A recombinant, chimeric enzyme with a novel mechanism of action leading to greater potency and selectivity than tissue-type plasminogen activator.

Robinson, Jan; Browne, Michael; Carey, J.E.; Chamberlain, PD; Chapman, C.G.; Cronk, David; Dodd, Ian B.; Entwisle, Claire; Esmail, A.F.; Kalindjian, S. Barret

doi:10.1161/01.cir.86.2.548

Cited by 13 publications

(2 citation statements)

References 27 publications

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“…we have shown in vitro (11,12) and in vivo (Fig.a) that recombinant plasminogen c( ^)' chain/t-PA ccB)) chain hybrid plasminogen activators are inhibited rapidly by plasma protease inhibitors, in particular by alpha2-antiplasmin (11, lz). The precise mechanism of inhibition is not clear, but it is likely to be similar to the mechanism of plasmin inhibiton by alpha2-antiplasmin, that is a rapid, primary, reversible interaction with the lysine-binding sites on the kringle domains of the plasmin A chain, followed by a secondary slower, covalent interaction with the active site of the B chain (25).…”

Section: Discussionmentioning

confidence: 93%

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The Use of Active Centre Acylation to Control the Pharmacokinetic Profile of a Recombinant Chimaeric Plasminogen Activator

et al. 1993

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SummaryRecombinant hybrid plasminogen activators consisting of the “A” chain of plasminogen linked to the “B” chain of t-PA that are inhibited rapidly by plasma protease inhibitors have recently been described (Robinson et al. Circulation 1992; 86: 548-552). We have now shown that following bolus administration of native hybrid to guinea pigs, fibrinolytic activity was cleared rapidly from the circulation. Active centre acylation appeared to protect the hybrid from inhibition and allowed material to circulate as potentially active species for prolonged periods. Clearance rates of a range of acyl derivatives of the hybrid were 7-35-fold slower than for native hybrid and 20-100-fold slower than for t-PA. Clearance rates were influenced markedly by deacylation rate, such that clearance half-life correlated well with deacylation halflife. We have thus shown that it is feasible to control the pharmacokinetic profile of a recombinant hybrid plasminogen activator over a wide range by selection of an appropriate acyl group for attachment to the active site. Such control is not possible with plasminogen activators that are cleared predominantly by mechanisms other than inhibition.

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Section: Discussionmentioning

confidence: 93%

“…Single and two chain forms of the recombinant hybrid plasminogen activator glul-cys5a1 plasminogen/set262-pro527 t-PA were produced as described previously (11,13). rt-PA was obtained from the recombinant Bowes melanoma cell line TRBM6 as described previously (14).…”

Section: Methodsmentioning

confidence: 99%