Abstract
We have created a number of new recombinant plasminogen activators based on tissue plasminogen activator (t-PA) including: (1) a t-PA mutant with a duplicated finger (F) domain, (2) a hybrid containing a Factor XII growth factor (G) domain in the place of the native G domain and (3) a hybrid containing the kringle (K) domain from urokinase inserted between the G and K1 domains of t-PA. We have also made two hybrids containing the five K domains from plasminogen: (1) linked to the urokinase B-chain or (2) linked to t-PA K2 and B-chain. The latter molecule contains six K domains. All the molecules were expressed in HeLa cells, purified and the rates of plasma clearance examined in a guinea pig model. Our results show that a wide range of strategies may be used to retard plasma clearance of plasminogen activators. Molecules containing the five plasminogen K domains were by far the most slowly cleared, up to approximately 100-fold more slowly than t-PA itself.
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