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Pharmacokinetic and thrombolytic properties of chimeric plasminogen
activators consisting of a single-chain Fv fragment of a fibrin- specific
antibody fused to single-chain urokinase
P Holvoet, Y Laroche, JM Stassen, HR Lijnen, B Van Hoef, F De Cock, A Van Houtven, Y Gansemans, G Matthyssens and D Collen
Center for Thrombosis and Vascular Research, University of Leuven, Belgium.
The pharmacokinetic and thrombolytic properties were determined of two
recombinant single-chain chimeric plasminogen activators (PA) consisting of
u-PA-33k, a low-molecular weight derivative of single- chain urokinase-type
PA (scu-PA) comprising amino acids Ala132 through Leu411, and of either a
single-chain variable region fragment (Fv) derived from the fibrin fragment
D-dimer-specific monoclonal antibody MA-15C5 (K12G0S32) or of the
deglycosylated single-chain Fv fragment obtained by substitution of Asn88
with Glu (K12G2S32). Following bolus injection in hamsters, clearances of
recombinant scu-PA (rscu-PA) and of K12G0S32 were similar. In contrast,
clearance of K12G2S32 was fourfold slower than that of rscu-PA. The
thrombolytic potency (percent lysis per u-PA administered in milligrams per
kilogram body weight) and specific thrombolytic activity (percent lysis per
microgram per milliliter steady-state plasma u-PA antigen level) of these
compounds were studied in hamsters with an experimental pulmonary embolus
consisting of a human plasma clot injected via the jugular vein. The doses
of K12G0S32 and K12G2S32 required to obtain maximal rate of clot lysis were
sixfold and 11-fold lower than that of rscu-PA. The steady- state
u-PA-related plasma antigen levels of K12G0S32 and K12G2S32 required to
obtain maximal rate of clot lysis were 10-fold and fourfold lower than that
of rscu-PA. Thus, targeting of K12G0S32 to the clot surface by means of its
glycosylated Fv fragment results in a 10-fold increase of its specific
thrombolytic activity and sixfold increase of its thrombolytic potency as
compared with those of rscu-PA. Targeting of K12G2S32 to the clot surface
by means of its deglycosylated Fv fragment results in only a twofold
increase of its thrombolytic activity. However, its fourfold slower
clearance, combined with its twofold higher specific thrombolytic activity,
results in an 11-fold increase of its thrombolytic potency over that of
rscu-PA. These findings indicate that the thrombolytic potency of chimeric
antibody- targeted PA may be increased by increasing the specific
thrombolytic activity, reducing the clearance, or both.
Volume 81,
Issue 3,
pp. 696-703,
02/01/1993
Copyright © 1993 by The American Society of Hematology
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