Single‐domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors
Abstract Novel therapies for hemophilia, including non‐factor replacement and in vivo gene therapy, are showing promising results in the clinic, including for patients having a history of inhibitor development. Here, we propose a novel therapeutic approach for hemophilia based on llama‐derived singl...
| Main Authors: | , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2020-04-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201911298 |
| _version_ | 1797284085684502528 |
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| author | Elena Barbon Gabriel Ayme Amel Mohamadi Jean‐François Ottavi Charlotte Kawecki Caterina Casari Sebastien Verhenne Solenne Marmier Laetitia van Wittenberghe Severine Charles Fanny Collaud Cecile V Denis Olivier D Christophe Federico Mingozzi Peter J Lenting |
| author_facet | Elena Barbon Gabriel Ayme Amel Mohamadi Jean‐François Ottavi Charlotte Kawecki Caterina Casari Sebastien Verhenne Solenne Marmier Laetitia van Wittenberghe Severine Charles Fanny Collaud Cecile V Denis Olivier D Christophe Federico Mingozzi Peter J Lenting |
| author_sort | Elena Barbon |
| collection | DOAJ |
| description | Abstract Novel therapies for hemophilia, including non‐factor replacement and in vivo gene therapy, are showing promising results in the clinic, including for patients having a history of inhibitor development. Here, we propose a novel therapeutic approach for hemophilia based on llama‐derived single‐domain antibody fragments (sdAbs) able to restore hemostasis by inhibiting the antithrombin (AT) anticoagulant pathway. We demonstrated that sdAbs engineered in multivalent conformations were able to block efficiently AT activity in vitro, restoring the thrombin generation potential in FVIII‐deficient plasma. When delivered as a protein to hemophilia A mice, a selected bi‐paratopic sdAb significantly reduced the blood loss in a model of acute bleeding injury. We then packaged this sdAb in a hepatotropic AAV8 vector and tested its safety and efficacy profile in hemophilic mouse models. We show that the long‐term expression of the bi‐paratopic sdAb in the liver is safe and poorly immunogenic, and results in sustained correction of the bleeding phenotype in hemophilia A and B mice, even in the presence of inhibitory antibodies to the therapeutic clotting factor. |
| first_indexed | 2024-03-07T17:42:46Z |
| format | Article |
| id | doaj.art-4434607219fc41c0b6465b55049e9dff |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T17:42:46Z |
| publishDate | 2020-04-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-4434607219fc41c0b6465b55049e9dff2024-03-02T15:39:05ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842020-04-01124n/an/a10.15252/emmm.201911298Single‐domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitorsElena Barbon0Gabriel Ayme1Amel Mohamadi2Jean‐François Ottavi3Charlotte Kawecki4Caterina Casari5Sebastien Verhenne6Solenne Marmier7Laetitia van Wittenberghe8Severine Charles9Fanny Collaud10Cecile V Denis11Olivier D Christophe12Federico Mingozzi13Peter J Lenting14Genethon, Institut National de la Santé et de la Recherche Médicale U951 Integrare Université Paris‐Saclay University of Evry Evry FranceHITh, UMR_S1176 Institut National de la Santé et de la Recherche Médicale Université Paris‐Saclay Le Kremlin‐Bicêtre FranceHITh, UMR_S1176 Institut National de la Santé et de la Recherche Médicale Université Paris‐Saclay Le Kremlin‐Bicêtre FranceInovarion Paris FranceHITh, UMR_S1176 Institut National de la Santé et de la Recherche Médicale Université Paris‐Saclay Le Kremlin‐Bicêtre FranceHITh, UMR_S1176 Institut National de la Santé et de la Recherche Médicale Université Paris‐Saclay Le Kremlin‐Bicêtre FranceHITh, UMR_S1176 Institut National de la Santé et de la Recherche Médicale Université Paris‐Saclay Le Kremlin‐Bicêtre FranceGenethon, Institut National de la Santé et de la Recherche Médicale U951 Integrare Université Paris‐Saclay University of Evry Evry FranceGenethon, Institut National de la Santé et de la Recherche Médicale U951 Integrare Université Paris‐Saclay University of Evry Evry FranceGenethon, Institut National de la Santé et de la Recherche Médicale U951 Integrare Université Paris‐Saclay University of Evry Evry FranceGenethon, Institut National de la Santé et de la Recherche Médicale U951 Integrare Université Paris‐Saclay University of Evry Evry FranceHITh, UMR_S1176 Institut National de la Santé et de la Recherche Médicale Université Paris‐Saclay Le Kremlin‐Bicêtre FranceHITh, UMR_S1176 Institut National de la Santé et de la Recherche Médicale Université Paris‐Saclay Le Kremlin‐Bicêtre FranceGenethon, Institut National de la Santé et de la Recherche Médicale U951 Integrare Université Paris‐Saclay University of Evry Evry FranceHITh, UMR_S1176 Institut National de la Santé et de la Recherche Médicale Université Paris‐Saclay Le Kremlin‐Bicêtre FranceAbstract Novel therapies for hemophilia, including non‐factor replacement and in vivo gene therapy, are showing promising results in the clinic, including for patients having a history of inhibitor development. Here, we propose a novel therapeutic approach for hemophilia based on llama‐derived single‐domain antibody fragments (sdAbs) able to restore hemostasis by inhibiting the antithrombin (AT) anticoagulant pathway. We demonstrated that sdAbs engineered in multivalent conformations were able to block efficiently AT activity in vitro, restoring the thrombin generation potential in FVIII‐deficient plasma. When delivered as a protein to hemophilia A mice, a selected bi‐paratopic sdAb significantly reduced the blood loss in a model of acute bleeding injury. We then packaged this sdAb in a hepatotropic AAV8 vector and tested its safety and efficacy profile in hemophilic mouse models. We show that the long‐term expression of the bi‐paratopic sdAb in the liver is safe and poorly immunogenic, and results in sustained correction of the bleeding phenotype in hemophilia A and B mice, even in the presence of inhibitory antibodies to the therapeutic clotting factor.https://doi.org/10.15252/emmm.201911298anticoagulationcoagulationgene therapyhemophiliasingle‐domain antibodies |
| spellingShingle | Elena Barbon Gabriel Ayme Amel Mohamadi Jean‐François Ottavi Charlotte Kawecki Caterina Casari Sebastien Verhenne Solenne Marmier Laetitia van Wittenberghe Severine Charles Fanny Collaud Cecile V Denis Olivier D Christophe Federico Mingozzi Peter J Lenting Single‐domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors EMBO Molecular Medicine anticoagulation coagulation gene therapy hemophilia single‐domain antibodies |
| title | Single‐domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors |
| title_full | Single‐domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors |
| title_fullStr | Single‐domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors |
| title_full_unstemmed | Single‐domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors |
| title_short | Single‐domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors |
| title_sort | single domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors |
| topic | anticoagulation coagulation gene therapy hemophilia single‐domain antibodies |
| url | https://doi.org/10.15252/emmm.201911298 |
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