2. Academic Validation
  3. Complement factor D targeting protects endotheliopathy in organoid and monkey models of COVID-19

Complement factor D targeting protects endotheliopathy in organoid and monkey models of COVID-19

  • Cell Stem Cell. 2023 Oct 5;30(10):1315-1330.e10. doi: 10.1016/j.stem.2023.09.001.
Eri Kawakami 1,  Norikazu Saiki 2,  Yosuke Yoneyama 3,  Chiharu Moriya 3,  Mari Maezawa 3,  Shuntaro Kawamura 3,  Akiko Kinebuchi 3,  Tamaki Kono 1,  Masaaki Funata 1,  Ayaka Sakoda 4,  Shigeru Kondo 4,  Takeshi Ebihara 5,  Hisatake Matsumoto 5,  Yuki Togami 5,  Hiroshi Ogura 5,  Fuminori Sugihara 6,  Daisuke Okuzaki 7,  Takashi Kojima 5,  Sayaka Deguchi 8,  Sebastien Vallee 9,  Susan McQuade 10,  Rizwana Islam 9,  Madhusudan Natarajan 9,  Hirohito Ishigaki 11,  Misako Nakayama 11,  Cong Thanh Nguyen 11,  Yoshinori Kitagawa 11,  Yunheng Wu 12,  Kensaku Mori 13,  Takayuki Hishiki 14,  Tomohiko Takasaki 15,  Yasushi Itoh 11,  Kazuo Takayama 8,  Yasunori Nio 16,  Takanori Takebe 17
Affiliations

Affiliations

  • 1 T-CiRA Discovery & Innovation, Takeda Pharmaceutical Company Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan; Organoid Medicine Project, T-CiRA Joint Program, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
  • 2 Institute of Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Organoid Medicine Project, T-CiRA Joint Program, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
  • 3 Institute of Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan.
  • 4 T-CiRA Discovery & Innovation, Takeda Pharmaceutical Company Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan.
  • 5 Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, 2-15, Yamada-oka, Suita, Osaka 565-0871, Japan.
  • 6 Core Instrumentation Facility, Immunology Frontier Research Center and Research Institute for Microbial Diseases, Osaka University, 3-3-1, Yamada-oka, Suita, Osaka 565-0871, Japan.
  • 7 Genome Information Research Center, Research Institute for Microbial Disease, Osaka University, 3-1 Yamada-oka, Suita, Osaka 565-0871, Japan.
  • 8 Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto 606-8507, Japan.
  • 9 Rare Disease DDU, Takeda Pharmaceutical Company Ltd, 125 Binney Street, Cambridge, MA 02139, USA.
  • 10 Rare Disease DDU, Takeda Pharmaceutical Company Ltd, 125 Binney Street, Cambridge, MA 02139, USA; BPS Biosciences Inc., 6405 Mira Mesa Blvd. Suite 100, San Diego, CA 92121, USA.
  • 11 Department of Pathology, Shiga University of Medical Science, Setatsukinowa, Otsu, Shiga 520-2192, Japan.
  • 12 Graduate School of Informatics, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
  • 13 Graduate School of Informatics, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; Information Technology Center, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan; Research Center for Medical Bigdata, National Institute of Informatics, Tokyo 100-0003, Japan.
  • 14 Kanagawa Prefectural Institute of Public Health, 1-3-1, Shimomachiya, Chigasaki, Kanagawa 253-0087, Japan; Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, 1-23-1, Toyama, Shinjuku-ku, Tokyo 162-8640, Japan.
  • 15 Kanagawa Prefectural Institute of Public Health, 1-3-1, Shimomachiya, Chigasaki, Kanagawa 253-0087, Japan; Advanced Technology and Development Division, BML, INC, 1361-1, Matoba, Kawagoe-shi, Saitama 350-1101, Japan.
  • 16 T-CiRA Discovery & Innovation, Takeda Pharmaceutical Company Ltd, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan; Organoid Medicine Project, T-CiRA Joint Program, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: ynioh0506@gmail.com.
  • 17 Institute of Research, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8510, Japan; Organoid Medicine Project, T-CiRA Joint Program, 2-26-1, Muraoka-higashi, Fujisawa, Kanagawa 251-8555, Japan; Division of Gastroenterology, Hepatology and Nutrition & Division of Developmental Biology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; The Center for Stem Cell and Organoid Medicine (CuSTOM), Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; Department of Pediatrics, University of Cincinnati College of Medicine, 3333 Burnet Avenue, Cincinnati, OH 45229-3039, USA; Communication Design Center, Advanced Medical Research Center, Yokohama City University Graduate School of Medicine, Yokohama, Kanagawa, Japan; Premium Research Institute for Human Metaverse Medicine (WPI-PRIMe) and Department of Genome Biology, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan. Electronic address: takanori.takebe@cchmc.org.
PMID: 37802037 DOI: 10.1016/j.stem.2023.09.001
Abstract

COVID-19 is linked to endotheliopathy and coagulopathy, which can result in multi-organ failure. The mechanisms causing endothelial damage due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain elusive. Here, we developed an infection-competent human vascular Organoid from pluripotent stem cells for modeling endotheliopathy. Longitudinal serum proteome analysis identified aberrant complement signature in critically ill patients driven by the amplification cycle regulated by Complement Factor B and D (CFD). This deviant complement pattern initiates endothelial damage, neutrophil activation, and thrombosis specific to organoid-derived human blood vessels, as verified through intravital imaging. We examined a new long-acting, pH-sensitive (acid-switched) antibody targeting CFD. In both human and macaque COVID-19 models, this long-acting anti-CFD monoclonal antibody mitigated abnormal complement activation, protected endothelial cells, and curtailed the innate immune response post-viral exposure. Collectively, our findings suggest that the complement alternative pathway exacerbates endothelial injury and inflammation. This underscores the potential of CFD-targeted therapeutics against severe viral-induced inflammathrombotic outcomes.

Keywords

CFD; SARS-CoV-2; acid-switch half-life extended antibody; complement; cynomolgus macaque; endotheliopathy; iPSC; thrombopathy; vascular organoid.

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