Complement C3 inhibition in severe COVID-19 using compstatin AMY-101-Reference-Cited by-同舟云学术

Complement C3 inhibition in severe COVID-19 using compstatin AMY-101

Published:2022-08-19 Issue:33 Volume:8 Page:
ISSN:2375-2548
Container-title:Science Advances
language:en
Short-container-title:Sci. Adv.

Author:

Skendros Panagiotis¹^ORCID,Germanidis Georgios²^ORCID,Mastellos Dimitrios C.³^ORCID,Antoniadou Christina¹^ORCID,Gavriilidis Efstratios¹^ORCID,Kalopitas Georgios²^ORCID,Samakidou Anna⁴,Liontos Angelos⁵^ORCID,Chrysanthopoulou Akrivi¹,Ntinopoulou Maria¹,Kogias Dionysios¹^ORCID,Karanika Ioanna²,Smyrlis Andreas¹^ORCID,Cepaityte Dainora²^ORCID,Fotiadou Iliana¹^ORCID,Zioga Nikoleta¹^ORCID,Mitroulis Ioannis¹,Gatselis Nikolaos K.⁴^ORCID,Papagoras Charalampos¹^ORCID,Metallidis Simeon²,Milionis Haralampos⁵^ORCID,Dalekos George N.⁴^ORCID,Willems Loek⁶,Persson Barbro⁷,Manivel Vivek Anand⁷^ORCID,Nilsson Bo⁷,Connolly E. Sander⁸,Iacobelli Simona⁹,Papadopoulos Vasileios¹^ORCID,Calado Rodrigo T.¹⁰^ORCID,Huber-Lang Markus¹¹^ORCID,Risitano Antonio M.¹²,Yancopoulou Despina¹³,Ritis Konstantinos¹,Lambris John D.¹⁴^ORCID

Affiliation:

1. First Department of Internal Medicine and Laboratory of Molecular Hematology, Democritus University of Thrace, University Hospital of Alexandroupolis, Alexandroupolis, Greece.

2. First Department of Internal Medicine, AHEPA University Hospital, and Basic and Translational Research Unit, Special Unit for Biomedical Research and Education (SUBRE), School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece.

3. National Center for Scientific Research “Demokritos”, Athens, Greece.

4. Department of Medicine and Research Laboratory of Internal Medicine, National and European Expertise Center of Greece in Autoimmune Liver Diseases (ERN Rare-Liver), General University Hospital of Larissa, Larissa, Greece.

5. Department of Internal Medicine, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece.

6. R&D Department, Hycult Biotechnology, Uden, Netherlands.

7. Department of Immunology Genetics and Pathology, Uppsala University, Uppsala, Sweden.

8. Department of Neurological Surgery, Columbia University, New York, NY, USA.

9. Department of Biology, University of Rome Tor Vergata, Rome, Italy.

10. Department of Medical Imaging, Hematology and Oncology, University of São Paulo, School of Medicine, Ribeirão Preto, Brazil.

11. Institute for Clinical and Experimental Trauma-Immunology, Ulm University Hospital, Ulm, Germany.

12. AORN Moscati Avellino, Italy and Federico II University of Naples, Naples, Italy.

13. Amyndas Pharmaceuticals, Glyfada, Greece.

14. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA.

Abstract

Complement C3 activation contributes to COVID-19 pathology, and C3 targeting has emerged as a promising therapeutic strategy. We provide interim data from ITHACA, the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 (PaO2/FiO2 ≤ 300 mmHg). Patients received AMY-101 ( n = 16) or placebo ( n = 15) in addition to standard of care. AMY-101 was safe and well tolerated. Compared to placebo (8 of 15, 53.3%), a higher, albeit nonsignificant, proportion of AMY-101–treated patients (13 of 16, 81.3%) were free of supplemental oxygen at day 14. Three nonresponders and two placebo-treated patients succumbed to disease-related complications. AMY-101 significantly reduced CRP and ferritin and restrained thrombin and NET generation. Complete and sustained C3 inhibition was observed in all responders. Residual C3 activity in the three nonresponders suggested the presence of a convertase-independent C3 activation pathway overriding the drug’s inhibitory activity. These findings support the design of larger trials exploring the potential of C3-based inhibition in COVID-19 or other complement-mediated diseases.

Publisher

American Association for the Advancement of Science (AAAS)

Subject

Multidisciplinary

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