A factor XIa-activatable hirudin-albumin fusion protein reduces thrombosis in mice without promoting blood loss.

摘要: Hirudin is a potent thrombin inhibitor but its antithrombotic properties are offset by bleeding side-effects. Because hirudin’s N-terminus must engage thrombin’s active site for effective inhibition, fusing cleavable peptide at this may improve risk/benefit ratio as therapeutic agent. Previously we engineered plasmin cleavage (C) between human serum albumin (HSA) and hirudin variant 3 (HV3) in fusion protein HSACHV3. coagulation factor XI (FXI) more involved thrombosis than hemostasis, hypothesized that making HV3 activity FXIa-dependent would also HV3’s potential profile. We combined half-life extension of with positioning an FXIa N-terminal to HV3, assessed vitro vivo novel protein. EPR was employed. Fusion EPR-HV3HSA not HSAEPR-HV3 activated vitro. FVIIa, FXa, FXIIa, or failed activate EPR-HV3HSA. FXIa-cleavable reduced the time occlusion ferric chloride-treated murine arteries fibrin deposition endotoxemia; noncleavable mycHV3HSA without effect. elicited less blood loss constitutively HV3HSA liver laceration tail transection extended same extent. partially citrated plasma greater extent Releasing block using way limit side-effects, instability exposed blocking rendered it useful previously described plasmin-activatable