Science Translational Medicine
Author:
Keywords:
Science & Technology, Life Sciences & Biomedicine, Cell Biology, Medicine, Research & Experimental, Research & Experimental Medicine, RECEPTOR-BINDING DOMAIN, TRANSFORMATION, SITES, ACE2, Animals, Antibodies, Neutralizing, Antibodies, Viral, COVID-19, Humans, Models, Animal, SARS-CoV-2, Spike Glycoprotein, Coronavirus, C24/17/061#54270844, G0G4920N#55795248, 06 Biological Sciences, 11 Medical and Health Sciences, 3206 Medical biotechnology, 4003 Biomedical engineering
Abstract:
Broadly neutralizing antibodies are an important treatment for individuals with coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Antibody-based therapeutics are also essential for pandemic preparedness against future Sarbecovirus outbreaks. Camelid-derived single domain antibodies (VHHs) exhibit potent antimicrobial activity and are being developed as SARS-CoV-2–neutralizing antibody-like therapeutics. Here, we identified VHHs that neutralize both SARS-CoV-1 and SARS-CoV-2, including now circulating variants. We observed that the VHHs bound to a highly conserved epitope in the receptor binding domain of the viral spike protein that is difficult to access for human antibodies. Structure-guided molecular modeling, combined with rapid yeast-based prototyping, resulted in an affinity enhanced VHH-human immunoglobulin G1 Fc fusion molecule with subnanomolar neutralizing activity. This VHH-Fc fusion protein, produced in and purified from cultured Chinese hamster ovary cells, controlled SARS-CoV-2 replication in prophylactic and therapeutic settings in mice expressing human angiotensin converting enzyme 2 and in hamsters infected with SARS-CoV-2. These data led to affinity-enhanced selection of the VHH, XVR011, a stable anti–COVID-19 biologic that is now being evaluated in the clinic.