(Circulation. 2000;102:1766.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
Polyethylene Glycol–Derivatized Cysteine-Substitution Variants of Recombinant Staphylokinase for Single-Bolus Treatment of Acute Myocardial Infarction
From the Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute for Biotechnology, KU Leuven, Belgium (D.C., E.D., H.M., M.D.M., L.J.,Y.L.); and the Department of Cardiology, UZ Gasthuisberg (P.S., F.V.d.W.).
Correspondence to D. Collen, MD, PhD, Center for Transgene Technology and Gene Therapy, University of Leuven, Campus Gasthuisberg O & N, Herestraat 49, B-3000 Leuven, Belgium. E-mail desire.collen{at}med.kuleuven.ac.be
Background—Thrombolytic therapy of acute myocardial infarction (AMI) is evolving toward bolus administration. Derivatization of proteins with polyethylene glycol (PEG) may reduce their clearance.
Methods and Results—A staphylokinase (SakSTAR) variant with 12
amino acid substitutions to reduce its antigenicity, SakSTAR (K35A,
E65Q, K74R, E80A, D82A, T90A, E99D, T101S, E108A, K109A, K130T, K135R),
and with Ser in position 3 mutated into Cys (code SY161), was
derivatized with maleimide-PEG with Mr of
5000 (P5), 10 000 (P10), or 20 000 (P20). The PEGylated variants
recognized only one third of the antibodies elicited with wild-type
SakSTAR in AMI patients. In experimental animals, plasma clearances
were reduced 2.5- to 5-fold with P5, 5- to 20-fold with P10, and
20-fold with P20, and bolus injection induced pulmonary plasma
clot lysis at doses inversely related to their clearance.
Intravenous bolus injection of 5 mg of the P5, P10, or P20
variants in AMI patients was associated with plasma half-lives
(t1/2
) of 13, 30, and 120 minutes and clearances of 75,
43, and 8 mL/min, respectively, compared with 3 minutes and 360 mL/min
for SakSTAR. Injection of 5 mg P5 variant restored TIMI-3 flow within
60 minutes in 14 of 18 AMI patients (78%, 95% CI 55% to 91%) and of
2.5 mg in 7 of 11 patients (63%, 95% CI 35% to 85%), both in the
absence of fibrinogen degradation. The immunogenicity of the variants
was significantly (P<0.002) reduced.
Conclusions—The staphylokinase variant SY161-P5, derivatized with one linear polyethylene glycol molecule of Mr 5000, is a promising fibrin-selective agent for single-bolus coronary thrombolysis.
Key Words: myocardial infarction • thrombolysis • fibrinogen
This article has been cited by other articles:
 |
|
 |
|
  Q. Lian, S. J. Szarka, K. K. S. Ng, and S.-L. Wong Engineering of a Staphylokinase-based Fibrinolytic Agent with Antithrombotic Activity and Targeting Capability toward Thrombin-rich Fibrin and Plasma Clots J. Biol. Chem., July 11, 2003; 278(29): 26677 - 26686. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S.-C. Wu, F. J. Castellino, and S.-L. Wong A Fast-acting, Modular-structured Staphylokinase Fusion with Kringle-1 from Human Plasminogen as the Fibrin-targeting Domain Offers Improved Clot Lysis Efficacy J. Biol. Chem., May 9, 2003; 278(20): 18199 - 18206. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Llevadot, R. P. Giugliano, and E. M. Antman Bolus Fibrinolytic Therapy in Acute Myocardial Infarction JAMA, July 25, 2001; 286(4): 442 - 449. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. W. Armstrong and D. Collen Fibrinolysis for Acute Myocardial Infarction : Current Status and New Horizons for Pharmacological Reperfusion, Part 1 Circulation, June 12, 2001; 103(23): 2862 - 2866. [Full Text] [PDF]
|
|
|
|
 |
|
 L. Moons, I. Vanlinthout, I. Roelants, R. Moreadith, D. Collen, and H. J. Rapold Toxicology Studies with Recombinant Staphylokinase and with SY 161-P5, a Polyethylene Glycol-Derivatized Cysteine-Substitution Mutant Toxicol Pathol, April 1, 2001; 29(3): 285 - 291. [Abstract] [PDF]
|
|
|
|
 |
|
 D. Collen Ham-Wasserman Lecture: Role of the Plasminogen System in Fibrin-Homeostasis and Tissue Remodeling Hematology, January 1, 2001; 2001(1): 1 - 9. [Abstract] [Full Text] [PDF]
|
|