Single-domain antibodies targeting antithrombin reduce bleeding in hemophilic mice with or without inhibitors.
anticoagulation
coagulation
gene therapy
hemophilia
single-domain antibodies
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 04 2020
07 04 2020
Historique:
received:
14
08
2019
revised:
14
02
2020
accepted:
18
02
2020
pubmed:
12
3
2020
medline:
29
7
2021
entrez:
12
3
2020
Statut:
ppublish
Résumé
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.
Identifiants
pubmed: 32159286
doi: 10.15252/emmm.201911298
pmc: PMC7136963
doi:
Substances chimiques
Anticoagulants
0
Antithrombins
0
Single-Domain Antibodies
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e11298Subventions
Organisme : Agence Nationale de la Recherche (ANR)
ID : ANR-15-RAR3-0008
Pays : International
Organisme : EC|H2020|H2020 Priority Excellent Science|H2020 European Research Council (ERC)
ID : 617432
Pays : International
Organisme : Association Francaises des Hemophiles
ID : 2018-2020
Pays : International
Organisme : Inserm-Transfert
ID : CoPoC-2016
Pays : International
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2020 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Nucleic Acids Res. 1991 Aug 11;19(15):4133-7
pubmed: 1908075
J Thromb Haemost. 2014 Nov;12(11):1861-73
pubmed: 25224783
Biochemistry. 1991 Oct 29;30(43):10363-70
pubmed: 1931959
Mol Immunol. 1997 Nov-Dec;34(16-17):1121-31
pubmed: 9566760
Blood. 2014 Nov 27;124(23):3398-408
pubmed: 25253771
Blood. 2019 Jan 31;133(5):399-406
pubmed: 30559263
Protein Eng Des Sel. 2008 Jan;21(1):1-10
pubmed: 18073223
Nat Genet. 1995 May;10(1):119-21
pubmed: 7647782
Physiol Rev. 2013 Jan;93(1):327-58
pubmed: 23303912
EMBO Mol Med. 2020 Apr 7;12(4):e11298
pubmed: 32159286
Blood. 1997 Nov 15;90(10):3962-6
pubmed: 9354664
Nat Med. 2015 May;21(5):492-7
pubmed: 25849132
Prog Mol Biol Transl Sci. 2012;105:151-209
pubmed: 22137432
Int J Hematol. 2020 Jan;111(1):42-50
pubmed: 30302740
Blood. 2005 Mar 15;105(6):2316-23
pubmed: 15550487
Blood. 2017 Apr 27;129(17):2368-2374
pubmed: 28183693
World J Exp Med. 2012 Apr 20;2(2):30-6
pubmed: 24520531
Blood. 2009 Mar 26;113(13):2878-87
pubmed: 19008457
Arterioscler Thromb Vasc Biol. 2017 Sep;37(9):1736-1740
pubmed: 28642239
Mol Ther Methods Clin Dev. 2016 Dec 07;3:16083
pubmed: 27933310
Gene Ther. 2010 Apr;17(4):503-10
pubmed: 19956269
Haemophilia. 2004 Jul;10(4):319-26
pubmed: 15230944
Nanomedicine (Lond). 2013 Jun;8(6):1013-26
pubmed: 23730699
Semin Thromb Hemost. 2017 Sep;43(6):581-590
pubmed: 28750425
Br J Haematol. 2007 Aug;138(4):541-4
pubmed: 17659055
N Engl J Med. 2017 Aug 31;377(9):819-828
pubmed: 28691885
N Engl J Med. 2016 May 26;374(21):2054-64
pubmed: 27223147
J Biomed Nanotechnol. 2018 Jan 1;14(1):1-19
pubmed: 29463363
Mol Ther Methods Clin Dev. 2018 Nov 17;12:85-101
pubmed: 30581888
N Engl J Med. 2013 Jan 17;368(3):231-9
pubmed: 23323899
Blood. 2018 Mar 1;131(9):1022-1031
pubmed: 29246900
Drug Discov Today. 2016 Jul;21(7):1076-113
pubmed: 27080147
J Thromb Haemost. 2005 Dec;3(12):2730-7
pubmed: 16359510
Nat Biotechnol. 2016 Jul;34(7):746-51
pubmed: 27272383
Haemophilia. 2016 Jul;22(4):625-31
pubmed: 26936336
Lancet. 2003 May 24;361(9371):1801-9
pubmed: 12781551
Blood. 2003 Jul 15;102(2):480-8
pubmed: 12637328
Anal Biochem. 2013 Jul 1;438(1):82-9
pubmed: 23541519
N Engl J Med. 2011 Dec 22;365(25):2357-65
pubmed: 22149959
Nucleic Acids Res. 2006 Jan 12;34(1):322-33
pubmed: 16410612
Blood. 2013 Sep 12;122(11):1954-62
pubmed: 23926300
N Engl J Med. 2014 Nov 20;371(21):1994-2004
pubmed: 25409372
J Blood Med. 2018 Aug 22;9:135-140
pubmed: 30174468
Pathophysiol Haemost Thromb. 2002 Sep-Dec;32(5-6):249-53
pubmed: 13679651
Mol Ther Methods Clin Dev. 2016 Jul 20;3:16049
pubmed: 27722180
Hum Gene Ther. 2003 Sep 20;14(14):1297-305
pubmed: 14503965
N Engl J Med. 2017 Dec 7;377(23):2215-2227
pubmed: 29211678
Blood. 2018 Sep 13;132(11):1193-1197
pubmed: 30064978
J Clin Invest. 2003 May;111(9):1347-56
pubmed: 12727926
PLoS One. 2015 Feb 23;10(2):e0116878
pubmed: 25706993
N Engl J Med. 2017 Dec 28;377(26):2519-2530
pubmed: 29224506
Sci Transl Med. 2017 Nov 29;9(418):
pubmed: 29187643
FEBS Lett. 1997 Sep 15;414(3):521-6
pubmed: 9323027
Curr Opin Hematol. 2017 Sep;24(5):446-452
pubmed: 28632502