Abstract
The transmembrane serine protease 2 (TMPRSS2) plays a critical role in SARS-CoV-2 infection by priming the viral Spike (S) protein for host cell entry and thus represents a potential target for COVID-19 therapy. Here monoclonal antibodies (mAbs) against human TMPRSS2 were established for therapeutic application. In vitro infection by SARS-CoV-2 of cell lines and human lung organoids was strongly inhibited by the TMPRSS2 mAbs. These mAbs inhibited infection of all SARS-CoV-2 variants tested including omicron. mAbs recognized epitopes different from the enzymatic active site and did not inhibit protease activity, suggesting blockade of steric interactions of S protein-ACE2/TMPRSS2. The inhibitory activity of the mAbs in vivo was examined in human ACE2/TMPRSS2-double knock-in mouse and macaque models. Analysis of viral titers and histopathological analysis of the lung in these infected animals indicated that the TMPRSS2 mAb effectively suppressed viral titers and induction of inflammation in vivo.