Prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures during FVIII inhibitor eradication.
Journal
Blood advances
ISSN: 2473-9537
Titre abrégé: Blood Adv
Pays: United States
ID NLM: 101698425
Informations de publication
Date de publication:
09 05 2023
09 05 2023
Historique:
accepted:
24
08
2022
received:
08
02
2022
medline:
1
5
2023
pubmed:
9
9
2022
entrez:
8
9
2022
Statut:
ppublish
Résumé
Factor VIII (FVIII) inhibitor formation is a major clinical concern during replacement therapy in patients with hemophilia A. Immune tolerance induction (ITI) is the only therapeutic approach to attempt inhibitor eradication and establishment of long-term immune tolerance to FVIII. Hemophilia Inhibitor Previously Untreated Patient (PUP) Study (HIPS) was a prospective clinical trial to investigate changes in the immune system of PUPs with severe hemophilia A. Five patients who developed persistent FVIII inhibitors during HIPS entered an ITI extension arm (HIPS-ITI). During HIPS-ITI, inhibitor patients received ITI with the same FVIII product (a single source of recombinant, human full-length FVIII) used in HIPS until successful tolerance, declared failure, or a maximum of 2 years after HIPS-ITI enrollment, whichever came first. Blood samples and clinical data were collected monthly. Longitudinal FVIII-binding antibody signatures, associated binding specificities, and apparent affinities were determined for each patient at each sampling time point. ITI was successful or partially successful in 2 patients and failed in 3. Both groups presented with distinct FVIII-specific antibody signatures. ITI success required the disappearance of FVIII inhibitors, which was associated with the eradication or sustained titer minimization of high-affinity FVIII-specific antibodies, particularly of the immunoglobulin G1 (IgG1) and IgG4 subclasses. In contrast, ITI failure, as reflected by FVIII inhibitor persistence, was associated with persistent high-affinity FVIII-specific antibodies. Interestingly, 1 patient with partial ITI success and 1 patient with ITI failure developed apparent oligoreactive FVIII-binding antibodies during ITI. The explanation of the true nature of these antibodies requires more comprehensive follow-ups in future studies. This trial was registered at www.clinicaltrials.gov as #NCT01652027.
Identifiants
pubmed: 36074992
pii: 486551
doi: 10.1182/bloodadvances.2022007267
pmc: PMC10165197
doi:
Substances chimiques
Factor VIII
9001-27-8
Hemostatics
0
Immunoglobulin G
0
Banques de données
ClinicalTrials.gov
['NCT01652027']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1831-1848Informations de copyright
© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.
Références
Immunol Rev. 2003 Aug;194:8-18
pubmed: 12846803
Haemophilia. 2012 Jan;18(1):e18-20
pubmed: 21951822
Haemophilia. 2010 May;16(102):25-34
pubmed: 20536983
Blood Adv. 2022 Feb 8;6(3):946-958
pubmed: 34847225
Eur J Haematol. 2012 May;88(5):371-9
pubmed: 22260405
Semin Hematol. 2004 Jan;41(1 Suppl 1):82-8
pubmed: 14872427
J Autoimmun. 2001 Mar;16(2):163-72
pubmed: 11247642
Transfus Apher Sci. 2019 Oct;58(5):578-589
pubmed: 31447396
Immunity. 2017 Dec 19;47(6):1142-1153.e4
pubmed: 29262350
J Thromb Haemost. 2007 Nov;5(11):2306-8
pubmed: 17958750
Immunol Rev. 2021 Sep;303(1):138-153
pubmed: 34337772
Immunity. 2020 Dec 15;53(6):1230-1244.e5
pubmed: 33096040
Blood. 2005 Nov 15;106(10):3415-22
pubmed: 16091456
Haemophilia. 2019 Jan;25(1):33-44
pubmed: 30427582
Nat Immunol. 2007 Apr;8(4):419-29
pubmed: 17322888
Adv Immunol. 2020;146:57-107
pubmed: 32327153
Haemophilia. 2022 Jan;28(1):55-64
pubmed: 34727394
FEBS J. 2010 Jul;277(14):3039-50
pubmed: 20546303
J Exp Med. 2004 May 17;199(10):1401-8
pubmed: 15148338
Blood. 2012 Feb 9;119(6):1335-44
pubmed: 22101900
Haemophilia. 2010 May;16(102):66-70
pubmed: 19298384
J Clin Invest. 1994 Oct;94(4):1496-505
pubmed: 7523452
J Immunol. 2004 May 15;172(10):5900-7
pubmed: 15128770
J Biol Chem. 2006 Jan 6;281(1):439-46
pubmed: 16246843
J Immunol Methods. 2000 Jul 31;241(1-2):1-10
pubmed: 10915844
J Thromb Haemost. 2009 Dec;7(12):2006-2015
pubmed: 19817985
Br J Haematol. 2018 Feb;180(4):501-510
pubmed: 29270992
Haemophilia. 1998 Jan;4(1):68
pubmed: 9873872
Trends Immunol. 2003 Feb;24(2):53-4
pubmed: 12547498
Nat Rev Immunol. 2015 Mar;15(3):160-71
pubmed: 25698678
Trends Mol Med. 2016 Mar;22(3):200-213
pubmed: 26875449
Expert Rev Hematol. 2019 May;12(5):335-344
pubmed: 30951401
Blood. 2009 Mar 12;113(11):2587-94
pubmed: 19144987
Blood Rev. 2018 Jul;32(4):326-338
pubmed: 29482894
Haemophilia. 2018 Jul;24(4):570-577
pubmed: 29901839
J Thromb Haemost. 2011 Oct;9(10):1948-58
pubmed: 21838755
Nat Immunol. 2014 Jul;15(7):631-7
pubmed: 24880458
Immunity. 2014 Dec 18;41(6):1040-51
pubmed: 25484301
Haemophilia. 2003 Jul;9(4):418-35
pubmed: 12828678
Trends Immunol. 2004 Apr;25(4):174-9
pubmed: 15039043
N Engl J Med. 2016 May 26;374(21):2054-64
pubmed: 27223147
Blood. 2012 Mar 22;119(12):2922-34
pubmed: 22282501
Cells. 2021 Jun 15;10(6):
pubmed: 34203839
Front Immunol. 2020 Jan 10;10:2991
pubmed: 31998296
Nat Immunol. 2011 Dec 25;13(2):170-80
pubmed: 22197976
J Biol Chem. 2014 Jun 20;289(25):17767-79
pubmed: 24802758
Haemophilia. 2018 Mar;24(2):186-197
pubmed: 29446525
Arch Biochem Biophys. 1991 Jan;284(1):78-83
pubmed: 1846518
Br J Haematol. 2013 Jan;160(2):153-70
pubmed: 23157203
N Engl J Med. 2013 Jan 17;368(3):231-9
pubmed: 23323899
Haemophilia. 2012 May;18(3):e260-5
pubmed: 22250850
J Immunol. 2013 Aug 1;191(3):993-9
pubmed: 23873158
Haemophilia. 2018 Apr;24 Suppl 3:3-14
pubmed: 29543371
Thromb Haemost. 1995 Feb;73(2):247-51
pubmed: 7792738
J Intern Med. 2015 Jan;277(1):1-15
pubmed: 25169114
Haemophilia. 2015 Sep;21(5):559-67
pubmed: 26032231
Haemophilia. 2016 Sep;22(5):657-66
pubmed: 27562315
Crit Rev Immunol. 2018;38(2):145-158
pubmed: 29887727
Blood. 2017 Mar 9;129(10):1245-1250
pubmed: 28034891
Haemophilia. 2011 Mar;17(2):282-7
pubmed: 21070501
Thromb Haemost. 2012 Jun;107(6):1072-82
pubmed: 22476554
Br J Haematol. 2007 Jan;136(1):12-25
pubmed: 17222196
Blood. 2015 Feb 12;125(7):1180-8
pubmed: 25515962
Free Radic Biol Med. 1988;4(3):185-98
pubmed: 2833431
Antioxid Redox Signal. 2008 Jun;10(6):1089-100
pubmed: 18315494
Immunity. 2018 Jul 17;49(1):120-133.e9
pubmed: 30005826
Trends Immunol. 2019 Apr;40(4):345-357
pubmed: 30846256
N Engl J Med. 2009 Apr 16;360(16):1618-27
pubmed: 19369668
Nat Immunol. 2000 Jul;1(1):31-6
pubmed: 10881171
Eur J Immunol. 1998 Jul;28(7):2108-14
pubmed: 9692879
Blood Adv. 2020 Nov 24;4(22):5785-5796
pubmed: 33232473
J Biol Chem. 2007 Sep 14;282(37):26696-26706
pubmed: 17636257
Blood. 2013 Feb 7;121(6):1039-48
pubmed: 23243272
Immunol Rev. 2019 Mar;288(1):128-135
pubmed: 30874357
Thromb Diath Haemorrh. 1975 Nov 15;34(2):612
pubmed: 1198543
Haemophilia. 2000 Jul;6 Suppl 1:38-40
pubmed: 10982266
Haemophilia. 2002 May;8(3):280-7
pubmed: 12010424
N Engl J Med. 2017 Aug 31;377(9):809-818
pubmed: 28691557
Biomed J. 2019 Aug;42(4):233-242
pubmed: 31627865
N Engl J Med. 1993 Feb 18;328(7):453-9
pubmed: 8421474
Cell Immunol. 2018 Mar;325:64-68
pubmed: 29395036
N Engl J Med. 2001 Sep 6;345(10):747-55
pubmed: 11547745
J Clin Invest. 1996 Mar 15;97(6):1382-8
pubmed: 8617869