An Innovative antibody-based Plug-and-Play strategy for SARS-CoV-2

Shivange, Gururaj; Gogoi, Debananda; Tushir-Singh, Jogender

The novel and highly pathogenic coronavirus (SARS-CoV-2) remains a public health threat worldwide. SARS-CoV-2 enters human host lung cells via its spike protein binding to angiotensin-converting enzyme 2 (ACE2) in a process critical dependent on host protease-mediated fusion event. Thus, effective targeted therapies blocking the first step of viral fusion and cellular entry remains a critical unmet medical need to overcome disease pathology. Here we engineered and describe an antibody-based novel and targeted plug-and-play strategy, which directly competes with the proteolytic activation function of SAR-CoV-2 spike protein. The described strategy involves the engineering of furin substrate residues in IgG1 Fc-extended flexible region of spike targeting antibody. Our results with spike receptor-binding domain (RBD) targeting CR3022 antibody support blockade of the viral function using proof of concept ACE2 overexpressing cells. Our study reveals analytical, safe, and selective mechanistic insights for SARS-CoV-2 therapeutic design and is broadly applicable to the future coronaviridae family members (including mutant variants) exploiting the host protease system for cellular entry.