Modified coagulation factors with prolonged in vivo half-life

摘要

The present invention relates to nucleic acid sequences coding for modified coagulation factors, preferably coagulation factor VIII, and their derivatives; recombinant expression vectors containing such nucleic acid sequences; host cells transformed with such recombinant expression vectors; and recombinant polypeptides and derivatives coded for by said nucleic acid sequences, whereby said recombinant polypeptides and derivatives have biological activities and prolonged in vivo half-lives compared to the unmodified wild-type proteins. The invention also relates to corresponding sequences that result in improved in vitro stability. The present invention further relates to processes for the manufacture of such recombinant proteins and their derivatives. The invention also relates to a transfer vector for use in human gene therapy, which comprises such nucleic acid sequences.

主权项

1. A modified factor VIII (FVIII) polypeptide, comprising a FVIII polypeptide having an N-terminal amino acid and a C-terminal amino acid, and a half-life enhancing polypeptide (HLEP) inserted within the B-domain between the N-terminal amino acid and the C-terminal amino acid of the FVIII polypeptide,
wherein the FVIII polypeptide is capable of being cleaved from the HLEP moiety during activation in vivo, wherein the modified FVIII polypeptide exhibits a prolonged half-life prior to activation during a bleeding event and a half-life substantially the same as that of an unmodified FVIII peptide following activation, and wherein the HLEP comprises albumin or an immunoglobulin constant region polypeptide.