Proteolytic enzymes are involved in generation of a number of endogenous
angiogenesis inhibitors and it has been shown that urokinase-activated plasmin
can process plasminogen to release an angiogenesis inhibitor, K1-5 (protease-activated
kringles 1-5). However, this proteolytic protein (proteolytic K1-5) cannot be secreted
(exported) from cells and thus is limited in its application as a therapeutic.
The present inventor has now engineered a recombinant protein derived from plasminogen
which is folded correctly such that it can be secreted from cells in which it is
expressed. The inventor surprisingly found that in order to fold correctly such
that it can be secreted, the recombinant protein must comprise a secretory signal
peptide and a pre-activation peptide derived from plasminogen.