Single‐domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors

Autor: Barbon, Elena, Ayme, Gabriel, Mohamadi, Amel, Ottavi, Jean-François, Kawecki, Charlotte, Casari, Caterina, Verhenne, Sebastien, Marmier, Solenne, Van Wittenberghe, Laetitia, Charles, Severine, Collaud, Fanny, Denis, Cecile, Christophe, Olivier, Mingozzi, Federico, Lenting, Peter
Přispěvatelé: Approches génétiques intégrées et nouvelles thérapies pour les maladies rares (INTEGRARE), Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Généthon, Hémostase, Inflammation, Thrombose (HITH - U1176 Inserm - CHU Bicêtre), Université Paris-Sud - Paris 11 (UP11)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)-Institut National de la Santé et de la Recherche Médicale (INSERM), Inovarion [Paris], This work was supported by the E-RARE grant ANR- 15-RAR3-0008 (Agence Nationale de la Recherche, SMART-Haemo-Care to PJL & FM), a grant from the Association Françaises des Hémophiles (toODC), a proof-of-concept grant from Inserm Transfert (to ODC and PJL), and anERC-2013-CoG Consolidator Grant (grant agreement 617432, MoMAAV, to FM), ANR-15-RAR3-0008,SMART-HaemoCare,Small Antibody Fragment as Alternative Tools in Haemophilia Care(2015), European Project: 617432,EC:FP7:ERC,ERC-2013-CoG,MOMAAV(2014), Lenting, Peter, Small Antibody Fragment as Alternative Tools in Haemophilia Care - - SMART-HaemoCare2015 - ANR-15-RAR3-0008 - E-Rare-3 - VALID, Molecular signatures and Modulation of immunity to Adeno-Associated Virus vectors - MOMAAV - - EC:FP7:ERC2014-07-01 - 2019-06-30 - 617432 - VALID, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AP-HP Hôpital Bicêtre (Le Kremlin-Bicêtre)
Jazyk: angličtina
Rok vydání: 2020
Předmět:
Zdroj: EMBO Molecular Medicine
EMBO Molecular Medicine, Wiley Open Access, 2020, 12 (4), pp.e11298. ⟨10.15252/emmm.201911298⟩
EMBO Molecular Medicine, 2020, 12 (4), pp.e11298. ⟨10.15252/emmm.201911298⟩
EMBO Molecular Medicine, Vol 12, Iss 4, Pp n/a-n/a (2020)
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.201911298⟩
Popis: 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.
This study presents a novel therapeutic approach for hemophilia A and B, with and without inhibitors. By using single‐domain antibodies targeting the anticoagulant antithrombin, a sustained correction of the in vivo bleeding phenotype was achieved following protein or AAV8‐based gene therapy.
Databáze: OpenAIRE
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