Thromb Haemost 2007; 98(04): 721-725
DOI: 10.1160/TH07-05-0349
Blood Coagulation, Fibrinolysis and Cellular Haemostasis
Schattauer GmbH

Immunogenicity of novel recombinant human activated factor VII analogues on factor VII neonatally-tolerized rats

Christian Sommer
1   Biopharm Toxicology and Safety Pharmacology, Novo Nordisk A/S, Måløv, Denmark
,
Peer Norbert Jørgensen
2   Antibody Analysis, Novo Nordisk A/S, Måløv, Denmark
,
Jes Thorn Clausen
3   LAB Scantox, Ejby, Denmark
,
Zaki Salanti
4   Antibody and Cell Technology, Novo Nordisk A/S, Måløv, Denmark
,
Lisbeth Bjerring Jensen
2   Antibody Analysis, Novo Nordisk A/S, Måløv, Denmark
› Institutsangaben
Financial support: This study was supported by Novo Nordisk A/S, Bagsvaerd, Denmark.
Weitere Informationen

Publikationsverlauf

Received 14. Mai 2007

Accepted after revision 13. Juni 2007

Publikationsdatum:
01. Dezember 2017 (online)

Summary

Recombinant activated factorVII (rFVIIa; NovoSeven®) has been widely used to treat bleeding in patients with haemophilia with inhibitors. To increase the intrinsic activity, analogues of rFVIIa (rFVIIaQ, rFVIIaDVQ, and rFVIIaDVQA) with altered amino acid sequence at or near the active centre have been developed. The immunogenicity of these analogues was tested in a rat immune tolerance model.Neonatal rats received rFVIIa intraperitoneally on post-natal Day 1 and were subsequently challenged with rFVIIa in Freunds Incomplete Adjuvant subcutaneously on Days 10 and 24. Rats were tested for tolerance on Day 32; the tolerant cohort and a parallel cohort of untreated control rats were challenged with rFVIIa, rFVIIaQ, rFVIIaDVQ, or rFVIIaDVQA on Days 46 and 76. Immune responses determined by enzymelinked immunosorbent assay (ELISA) on Day 84 showed no statistically significant difference between the responses in the four control cohorts. Immune responses were higher in the control than in the tolerant cohort. Compared with rFVIIa (4/16), there was no difference in the proportion of rats that broke tolerance following challenge with rFVIIaDVQ (3/16) and rFVIIaDVQA (7/16), whereas a statistically significant greater proportion broke tolerance after challenge with rFVIIaQ (11/16). Therefore, in this model rFVIIaDVQ or rFVIIa DVQA were not more immunogenic than rFVIIa.

 
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