Factor IX Variants with Clotting Activity in Absence of Their Cofactor and/or With Increased F.IX Clotting Activity and Their Use for Treating Bleeding Disorders

摘要

The present invention relates to variants of factor IX (F.IX) or activated factor IX (F.IXa), wherein the variant is characterized in that it has clotting activity in absence of its cofactor. The present invention furthermore relates to variants of factor IX (F.IX) or activated factor IX (F.IXa), wherein the variant is characterized in that it has increased F.IX clotting activity compared to wildtype. The present invention furthermore relates to the use of these variants for the treatment and/or prophylaxis of bleeding disorders, in particular hemophilia A and/or hemophilia B or hemophilia caused or complicated by inhibitory antibodies to F.VIII. The present invention also relates to further variants of factor IX (F.IX) which have desired properties and can, thus be tailored for respective specific therapeutic applications.

主权项

1. A variant of factor IX (F.IX) or activated factor IX (F.IXa), which is characterized in that it has clotting activity in an absence of its cofactor,
wherein the cofactor is factor VIII (F.VIII) or activated factor VIII (F.VIIIa), and wherein said variant factor IX or activated factor IX comprises at least one amino acid substitution in position 265 in combination with amino acid substitution V181I and/or I383V, said variant factor IX or activated factor IX further comprising amino acid substitution(s) in position(s) in one or more selected from the group of 6, 11, 25, 44, 54, 72, 75, 78, 86, 89, 102, 105, 113, 119, 122, 125, 135, 139, 154, 159, 185, 195, 196, 211, 219, 222, 224, 236, 243, 251, 260, 262, 263, 268, 289, 299, 302, 304, 310, 319, 330, 334, 336, 338, 366, 368, 376, 383, 386, 391, 392, 394, 399 and/or a modification of the 99-loop.