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- Title
In silico and in vitro immunogenicity assessment of B‐domain‐modified recombinant factor VIII molecules.
- Authors
Bartholdy, C.; Reedtz‐Runge, S. L.; Wang, J.; Hjerrild Zeuthen, L.; Gruhler, A.; Gudme, C. N.; Lamberth, K.
- Abstract
Introduction: B‐domain modification can improve production of recombinant factor VIII (rFVIII) proteins. However, the engineered junction results in non‐native peptide sequences with the potential to elicit immune responses via major histocompatibility complex class‐II (MHC‐II)‐binding and CD4+ T cell activation. Aim: Assess the immunogenic potential of B‐domain junction peptides of turoctocog alfa and other B‐domain‐modified rFVIII proteins using in silico and in vitro immunogenicity assessment techniques. Methods: Peptides with amino acid sequences identical to the B‐domain junction of turoctocog alfa, simoctocog alfa and moroctocog alfa were evaluated by in silico peptide‐MHC‐II binding prediction, in vitro peptide‐MHC‐II‐binding measurement and in vitro T cell‐activation assays. Moreover, turoctocog alfa was assessed for peptide presentation on dendritic cells (DCs) using MHC‐associated peptide proteomics. Results: In silico analysis predicted virtually no neo‐epitopes in the B‐domain junction for turoctocog alfa, whereas some were predicted for simoctocog alfa and moroctocog alfa. Turoctocog alfa and moroctocog alfa peptides showed minimal capacity to bind high‐frequency MHC‐II molecules in vitro, whereas simoctocog alfa peptide demonstrated some degree of binding to approximately half of the MHC‐II molecules tested. In line with this, no B‐domain peptides from turoctocog alfa were found to be presented on MHC‐II complexes on DCs. B‐domain junction peptides from all 3 compounds induced T cell responses in only a few percentages of donors. Conclusion: All 3 junction peptides were found to have a low immunogenicity potential, suggesting that modification of the B‐domain does not constitute an increased immunogenicity risk for any of the products examined.
- Subjects
BLOOD coagulation factor VIII; HEMOPHILIA; IMMUNOGENETICS; PEPTIDES; DENDRITIC cells; T cells; IMMUNE response
- Publication
Haemophilia, 2018, Vol 24, Issue 5, pe354
- ISSN
1351-8216
- Publication type
Article
- DOI
10.1111/hae.13555