PMID- 8427962
OWN - NLM
STAT- MEDLINE
DCOM- 19930310
LR  - 20210216
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 81
IP  - 3
DP  - 1993 Feb 1
TI  - 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.
PG  - 696-703
AB  - 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.
FAU - Holvoet, P
AU  - Holvoet P
AD  - Center for Thrombosis and Vascular Research, University of Leuven, Belgium.
FAU - Laroche, Y
AU  - Laroche Y
FAU - Stassen, J M
AU  - Stassen JM
FAU - Lijnen, H R
AU  - Lijnen HR
FAU - Van Hoef, B
AU  - Van Hoef B
FAU - De Cock, F
AU  - De Cock F
FAU - Van Houtven, A
AU  - Van Houtven A
FAU - Gansemans, Y
AU  - Gansemans Y
FAU - Matthyssens, G
AU  - Matthyssens G
FAU - Collen, D
AU  - Collen D
LA  - eng
PT  - Journal Article
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Fibrinolytic Agents)
RN  - 0 (Macromolecular Substances)
RN  - 0 (Oligodeoxyribonucleotides)
RN  - 0 (Recombinant Fusion Proteins)
RN  - 0 (Recombinant Proteins)
RN  - 9001-31-4 (Fibrin)
RN  - 9007-49-2 (DNA)
RN  - EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)
SB  - IM
MH  - Amino Acid Sequence
MH  - Animals
MH  - Antibodies, Monoclonal/metabolism/therapeutic use
MH  - Base Sequence
MH  - Cell Line
MH  - Cricetinae
MH  - DNA/genetics/isolation & purification
MH  - Fibrin/*immunology
MH  - Fibrinolytic Agents/*pharmacokinetics/*therapeutic use
MH  - Humans
MH  - Insecta
MH  - Macromolecular Substances
MH  - Molecular Sequence Data
MH  - Molecular Weight
MH  - Mutagenesis, Site-Directed
MH  - Oligodeoxyribonucleotides
MH  - Pulmonary Embolism/*drug therapy
MH  - Rabbits
MH  - Recombinant Fusion Proteins/*pharmacokinetics/*therapeutic use
MH  - Recombinant Proteins/pharmacokinetics/therapeutic use
MH  - Urokinase-Type Plasminogen Activator/genetics/*pharmacokinetics/*pharmacology
EDAT- 1993/02/01 00:00
MHDA- 1993/02/01 00:01
CRDT- 1993/02/01 00:00
PHST- 1993/02/01 00:00 [pubmed]
PHST- 1993/02/01 00:01 [medline]
PHST- 1993/02/01 00:00 [entrez]
AID - S0006-4971(20)82066-7 [pii]
PST - ppublish
SO  - Blood. 1993 Feb 1;81(3):696-703.