Thrombolytic activity of BB-10153, a thrombin-activatable plasminogen.
BACKGROUND
BB-10153 is an engineered variant of human plasminogen, modified to be activated to plasmin by thrombin. Thrombin-activatable plasminogen was designed as a novel thrombolytic agent which would persist in the blood as a prodrug and be activated to plasmin only at fresh or forming thrombi by the thrombin that is tightly localized there. We previously described the construction of several thrombin-activatable plasminogens and their in vitro clot lysis activity.


OBJECTIVE
The current study was an examination of the thrombolytic properties of BB-10153 in vivo; comparison was made with tissue-type plasminogen activator (t-PA) in a femoral artery copper coil thrombosis model in the anesthetized dog and rabbit. Heparin was not coadministered so that the fundamental activity of the agents could be compared.


RESULTS
BB-10153, administered as an intravenous bolus of 5 mg kg(-1) in the dog and 10 mg kg(-1) in the rabbit, produced a comparable incidence of reperfusion to 3 mg kg(-1) t-PA. Reocclusion at these doses occurred in 4/4 dogs and 5/7 rabbits treated with t-PA and in 2/6 dogs and 0/10 rabbits treated with BB-10153. There was no reocclusion in three dogs dosed with 10 mg kg(-1) BB-10153. BB-10153 did not affect plasma alpha2-antiplasmin levels or the bleeding time, whereas 3 mg kg(-1) t-PA caused marked depletion of alpha2-antiplasmin and fibrinogen and increased the bleeding time. The plasma half-life of BB-10153 was 3-4 h.


CONCLUSIONS
The long half-life and thrombus-selective thrombolytic activity of BB-10153 might allow it to overcome the bleeding and reocclusion shortfalls in the performance of current thrombolytics.
Comer
M B
MB
British Biotech, Oxford, UK.
Cackett
K S
KS
Gladwell
S
S
Wood
L M
LM
Dawson
K M
KM
D000818:Animals; D001760:Bleeding Time; D004285:Dogs; D005340:Fibrinogen / Q000737:chemistry; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D008297:Male; D016297:Mutagenesis, Site-Directed; D010958:Plasminogen / Q000737:chemistry* / Q000494:pharmacology*; D010960:Plasminogen Activators / Q000737:chemistry; D011817:Rabbits; D012306:Risk; D012307:Risk Factors; D013917:Thrombin / Q000737:chemistry*; D013927:Thrombosis; D013997:Time Factors; D000979:alpha-2-Antiplasmin / Q000737:chemistry
C501338:BB-10153; D005343:Fibrinolytic Agents; D000979:alpha-2-Antiplasmin; D005340:Fibrinogen; D010958:Plasminogen; D010960:Plasminogen Activators; D013917:Thrombin