Mary Wilson
Well-known member
Posted January 02, 2023.
doi: https://doi.org/10.1101/2022.12.29.522275
Emiko Urano, Yumi Itoh, Tatsuya Suzuki, Takanori Sasaki, Jun-ichi Kishikawa, Kanako Akamatsu, Yusuke Higuchi, Yusuke Sakai, Tomotaka Okamura, Shuya Mitoma, Fuminori Sugihara, Akira Takada, Mari Kimura, Mika Hirose, Tadahiro Sasaki, Ritsuko Koketsu, Shunya Tsuji, Shota Yanagida, Tatsuo Shioda, Eiji Hara, Satoaki Matoba, Yoshiharu Matsuura, Yasunari Kanda, Hisashi Arase, Masato Okada, Junichi Takagi, Takayuki Kato, Atsushi Hoshino, Yasuhiro Yasutomi, Akatsuki Saito, Toru Okamoto
Abstract
The Omicron variant continuously evolves under the humoral immune pressure obtained by vaccination and SARS-CoV-2 infection and the resultant Omicron subvariants exhibit further immune evasion and antibody escape. Engineered ACE2 decoy composed of high-affinity ACE2 and IgG1 Fc domain is an alternative modality to neutralize SARS-CoV-2 and we previously reported its broad spectrum and therapeutic potential in rodent models. Here, we show that engineered ACE2 decoy retains the neutralization activity against Omicron subvariants including the currently emerging XBB and BQ.1 which completely evade antibodies in clinical use. The culture of SARS-CoV-2 under suboptimal concentration of neutralizing drugs generated SARS-CoV-2 mutants escaping wild-type ACE2 decoy and monoclonal antibodies, whereas no escape mutant emerged against engineered ACE2 decoy. As the efficient drug delivery to respiratory tract infection of SARS-CoV-2, inhalation of aerosolized decoy treated mice infected with SARS-CoV-2 at a 20-fold lower dose than the intravenous administration. Finally, engineered ACE2 decoy exhibited the therapeutic efficacy for COVID-19 in cynomolgus macaques. Collectively, these results indicate that engineered ACE2 decoy is the promising therapeutic strategy to overcome immune-evading SARS-CoV-2 variants and that liquid aerosol inhalation can be considered as a non-invasive approach to enhance efficacy in the treatment of COVID-19.
https://www.biorxiv.org/content/10.1101/2022.12.29.522275v1.full
doi: https://doi.org/10.1101/2022.12.29.522275
Emiko Urano, Yumi Itoh, Tatsuya Suzuki, Takanori Sasaki, Jun-ichi Kishikawa, Kanako Akamatsu, Yusuke Higuchi, Yusuke Sakai, Tomotaka Okamura, Shuya Mitoma, Fuminori Sugihara, Akira Takada, Mari Kimura, Mika Hirose, Tadahiro Sasaki, Ritsuko Koketsu, Shunya Tsuji, Shota Yanagida, Tatsuo Shioda, Eiji Hara, Satoaki Matoba, Yoshiharu Matsuura, Yasunari Kanda, Hisashi Arase, Masato Okada, Junichi Takagi, Takayuki Kato, Atsushi Hoshino, Yasuhiro Yasutomi, Akatsuki Saito, Toru Okamoto
Abstract
The Omicron variant continuously evolves under the humoral immune pressure obtained by vaccination and SARS-CoV-2 infection and the resultant Omicron subvariants exhibit further immune evasion and antibody escape. Engineered ACE2 decoy composed of high-affinity ACE2 and IgG1 Fc domain is an alternative modality to neutralize SARS-CoV-2 and we previously reported its broad spectrum and therapeutic potential in rodent models. Here, we show that engineered ACE2 decoy retains the neutralization activity against Omicron subvariants including the currently emerging XBB and BQ.1 which completely evade antibodies in clinical use. The culture of SARS-CoV-2 under suboptimal concentration of neutralizing drugs generated SARS-CoV-2 mutants escaping wild-type ACE2 decoy and monoclonal antibodies, whereas no escape mutant emerged against engineered ACE2 decoy. As the efficient drug delivery to respiratory tract infection of SARS-CoV-2, inhalation of aerosolized decoy treated mice infected with SARS-CoV-2 at a 20-fold lower dose than the intravenous administration. Finally, engineered ACE2 decoy exhibited the therapeutic efficacy for COVID-19 in cynomolgus macaques. Collectively, these results indicate that engineered ACE2 decoy is the promising therapeutic strategy to overcome immune-evading SARS-CoV-2 variants and that liquid aerosol inhalation can be considered as a non-invasive approach to enhance efficacy in the treatment of COVID-19.
https://www.biorxiv.org/content/10.1101/2022.12.29.522275v1.full