This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Collen, D. Articles by Vanderschueren, S. Search for Related Content PubMed PubMed Citation Articles by Collen, D. Articles by Vanderschueren, S.

(Circulation. 1997;95:463-472.)
© 1997 American Heart Association, Inc.

Articles

Recombinant Staphylokinase Variants With Altered Immunoreactivity

IV: Identification of Variants With Reduced Antibody Induction but Intact Potency

Desire Collen, MD, PhD; Luc Stockx, MD; Henri Lacroix, MD; Raphael Suy, MD; Steven Vanderschueren, MD, PhD

the Center for Molecular and Vascular Biology (D.C., S.V.), the Department of Radiology (L.S.), and the Department of Vascular Surgery (H.L., R.S.), University of Leuven, and the Center for Transgene Technology and Gene Therapy (D.C.), Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.

Correspondence to D. Collen, MD, PhD, Center for Molecular and Vascular Biology, University of Leuven, Campus Gasthuisberg O & N, Herestr 49, B-3000 Leuven, Belgium. E-mail desire.collen{at}med.kuleuven.ac.be

Background The thrombolytic potency and antibody induction of selected variants of recombinant staphylokinase (SakSTAR), including SakSTAR(K₇₄) with Lys74, SakSTAR(E₇₅) with Glu75, SakSTAR(EER) with Glu38, Glu75, and Arg77, and SakSTAR(K₇₄ER) with Lys74, Glu75, and Arg77 replaced by Ala, were studied.

Methods and Results In rabbits, SakSTAR(K₇₄) and SakSTAR(EER) elicited significantly less circulating neutralizing activity than SakSTAR and SakSTAR(E₇₅) (P=.005 and P=.0002 versus SakSTAR, respectively). In baboons, SakSTAR(K₇₄) induced significantly fewer antibodies than wild-type SakSTAR (P<.05). Intra-arterial administration in patients with peripheral arterial occlusion of SakSTAR(K₇₄) (n=11) or SakSTAR(K₇₄ER) (n=6) induced significantly fewer circulating neutralizing antibodies [median values and interquartile ranges, 20 (3.8 to 26) and 2.4 (0.2 to 59) µg compound neutralized/mL plasma after 3 to 4 weeks (P=.01 and P=.035 versus SakSTAR, respectively)] than SakSTAR (n=9) [median value and interquartile range, 93 (24 to 110) µg compound neutralized/mL plasma]. Overt neutralizing antibody induction (>10 µg compound neutralized/mL plasma) occurred in all 9 patients given wild-type SakSTAR, in 6 of the 11 SakSTAR(K₇₄) patients (P=.038 versus SakSTAR), and in 2 of the 6 SakSTAR(K₇₄ER) patients (P=.011 versus SakSTAR).

Conclusions SakSTAR(K₇₄), a variant of recombinant staphylokinase with a single substitution of Lys74 with Ala, and SakSTAR(K₇₄ER), with Lys74, Glu75, and Arg77 substituted with Ala, have intact thrombolytic potencies but induce significantly less antibody formation in patients.

Key Words: thrombolysis • infarction • plasminogen activators

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]

				P. A. M. Warmerdam, K. Vanderlick, P. Vandervoort, H. De Smedt, S. Plaisance, M. De Maeyer, and D. Collen Staphylokinase-Specific Cell-Mediated Immunity in Humans J. Immunol., January 1, 2002; 168(1): 155 - 161. [Abstract] [Full Text] [PDF]

				Y. Laroche, S. Heymans, S. Capaert, F. De Cock, E. Demarsin, and D. Collen Recombinant staphylokinase variants with reduced antigenicity due to elimination of B-lymphocyte epitopes Blood, August 15, 2000; 96(4): 1425 - 1432. [Abstract] [Full Text] [PDF]

				S. Vanwetswinkel, S. Plaisance, Z. Zhi-yong, I. Vanlinthout, K. Brepoels, I. Lasters, D. Collen, and L. Jespers Pharmacokinetic and thrombolytic properties of cysteine-linked polyethylene glycol derivatives of staphylokinase Blood, February 1, 2000; 95(3): 936 - 942. [Abstract] [Full Text] [PDF]

				D. Collen, F. De Cock, E. Demarsin, S. Jenne, I. Lasters, Y. Laroche, P. Warmerdam, and L. Jespers Recombinant Staphylokinase Variants With Altered Immunoreactivity: III: Species Variability of Antibody Binding Patterns Circulation, January 21, 1997; 95(2): 455 - 462. [Abstract] [Full Text]