Monoclonal antibodies against human TMPRSS2 prevent infection by any SARS-CoV-2 variant
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. <i>In vitro</i> 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 <i>in vivo</i> was examined in human <i>ACE2</i>/<i>TMPRSS2</i>-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 <i>in vivo</i>.
Authors
- Mizuki Yamamoto (ORCID: https://orcid.org/0000-0003-3731-1702)
- Hirohito Ishigaki (ORCID: https://orcid.org/0000-0002-5249-8598)
- Misako Nakayama (ORCID: https://orcid.org/0000-0001-8611-0662)
- Toshie Kaizuka
- Akiko Sugimoto-Ishige
- Yoshiko Ishizuka‐Katsura
- Cong Thanh Nguyen (ORCID: https://orcid.org/0000-0002-5973-6210)
- Minoru Yoshida
- Mikako Shirouzu (ORCID: https://orcid.org/0000-0002-7997-2149)
- Rina Hashimoto (ORCID: https://orcid.org/0000-0002-7174-4563)
- Tamao Hisano (ORCID: https://orcid.org/0000-0002-5832-8442)
- Yasushi Itoh
- Kazushige Katsura (ORCID: https://orcid.org/0000-0002-4333-0224)
- Takehisa Matsumoto (ORCID: https://orcid.org/0000-0002-4667-9739)
- Natsumi Yoneda
- Akiko Idei (ORCID: https://orcid.org/0009-0000-4257-9151)
- Mariko Ikeda (ORCID: https://orcid.org/0000-0001-8043-9440)
- Kazuo Takayama (ORCID: https://orcid.org/0000-0002-1132-2457)
- Yoshinobu Hashizume
- Natsuki Kojima
- Takashi Saito (ORCID: https://orcid.org/0000-0001-9495-3547)
- Toshiaki Hosaka (ORCID: https://orcid.org/0000-0002-7652-8114)
- Jun‐ichiro Inoue (ORCID: https://orcid.org/0000-0001-6389-7036)
- Yasushi Kawaguchi (ORCID: https://orcid.org/0000-0001-8232-6925)
- Jayant Sastri Goda (ORCID: https://orcid.org/0000-0002-3915-8927)
- Michishige Harada
- Tatsuya Yamamoto (ORCID: https://orcid.org/0000-0003-4297-6354)
- Kazuharu Hanada (ORCID: https://orcid.org/0000-0002-5998-1849)
- Makoto Takeda (ORCID: https://orcid.org/0000-0002-8194-7727)
- Machie Sakuma
- Haruhiko Koseki (ORCID: https://orcid.org/0000-0001-8424-5854)
- Kosuke Miyauchi (ORCID: https://orcid.org/0000-0002-2349-6665)
- Manabu Nakayama (ORCID: https://orcid.org/0009-0001-0488-1664)
- K. Ohtaki
- Masashi Matsuda
Institutions
- Chiba University (JP)
- Shiga University of Medical Science (JP)
- Kyoto University (JP)
- National Institute of Infectious Diseases (JP)
- RIKEN Center for Sustainable Resource Science (JP)
- Kazusa DNA Research Institute (JP)
- RIKEN Center for Integrative Medical Sciences (JP)
- The University of Tokyo (JP)
Publication Details
- Journal
- iScience
- Published
- 2025-08-22
- DOI
- https://doi.org/10.1016/j.isci.2025.113424
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Japan Agency for Medical Research and Development
- Japanese Respiratory Society