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The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development

Reipert, B M ; Gangadharan, B ; Hofbauer, C J ; Berg, V ; Schweiger, H ; Bowen, J ; Blatny, J ; Fijnvandraat, K ; Mullins, E S and Klintman, J LU , et al. (2020) In Blood Advances 4(22). p.5785-5796
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... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
in
Blood Advances
volume
4
issue
22
pages
12 pages
publisher
American Society of Hematology
external identifiers
  • scopus:85097235672
  • pmid:33232473
ISSN
2473-9529
DOI
10.1182/bloodadvances.2020002731
language
English
LU publication?
yes
additional info
© 2020 by The American Society of Hematology. B.M.R. and B.G. contributed equally to this study.
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bcb47b21-370a-4509-968b-9114eecfea73
date added to LUP
2020-11-26 15:08:58
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2021-01-06 04:15:24
@article{bcb47b21-370a-4509-968b-9114eecfea73,
  abstract     = {<p>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.</p>},
  author       = {Reipert, B M and Gangadharan, B and Hofbauer, C J and Berg, V and Schweiger, H and Bowen, J and Blatny, J and Fijnvandraat, K and Mullins, E S and Klintman, J and Male, C and McGuinn, C and Meeks, S L and Radulescu, V C and Ragni, M V and Recht, M and Shapiro, A D and Staber, J M and Yaish, H M and Santagostino, E and Brown, D L},
  issn         = {2473-9529},
  language     = {eng},
  month        = {11},
  number       = {22},
  pages        = {5785--5796},
  publisher    = {American Society of Hematology},
  series       = {Blood Advances},
  title        = {The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development},
  url          = {http://dx.doi.org/10.1182/bloodadvances.2020002731},
  doi          = {10.1182/bloodadvances.2020002731},
  volume       = {4},
  year         = {2020},
}