@article{46a61968fe4641d19b8018b893d06572,
title = "The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development",
abstract = "Preventing factor VIII (FVIII) inhibitors following replacement therapies with FVIII products in patients with hemophilia A remains an unmet medical need. Better understanding of the early events of evolving FVIII inhibitors is essential for risk identification and the design of novel strategies to prevent inhibitor development. The Hemophilia Inhibitor Previously Untreated Patients (PUPs) Study (HIPS; www.clinicaltrials.gov #NCT01652027) is the first prospective cohort study to evaluate comprehensive changes in the immune system during the first 50 exposure days (EDs) to FVIII in patients with severe hemophilia A. HIPS participants were enrolled prior to their first exposure to FVIII or blood products (“true PUPs”) and were evaluated for different immunological and clinical parameters at specified time points during their first 50 EDs to a single source of recombinant FVIII. Longitudinal antibody data resulting from this study indicate that there are 4 subgroups of patients expressing distinct signatures of FVIII-binding antibodies. Subgroup 1 did not develop any detectable FVIII-binding immunoglobulin G (IgG) antibodies. Subgroup 2 developed nonneutralizing, FVIII-binding IgG1 antibodies, but other FVIII-binding IgG subclasses were not observed. Subgroup 3 developed transient FVIII inhibitors associated with FVIII-binding IgG1 antibodies, similar to subgroup 2. Subgroup 4 developed persistent FVIII inhibitors associated with an initial development of high-affinity, FVIII-binding IgG1 antibodies, followed by IgG3 and IgG4 antibodies. Appearance of FVIII-binding IgG3 was always associated with persistent FVIII inhibitors and the subsequent development of FVIII-binding IgG4. Some of the antibody signatures identified in HIPS could serve as candidates for early biomarkers of FVIII inhibitor development.",
author = "Reipert, {B. M.} and B. Gangadharan and Hofbauer, {C. J.} and V. Berg and H. Schweiger and J. Bowen and J. Blatny and K. Fijnvandraat and Mullins, {E. S.} and J. Klintman and C. Male and C. McGuinn and Meeks, {S. L.} and Radulescu, {V. C.} and Ragni, {M. V.} and M. Recht and Shapiro, {A. D.} and Staber, {J. M.} and Yaish, {H. M.} and E. Santagostino and Brown, {D. L.}",
note = "Funding Information: Bioverat, Kedrion, Novo Nordisk, Pfizer, Shire/Takeda, and uniQure. A.D.S. received institutional research funding from Agios, Biomarin, Bioverativ, Daiichi Sankyo, Roche, and Bioverat, Glover Blood Therapeutics, Kendrion, Novartis, Novo Nordisk, OPKO, Octa-pharma, Pfizer, Prometic, Sangamo, and Takeda and consultant/ advisory board fees from Bioverativ, Roche, and Bioverat, Novo Nordisk, Prometic, Sangamo, and Shire/Takeda; no funding was personally accepted (all was paid to the Indiana Hemophilia & Thrombosis Center). J.M.S. received consultancy/advisory boards from Spark, Roche, and Bioverat, Novo Nordisk, Bayer, Takeda, and Sanofi. H.M.Y. received institutional research funding from Novo Nordisk, Takeda, Bayer, Agio, Genentics, and CSL and advisory/ consultancy board fees from Novo Nordisk, Takeda, Bayer, Gen-entics, and Octapharma. E.S. received advisory boards and/or Funding Information: The authors thank Keith Hoots and Donna DiMichele for their insights in the study design and analysis. They would also thank Fritz Scheiflinger (an employee of Baxalta Innovations at the time of the study), who supported the analytical part of the study, and Elizabeth Donnachie, who did the center qualification of the US clinical centers that participated in the study. The authors are grateful to Evelyn Lockhart Biomedical Communications (BMC) for support with virtual abstract design. HIPS is a collaborative clinical research study funded by Baxalta Innovations GmbH, a Takeda company, Vienna, Austria. Funding Information: HIPS is a collaborative clinical research study funded by Baxalta Innovations GmbH, a Takeda company, Vienna, Austria. Funding Information: Conflict-of-interest disclosure: B.M.R. was an employee of Baxalta Innovations at the time of the study but left after study completion. B.G. is an employee of Baxalta Innovations and holds Takeda stock options. C.J.H. was an employee of Baxalta Innovations at the time of the study but is now an employee of Takeda Pharmaceutical (Cambridge, MA) and holds Takeda stock options. V.B. and H.S. received institutional research funding from Baxalta Innovations. J. Bowen received research funding from the study sponsor, University of Texas Health Science Center (Houston, TX). J. Blatny has received consultation/speakers fees from Takeda, Novo Nordisk, Sobi, LFB, Roche, Pfizer, CSL Behring, and Octa-pharma. K.F. has received unrestricted institutional research grants from CSL Behring and Novo Nordisk and institutional consultancy fees from Grifols, Takeda, Novo Nordisk, and Roche. E.S.M. has received advisory board fees from Bayer and Takeda. C. Male has received institutional fees for study participation from Bayer, Bax-alta/Shire/Takeda, Biotest, CSL Behring, Novo Nordisk, and Sobi; an unrestricted institutional grant from Biotest and CSL Behring; and personal honoraria (consultancy, speaker, chair) from Bayer, CSL Behring, Novo Nordisk, and Roche. C. McGuinn received consultancy/advisory board fees from Roche, and Bioverat, Kend-rion, Octapharma, BPL. and Biomarin and institutional fees for study participation from Baxalta/Shire/Takeda, Pfizer/Spark, Novo Nordisk, Roche, and Bioverat/Roche, and Bioverativ/Sanofi. S.L.M. received consultancy/advisory board fees from Bayer, Baxalta/Shire/ Takeda, Bioverativ/Sanofi, CSL Behring, Roche, and Bioverat, Novo Nordisk, Octapharma, Pfizer, Sangamo, Spark/Roche, and Sobi. V.C.R. received institutional research funding and fees for study participation from Takeda, Pfizer, and Grifols. M.V.R. received research funding and advisory board fees from Alnylam, Biomarin, Bioverativ, Sangamo, and Spark. M.R. received institutional research funding from Bioverativ/Sanofi, Biomarin, Roche, and Bioverat, Novo Nordisk, Shire/Takeda, Spark/Roche, uniQure and consultancy/advisory board fees from Bioverativ/Sanofi, CSL Behring, Roche, and Publisher Copyright: {\textcopyright} 2020 by The American Society of Hematology",
year = "2020",
month = nov,
day = "24",
doi = "10.1182/bloodadvances.2020002731",
language = "English (US)",
volume = "4",
pages = "5785--5796",
journal = "Blood advances",
issn = "2473-9529",
publisher = "American Society of Hematology",
number = "22",
}