Chemistry: analytical and immunological testing – Involving an insoluble carrier for immobilizing immunochemicals
Reexamination Certificate
1999-01-26
2003-09-23
Chin, Christopher L. (Department: 1641)
Chemistry: analytical and immunological testing
Involving an insoluble carrier for immobilizing immunochemicals
C436S540000, C436S546000, C436S164000, C436S811000, C435S007100, C435S007200, C435S007900, C435S007920, C435S007930, C435S007940, C435S007950, C435S028000, C435S174000, C435S968000
Reexamination Certificate
active
06623981
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the detection of patients at risk for developing integrin antagonist/agonist mediated disease states. This invention relates to assays useful for the detection in a patient bodily fluid sample of drug-dependent antibodies which bind to integrins, or intergrin-associated proteins or complexes thereof in the presence of an integrin antagonist/agonist. This invention also relates to assays useful for the detection in a patient bodily fluid sample of drug-dependent antibodies (DDABs) that bind to integrins, including the platelet glycoprotein IIb/IIIa (GPIIb/IIIa), in the presence of a integrin agonist and/or antagonist. This invention also relates to procedures for identifying integrin antagonists/agonists that are less prone to elicit integrin antagonist/agonist mediated disease states.
This invention also relates to procedures which increase the recovery of integrin-directed antibodies in body fluids, resulting in an increased sensitivity and specificity of DDAB detection assays. This invention also relates to procedures for treating blood samples, which dissociate antibodies to GPIIb/IIIa from the platelet surface, thereby increasing the recovery from the platelet supernatant. This invention also relates to the use of different GPIIb/IIIa preparations to identify patients at risk for early-onset thrombocytopenia upon treatment with GPIIb/IIIa antagonist/agonists, thereby increasing the specificity of antibody detection.
This invention also relates to the use of DDABs as a positive control and calibration standard for DDAB assays.
Such methods, procedures and assays are useful for identifying patients who may be at risk to develop disease states mediated by treatment with integrin antagonists/agonists.
BACKGROUND OF THE INVENTION
Thromboembolic diseases, including stable and unstable angina pectoris, myocardial infarction, stroke and lung embolism, are the major cause of disability and mortality in most developed countries. Recently, therapeutic strategies aimed at interfering with the binding of ligands to the GPIIb/IIIa integrin have been explored to treat these patient groups. Platelet GPIIb/IIIa is the main platelet receptor for fibrinogen and other adhesive glycoproteins, including fibronectin, vitronectin and von Willebrand factor. Interference of ligand binding with this receptor has been proven beneficial in animal models of thromboembolic disease (Coller, B. S. GPIIb/IIIa Antagonists: Pathophysiologic and Therapeutic Insights From Studies of C7E3 FAB. Thromb. Haemost. 78: 1, 730-735, 1997), and in limited studies involving human subjects (White, H. D. Unmet Therapeutic Needs in the Management of Acute Ixchemia. Am. J. Cardiol. 80: 4A, 2B-10B, 1997; Tcheng, J. E. Glycoprotein IIb/IIIa Receptor Inhibitors: Putting EPIC, IMPACT II, RESTORE, and EPILOG Trials Into Perspective. Am. J. Cardiol. 78: 3A, 35-40, 1996).
A number of cell surface receptor proteins, referred to as integrins or adhesion protein receptors, have been identified which bind to extracellular matrix ligands or other cell adhesion protein ligands thereby mediating cell-cell and cell-matrix adhesion processes. The integrins are encoded by genes belonging to a gene superfamily and are typically composed of heterodimeric transmembrane proteins containing &agr;- and &bgr;-subunits. Integrin subfamilies contain a common &bgr;-subunit combined with different &agr;-subunits to form adhesion protein receptors with different specificities. In addition to GPIIb/IIIa, a number of other integrin cell surface receptors have been identified. For example, members of the &bgr;1 subfamily, &agr;4&bgr;1 and &agr;5&bgr;1, have been implicated in various inflammatory processes, including rheumatoid arthritis, allergy, asthma and autoimmune disorders.
The integrin GPIIb/IIIa, also referred to as the platelet fibrinogen receptor, is the membrane protein mediating platelet aggregation. GPIIb/IIIa in activated platelets is known to bind four soluble RGD containing adhesive proteins, namely fibrinogen, von Willebrand factor, fibronectin, and vitronectin. The term “IRGD” refers to the amino acid sequence Arg-Gly-Asp. The binding of fibrinogen and von Willebrand factor to GPIIb/IIIa causes platelets to aggregate. The binding of fibrinogen is mediated in part by the RGD recognition sequence which is common to the adhesive proteins that bind GPIIb/IIIa. RGD-peptidomimetic GPIIb/IIIa antagonist compounds are known to block fibrinogen binding and prevent platelet aggregation and the formation of platelet thrombi. GPIIb/IIIa antagonists represent an important new approach for anti-platelet therapy for the treatment of thromboembolic disorders.
Approximately 1% of individuals receiving certain GPIIb/IIIa antagonists develop life-threatening thrombocytopenia. The principal cause of these thrombocytopenias is thought to be immune mediated, due to the presence of drug-dependent anti-platelet antibodies (Berkowitz, S. D., Harrington, R. A., Rund, M. M., and Tcheng, J. E. Acute Profound Thrombocytopenia After C7E3 FAB (abciximab) Therapy. Circulation 95:809-813, 1997). However, such drug-dependent anti-platelet antibodies have not been found in all patients undergoing GPIIb/IIIa inhibitor treatment, leading to speculation that there may be other causes for GPIIb/IIIa-inhibitor-dependent thrombocytopenia.
The general phenomenon of drug-dependent thrombocytopenia/thromboembolic complications is well known. Clinically important examples are heparin-induced thrombocytopenia (HIT) (Amiral, J., Bridley, F., Wolf, M., et al., Antibodies to macromolecular platelet factor IV-heparin complexes in heparin-induced thrombocytopenia: A study of 44 cases. Thromb. Haemost. 1995, 73:21-28; Ansell, J., Deykin, D., Heparin-induced thrombocytopenia and recurrent thromboembolism. Am. J. Hematol. 1980, 8:325-332), and heparin-induced thrombotic thrombocytopenia (HITT), though many other drugs have been implicated (Kelton, J. G., Sheridan, D. P., Santos, A. V., et al. Heparin-induced thrombocytopenia: Laboratory studies. Blood, 1988, 72:925-930; Chong, B., Berndt, M. Heparin induced thrombocytopenia. Blut 1989, 58:53-57; Curtis, B. R., McFarland, J. G., Wu, G-G., Visentin, G. P., and Aster, R. H., Antibodies in sulfonamide-induced immune thrombocytopenia recognize calcium-dependent epitopes on the glycoprotein IIb/IIIa complex. Blood, 1994 84:176-183). HIT and HITT are thought to be of immune origin involving binding to the platelet of drug-dependent anti-platelet antibodies induced by the formation of heparin/platelet Factor IV/antibody complexes (Karpatikin, S., Drug-induced thrombocytopenia. 1971, Amer. J. Medical Sciences, 262:68-78). Platelet clearance is thought to be mediated by the reticuloendothelial system (RES). In some cases such drug/antibody complexes are reported to activate platelets, leading directly to platelet secretion and aggregation (Amiral, J., wolf, M., Fisher, A. M., Boyer-Neumann, C., Vissac, A. M., and Meyer, D. Pathogenicity of IgA and/or IgM antibodies to heparin-platelet Factor IV complexes in patients with heparin-induced thrombocytopenia. British J. of Haem. 1996, 92:954-959).
Cases of thrombocytopenia of unknown origin are referred to as idiopathic thrombocytopenic purpura (ITP). In most patients this disorder is thought to be caused by autoantibodies against platelet membrane glycoproteins (Gonzalez-Conejero, R., Rivera, J., Rosillo, M. C., Lozano, M. L., and Garcia, V. V., Comparative study of three methods to detect free plasma antiplatelet antibodies. Acta Haematol., 96:135-139, 1996; Stockelber, D., Hou, M., Jacobson, S., Kutti, J., Wadenvik, H., Detection of platelet antibodies in chronic idiopathic thrombocytopenic purpura (ITP). A comparative study using flow cytometry, a whole platelet ELISA, and an antigen capture ELISA. Eur. J. Haematol., 56:72-77, 1996) and possibly glycolipids (Arnout, J. The pathogensis of the antiphospholipid syndrome: A hypothesis based on parallelisms with heparin-induced thrombocytopenia. Thrombosis and Haemostasis, 75:536-541, 1996; Cuadrado, M. J.,
Billheimer Jeffrey T.
Breth Leah A.
Burn Timothy C.
Dicker Ira B.
George Henry J.
Bristol--Myers Squibb Company
Chin Christopher L.
Do Pensee T.
Golian Paul D.
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