Journal article
The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development
Blood advances, Vol.4(22), pp.5785-5796
11/24/2020
DOI: 10.1182/bloodadvances.2020002731
PMID: 33232473
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.
•Development of FVIII inhibitors within the first 50 EDs to FVIII is associated with distinct antibody signatures.•Patients with persistent FVIII inhibitors develop unique signatures of FVIII-binding IgG1, followed by IgG3 and IgG4.
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Details
- Title: Subtitle
- The prospective Hemophilia Inhibitor PUP Study reveals distinct antibody signatures prior to FVIII inhibitor development
- Creators
- B Gangadharan - Drug Discovery Austria, Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, AustriaC.J Hofbauer - Drug Discovery Austria, Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, AustriaV Berg - Institute Krems Bioanalytics, IMC University of Applied Sciences Krems, Krems, AustriaH Schweiger - Institute Krems Bioanalytics, IMC University of Applied Sciences Krems, Krems, AustriaJ Bowen - Indiana Hemophilia and Thrombosis Center, Indianapolis, INJ Blatny - Department of Paediatric Haematology, University Hospital Brno, Masaryk University, Brno, Czech RepublicK Fijnvandraat - Pediatric Hematology, Amsterdam UMC, University of Amsterdam–Emma Children's Hospital, Department of Molecular Cellular Hemostasis, Sanquin Research, Amsterdam, The NetherlandsE.S Mullins - Division of Hematology, Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, University of Cincinnati, Cincinnati, OHJ Klintman - Clinical Coagulation Research Unit, Department of Translational Medicine, Lund University, Malmö, SwedenC Male - Department of Pediatrics, Medical University of Vienna, Vienna, AustriaC McGuinn - Comprehensive Center for Hemophilia and Coagulation Disorders, Weill Cornell Medicine, New York, NYS.L Meeks - Aflac Cancer and Blood Disorders Center, Emory University, Children's Healthcare of Atlanta, Atlanta, GAV.C Radulescu - Hemophilia Treatment Center, University of Kentucky, Lexington, KYM.V Ragni - Division Hematology/Oncology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PAM Recht - Hemophilia Center, Oregon Health & Science University, Portland, ORA.D Shapiro - Indiana Hemophilia and Thrombosis Center, Indianapolis, INJ.M Staber - Carver College of Medicine–Stead Family Department of Pediatrics, University of Iowa, Iowa City, IAH.M Yaish - University of Utah School of Medicine, Salt Lake City, UTE Santagostino - IRCCS Ca' Granda Foundation, Maggiore Hospital Policlinico, University of Milan, Milan, ItalyD.L Brown - University of Texas Health Science Center, Houston, TXB.M Reipert - Drug Discovery Austria, Baxalta Innovations GmbH, a member of the Takeda group of companies, Vienna, Austria
- Resource Type
- Journal article
- Publication Details
- Blood advances, Vol.4(22), pp.5785-5796
- Publisher
- Elsevier Inc
- DOI
- 10.1182/bloodadvances.2020002731
- PMID
- 33232473
- ISSN
- 2473-9529
- eISSN
- 2473-9537
- Language
- English
- Date published
- 11/24/2020
- Academic Unit
- Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Hematology/Oncology
- Record Identifier
- 9984070837602771
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