Chemistry: molecular biology and microbiology – Measuring or testing process involving enzymes or... – Involving antigen-antibody binding – specific binding protein...
Patent
1992-01-31
1994-08-30
Parr, Margaret
Chemistry: molecular biology and microbiology
Measuring or testing process involving enzymes or...
Involving antigen-antibody binding, specific binding protein...
435 771, 435 792, 435 13, 435975, 436 69, 436506, 436538, C12Q 100, C12Q 156, G01N 3353, G01N 33564
Patent
active
053427556
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
This invention is directed to methods for the detection of antistreptokinase antibodies, that is, antibodies which recognize streptokinase and/or a complex of streptokinase with another protein. The methods of the invention are based upon the ability of streptokinase to simultaneously bind to other proteins such as lactate dehydrogenase (LD) subunit M and to antistreptokinase antibodies. Specifically, the addition of exogenous streptokinase to samples containing antistreptokinase antibodies and a streptokinase binding protein results in the formation of a three-part complex which can be revealed by reporter methods which detect the streptokinase binding protein or its subunits. The methods of the invention are useful as diagnostic tests for the detection of serum antibodies to streptokinase.
BACKGROUND OF THE INVENTION
Present day treatment for acute myocardial infarction entails intravenous administration of a thrombolytic drug within the first few hours after onset of symptoms to break up (lyse) blood clots within coronary arteries thereby reversing damage to the affected heart muscle. There are two major thrombolytic drugs now available, streptokinase and tissue plasminogen activator (TPA).
The activation of plasminogen by either streptokinase or TPA results in the formation of plasmin, a proteolytic enzyme that degrades fibrin, the principal component of the lattice which holds a blood clot together.
Streptokinase is a naturally occurring product from the bacteria streptococci. Because streptokinase is a bacterial product and an antigen, many individuals who have had previous streptococcal infections (e.g., strop throats) have anti-streptokinase antibodies in their blood. These antibodies neutralize streptokinase when it is administered as a drug (Brogden, R. N., et al., Drugs: 5:357-445 (1973)). Anti-streptokinase titers between 2 to 402 U/ml in a random sample of 120 people has been reported (Bachmann, F., J. Lab. Clin. Med. 72:228 (1968)). Streptokinase is biochemically inert when bound to this antibody and the complex of streptokinase and antibody is rapidly cleared from the circulation (Fletcher, A. P. et al., Clin. Invest. 37:1306 (1958)). Such antistreptokinase antibodies may account for some treatment failures of streptokinase in myocardial infarction due to inadequate dosing with the drug.
It is necessary to begin thrombolytic therapy early after onset of myocardial infarction (within 4 hours) to achieve satisfactory clinical results. Consequently, the choice of which drug to use and how much to use should be made quickly. For effective therapy when streptokinase is chosen, the dose of streptokinase must begin with a dosage in excess of that required to neutralize endogenous circulating antibodies to streptokinase (Bfogden, R. N., et al,, Drugs: 5:357-445 (1973)). Doses which are not in excess of the amount required to neutralize these endogenous antibodies are pharmacologically inactive. It is critical to determine the proper dose for streptokinase therapy. Doses which are too high may lead to the formation of excessive plasmin and result in the depletion of additional proteins which plasmin also degrades, such as circulating fibrinogen and clotting factors V and VIII. Thus, with too much streptokinase there is a risk of hemorrhage. When the hemorrhage occurs in the central nervous system, grave neurological impairment or death usually results (Braunwald, E. et al., J. Am. Coll. Cardiol. 10:970 (1987); Haber, E. et al., Science 243:51 (1989)).
Because there is such individual variability in the levels of antistreptokinase antibodies, a rapid determination of the presence of significant amounts of anti-streptokinase antibodies in a patient would be very useful in guiding medical decisions concerning the dosage of streptokinase needed for therapeutic treatment. With the knowledge that antistreptokinase antibodies are present, an appropriate initial neutralizing dose may be administered, followed by an infusion of the drug in an amount sufficient to maintain the level
REFERENCES:
patent: 4376110 (1983-03-01), David et al.
patent: 4690907 (1987-09-01), Hibino et al.
Edelberg, et al., Biochemistry, vol. 28, pp. 2370-2374, 1989.
Applicant's Ref. AR3; Podlasek, et al., (Clin. Chem. 34:1283 (1988)).
Clinical Chemistry, 35/1, 69-73 (1989), Podlasek et al.
Clinical Chemistry, 31/1, 527-532 (1985), Podlasek et al.
Clinical Investigations, 37, 1306-1315, 1958, Fletcher et al.
McPherson Richard A.
Podlasek Stanley J.
Georgetown University
Parr Margaret
Sisson Bradley L.
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