Journal article
Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity
Journal of thrombosis and haemostasis, Vol.13(11), pp.1989-1998
11/2015
DOI: 10.1111/jth.13141
PMID: 26362483
Abstract
Summary
Background
Vatreptacog alfa, a recombinant human factor VIIa (rFVIIa) analog developed to improve the treatment of bleeds in hemophilia patients with inhibitors, differs from native FVIIa by three amino acid substitutions. In a randomized, double‐blind, crossover, confirmatory phase III trial (adept™2), 8/72 (11%) hemophilia A or B patients with inhibitors treated for acute bleeds developed anti‐drug antibodies (ADAs) to vatreptacog alfa.
Objectives
To characterize the formation of anti‐vatreptacog alfa ADAs in hemophilia patients with inhibitors.
Methods/patients
This was a post hoc analysis of adept™2. Immunoglobulin isotype determination, specificity analysis of rFVIIa cross‐reactive antibodies, epitope mapping of rFVIIa single mutant analogs and pharmacokinetic (PK) profiling were performed to characterize the ADAs.
Results
Immunoglobulin isotyping indicated that the ADAs were of the immunoglobulin G subtype. In epitope mapping, none of the rFVIIa single mutant analogs (V158D, E296V or M298Q) contained the complete antibody epitope, confirming that the antibodies were specific for vatreptacog alfa. In two patients, for whom PK profiling was performed both before and after the development of ADAs, vatreptacog alfa showed a prolonged elimination phase following ADA development. During the follow‐up evaluation, the rFVIIa cross‐reactivity disappeared after the last vatreptacog alfa exposure, despite continued exposure to rFVIIa as part of standard care.
Conclusions
Results from the vatreptacog alfa phase III trial demonstrate that the specific changes made, albeit relatively small, to the FVIIa molecule alter its clinical immunogenicity.
Details
- Title: Subtitle
- Changes in the amino acid sequence of the recombinant human factor VIIa analog, vatreptacog alfa, are associated with clinical immunogenicity
- Creators
- J. N Mahlangu - University of the Witwatersrand and National Health Laboratory ServiceK. N Weldingh - Novo Nordisk A/SS. R Lentz - University of Iowa Carver College of MedicineS Kaicker - Maimonides Medical CentreF. A Karim - National Blood CentreT Matsushita - Nagoya University HospitalM Recht - Oregon Health and Science UniversityW Tomczak - Medical University of LublinJ Windyga - Institute of Hematology and Transfusion MedicineS Ehrenforth - Novo Nordisk A/SK Knobe - Novo Nordisk A/SAnsgar WeltermannErich PaulaMonica CerqueiraSilva Zupancic‐SalekOlga KatsarouMarina EconomouLaszlo NemesZoltan BodaElena SantagostinoGiuseppe TagarielloHideji HanabusaKatsuyuki FukutakeMidori ShimaMargit SerbanI ElezovicAleksandar SavicMing ShenAmpaiwan ChuansumritPantep AngchaisuksiriKaan KavakliIlgen SasmazBella MadanPaul GiangrandeChristine KemptonGuy YoungDoris QuonAfshin AmeriPhilip KuriakoseDana ObzutMichael WangAdept 2 InvestigatorsIdith Ortiz
- Resource Type
- Journal article
- Publication Details
- Journal of thrombosis and haemostasis, Vol.13(11), pp.1989-1998
- DOI
- 10.1111/jth.13141
- PMID
- 26362483
- NLM abbreviation
- J Thromb Haemost
- ISSN
- 1538-7933
- eISSN
- 1538-7836
- Number of pages
- 10
- Grant note
- Novo Nordisk
- Language
- English
- Date published
- 11/2015
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984094319902771
Metrics
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