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Development, Characterization, and in vivo Validation of a Humanized C6 Monoclonal Antibody that Inhibits the Membrane Attack Complex

Damage and disease of nerves activates the complement system. We demonstrated that activation of the terminal pathway of the complement system leads to the formation of the membrane attack complex (MAC) and delays regeneration in the peripheral nervous system. Animals deficient in the complement com...

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Autores principales: Gytz Olesen, Heidi, Michailidou, Iliana, Zelek, Wioleta M., Vreijling, Jeroen, Ruizendaal, Patrick, de Klein, Ferry, Marquart, J. Arnoud, Kuipers, Thomas B., Mei, Hailiang, Zhang, Yuchun, Ahasan, Muhammad, Johnson, Krista K., Wang, Yi, Morgan, B. Paul, van Dijk, Marcus, Fluiter, Kees, Andersen, Gregers Rom, Baas, Frank
Formato: Online Artículo Texto
Lenguaje:English
Publicado: S. Karger AG 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643903/
https://www.ncbi.nlm.nih.gov/pubmed/35551129
http://dx.doi.org/10.1159/000524587
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author Gytz Olesen, Heidi
Michailidou, Iliana
Zelek, Wioleta M.
Vreijling, Jeroen
Ruizendaal, Patrick
de Klein, Ferry
Marquart, J. Arnoud
Kuipers, Thomas B.
Mei, Hailiang
Zhang, Yuchun
Ahasan, Muhammad
Johnson, Krista K.
Wang, Yi
Morgan, B. Paul
van Dijk, Marcus
Fluiter, Kees
Andersen, Gregers Rom
Baas, Frank
author_facet Gytz Olesen, Heidi
Michailidou, Iliana
Zelek, Wioleta M.
Vreijling, Jeroen
Ruizendaal, Patrick
de Klein, Ferry
Marquart, J. Arnoud
Kuipers, Thomas B.
Mei, Hailiang
Zhang, Yuchun
Ahasan, Muhammad
Johnson, Krista K.
Wang, Yi
Morgan, B. Paul
van Dijk, Marcus
Fluiter, Kees
Andersen, Gregers Rom
Baas, Frank
author_sort Gytz Olesen, Heidi
collection PubMed
description Damage and disease of nerves activates the complement system. We demonstrated that activation of the terminal pathway of the complement system leads to the formation of the membrane attack complex (MAC) and delays regeneration in the peripheral nervous system. Animals deficient in the complement component C6 showed improved recovery after neuronal trauma. Thus, inhibitors of the MAC might be of therapeutic use in neurological disease. Here, we describe the development, structure, mode of action, and properties of a novel therapeutic monoclonal antibody, CP010, against C6 that prevents formation of the MAC in vivo. The monoclonal antibody is humanized and specific for C6 and binds to an epitope in the FIM1-2 domain of human and primate C6 with sub-nanomolar affinity. Using biophysical and structural studies, we show that the anti-C6 antibody prevents the interaction between C6 and C5/C5b by blocking the C6 FIM1-2:C5 C345c axis. Systemic administration of the anti-C6 mAb caused complete depletion of free C6 in circulation in transgenic rats expressing human C6 and thereby inhibited MAC formation. The antibody prevented disease in experimental autoimmune myasthenia gravis and ameliorated relapse in chronic relapsing experimental autoimmune encephalomyelitis in human C6 transgenic rats. CP010 is a promising complement C6 inhibitor that prevents MAC formation. Systemic administration of this C6 monoclonal antibody has therapeutic potential in the treatment of neuronal disease.
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spelling pubmed-106439032022-05-12 Development, Characterization, and in vivo Validation of a Humanized C6 Monoclonal Antibody that Inhibits the Membrane Attack Complex Gytz Olesen, Heidi Michailidou, Iliana Zelek, Wioleta M. Vreijling, Jeroen Ruizendaal, Patrick de Klein, Ferry Marquart, J. Arnoud Kuipers, Thomas B. Mei, Hailiang Zhang, Yuchun Ahasan, Muhammad Johnson, Krista K. Wang, Yi Morgan, B. Paul van Dijk, Marcus Fluiter, Kees Andersen, Gregers Rom Baas, Frank J Innate Immun Research Article Damage and disease of nerves activates the complement system. We demonstrated that activation of the terminal pathway of the complement system leads to the formation of the membrane attack complex (MAC) and delays regeneration in the peripheral nervous system. Animals deficient in the complement component C6 showed improved recovery after neuronal trauma. Thus, inhibitors of the MAC might be of therapeutic use in neurological disease. Here, we describe the development, structure, mode of action, and properties of a novel therapeutic monoclonal antibody, CP010, against C6 that prevents formation of the MAC in vivo. The monoclonal antibody is humanized and specific for C6 and binds to an epitope in the FIM1-2 domain of human and primate C6 with sub-nanomolar affinity. Using biophysical and structural studies, we show that the anti-C6 antibody prevents the interaction between C6 and C5/C5b by blocking the C6 FIM1-2:C5 C345c axis. Systemic administration of the anti-C6 mAb caused complete depletion of free C6 in circulation in transgenic rats expressing human C6 and thereby inhibited MAC formation. The antibody prevented disease in experimental autoimmune myasthenia gravis and ameliorated relapse in chronic relapsing experimental autoimmune encephalomyelitis in human C6 transgenic rats. CP010 is a promising complement C6 inhibitor that prevents MAC formation. Systemic administration of this C6 monoclonal antibody has therapeutic potential in the treatment of neuronal disease. S. Karger AG 2022-05-12 /pmc/articles/PMC10643903/ /pubmed/35551129 http://dx.doi.org/10.1159/000524587 Text en Copyright © 2022 by The Author(s). Published by S. Karger AG, Basel https://creativecommons.org/licenses/by-nc/4.0/This article is licensed under the Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC). Usage and distribution for commercial purposes requires written permission.
spellingShingle Research Article
Gytz Olesen, Heidi
Michailidou, Iliana
Zelek, Wioleta M.
Vreijling, Jeroen
Ruizendaal, Patrick
de Klein, Ferry
Marquart, J. Arnoud
Kuipers, Thomas B.
Mei, Hailiang
Zhang, Yuchun
Ahasan, Muhammad
Johnson, Krista K.
Wang, Yi
Morgan, B. Paul
van Dijk, Marcus
Fluiter, Kees
Andersen, Gregers Rom
Baas, Frank
Development, Characterization, and in vivo Validation of a Humanized C6 Monoclonal Antibody that Inhibits the Membrane Attack Complex
title Development, Characterization, and in vivo Validation of a Humanized C6 Monoclonal Antibody that Inhibits the Membrane Attack Complex
title_full Development, Characterization, and in vivo Validation of a Humanized C6 Monoclonal Antibody that Inhibits the Membrane Attack Complex
title_fullStr Development, Characterization, and in vivo Validation of a Humanized C6 Monoclonal Antibody that Inhibits the Membrane Attack Complex
title_full_unstemmed Development, Characterization, and in vivo Validation of a Humanized C6 Monoclonal Antibody that Inhibits the Membrane Attack Complex
title_short Development, Characterization, and in vivo Validation of a Humanized C6 Monoclonal Antibody that Inhibits the Membrane Attack Complex
title_sort development, characterization, and in vivo validation of a humanized c6 monoclonal antibody that inhibits the membrane attack complex
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643903/
https://www.ncbi.nlm.nih.gov/pubmed/35551129
http://dx.doi.org/10.1159/000524587
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