike glycoprotein were cloned from B cells isolated from convalescent patients with rationally designed SARS-CoV-2 stabilized S2 and SARS-CoV/SARS-CoV-2 S1S2 chimera recombinant protein probes. mAbs emerged capable of binding SARS-CoV-2, including the variants of concern (Beta, Gamma, Delta, and Omicron), SARS-CoV and MERS-CoV. The most potent neutralizing mAb with greatest breadth, 1249A8, recognizes all beta-coronaviruses tested including high affinity for SARS-CoV-2, SARS-CoV, and MERS-CoV. The 1249A8 lineage appears to have developed from a pre-existing OC43-specific memory B cell that was expanded as result of SARS-CoV-2 infection, and further expanded following COVID-19 vaccination. Treating K18 hACE2 transgenic mice with 1249A8 intraperitoneally prior to co-infection with SARS-CoV-2 Wa-1 and Beta VoC strains prevented weight loss and death, with viral titers below detectable levels by 4 days post-infection. 1249A8 delivered as a single 4mg/kg intranasal (i.n.) dose to hamsters 12 hours following infection with SARS-CoV-2/Delta significantly protected them from weight loss, with therapeutic activity enhanced when combined with an S1-specific neutralizing mAb. As little as 2 mg/kg of 1249A8 i.n. 20 hours following infection with SARS-CoV/Urbani protected hamsters from weight loss. 1249A8 recognizes a highly conserved region near HR2 of the S2 domain of Spike. These results indicate that potent pan-coronavirus neutralizing mAbs with therapeutic potential can be induced in humans and can inform pan-coronavirus vaccine development. Supported in-part by Aridis Pharmaceuticals and NIH (R01AI161175).