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Hamostaseologie 1999; 19(03): 101-107
DOI: 10.1055/s-0038-1660390
Übersichts- und Originalarbeiten/Review and Original Articles
Schattauer GmbH

Pharmacological Properties of Abciximab

Mary Ann Mascelli
1   Clinical Pharmacology, Centocor, Malvern, PA, USA
,
Marian T. Nakada
1   Clinical Pharmacology, Centocor, Malvern, PA, USA
› Author Affiliations
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Publication History

Publication Date:
27 June 2018 (online)

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Abstract

Abciximab is the first of a new class of therapeutic agents that specifically block the function of the platelet cell adhesion receptor, glycoprotein (GP) IIb/IIIa and the subsequent platelet aggregation that contributes to thrombosis. Abciximab displays high avidity for the GPIIb/IIIa receptor, which results in a prolonged platelet-bound half-life, and a sustained duration of platelet inhibition resulting from the redistribution and equilibration of abciximab molecules among circulating platelets at gradually diminishing levels of GPIIb/IIIa receptor occupancy. In contrast to its extended platelet bound life-span, unbound abciximab is cleared rapidly (half-life <10 min) after an intravenous bolus dose. Nevertheless, a subsequent continuous infusion that maintains relatively low concentrations of free abciximab (50 to 100 ng/ml) sustains the pharmacologic GPIIb/IIIa receptor blockade throughout the duration of treatment. In addition, abciximab also interacts with other potentially important biological targets. The agent binds with equal affinity to the other β3 containing integrin, the vitronectin (αvβ3) receptor, and more weakly to the leukocyte Mac-1 receptor. The high avidity and multi-receptor specificity of abciximab are consistent both short- and long-term therapeutic benefits in patients with acute coronary syndromes.

Keywords

Abciximab - glycoprotein IIb/IIIa
 

  • References

  • 1 Lefkovits J, Plow E.F, Topol E.J. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med 1995; 332: 1553-59.
    CrossrefPubMedGoogle Scholar
  • 2 Coller B.S. The role of platelets in arterial thrombosis and the rationale for blockade of platelet GPIIb/IIIa receptors as antithrombotic therapy. Eur Heart J 1995; 16 suppl L 11-15.
    PubMedGoogle Scholar
  • 3 Ferguson J.J, Waly H.M, Wilson J.M. Fundamentals of coagulation and glycoprotein IIb/IIIa receptor inhibition. Am Heart J 1998; 135 suppl S35-S42.
    CrossrefPubMedGoogle Scholar
  • 4 Roth A.A. Platelet arachidonate metabolism and platelet activating factor. In: Phillips D.R, Schuman M.A. (eds) Biochemistry of platelets. New York: Academic Press; 1986: 69-113.
    CrossrefGoogle Scholar
  • 5 Salzman E.W, Hirsh J, Marder V.J. Clinical use of heparin. In: Colman R.W, Hirsh J, Marder V.J, Salzman E.W. (eds) Hemostasis and thrombosis. Philadelphia: J. B. Lippin-cott Co.; 1994
    Google Scholar
  • 6 Schor K. The basic pharmacology of antiplatelet agents ticlopidine and Clopidogrel. Platelets 1993; 4: 252-61.
    CrossrefPubMedGoogle Scholar
  • 7 Coller B.S, Scudder L.E, Beer J, Gold H.K, Folts J.D, Cavagnaro J, Jordan R, Wagner C, Iuliucci J, Knight D, Ghrayeb J, Smith C, Weisman H.F, Berger H. Monoclonal antibodies to platelet glycoprotein IIb/IIIa as antithrombotic agents. Ann NY Acad Sci 1991; 614: 193-213.
    CrossrefPubMedGoogle Scholar
  • 8 Coller B.S. Blockade of platelet GPIIb/IIIa receptors as an antithrombotic strategy. Circulation 1995; 92: 2373-80.
    CrossrefPubMedGoogle Scholar
  • 9 Suzuki K, Sakai Y, Hisamichi N, Taniuchi Y, Sato K, Terazaki C, Kaku S, Kawasaki T, Yano S, Inagaki O, Masuho Y. Comparison of the antiplatelet effect of YM337 and abciximab in rhesus monkeys. Eur J Pharmacol 1997; 336: 169-76.
    CrossrefPubMedGoogle Scholar
  • 10 Scarborough R.M, Naughton M.A, Teng W, Rose J.W, Phillips D.R, Nannizzi L, Arfsten A, Campbell A.M, Charo I.F. Design of potent and specific integrin antagonists: peptide antagonists with high specificity for glycoprotein IIb-IIIa. J Biol Chem 1993; 268: 1066-73.
    PubMedGoogle Scholar
  • 11 Weller T, Alig L, Müller M.H, Kouns W.C, Steiner B. Fibrinogen receptor antagonists: a novel class of promising antithrombotics. Drugs Future 1994; 19: 461-76.
    CrossrefPubMedGoogle Scholar
  • 12 Mousa S.A, Bennett J.S. Platelets in health and disease: platelet GPIIb/IIIa structure and function: recent advances in antiplatelet therapy. Drugs Future 1996; 21: 1141-54.
    PubMedGoogle Scholar
  • 13 Coller B.S. A new murine monoclonal antibody antibody reports an activation-dependent change in the conformation and/or microenvironment of the platelet glycoprotein IIb/IIIa complex. J Clin Invest 1985; 76: 101-8.
    CrossrefPubMedGoogle Scholar
  • 14 Jordan R.E, Wagner C.L, Mascelli M.A, Treacy G, Nedelman M.A, Woody J.N, Weisman H.F, Coller B.S. Preclinical development of c7E3 Fab; a mouse/human chimeric monoclonal antibody fragment that inhibits platelet function by blockade of GPIIb/IIIa receptors with observations on the immunogenicity of c7E3 Fab in humans. In: Horton M.A. (ed.) Adhesion receptors as therapeutic targets. New York: CRC Press.; 1996: 281-305.
    Google Scholar
  • 15 Knight D.M, Wagner C, Jordan R, McAleer M.F, DeRita R, Fass D.N, Coller B.S, Weisman H.F, Ghrayeb J. The immunogenicity of the 7E3 murine monoclonal Fab antibody fragment variable region is dramatically reduced in humans by substitution of human for murine constant regions. Molec Immunol 1995; 32: 1271-81.
    CrossrefPubMedGoogle Scholar
  • 16 Data on file at Centocor.
    PubMed
  • 17 Wagner C.L, Mascelli M.A, Neblock D.S, Weisman H.F, Coller B.S, Jordan R.E. Analysis of GPIIb/IIIa receptor number by quantification of 7E3 binding to human platelets. Blood 1996; 88: 907-14.
    CrossrefPubMedGoogle Scholar
  • 18 Tarn S.H, Sassoli P.M, Jordan R.E, Nakada M.T. Abciximab (ReoPro®, chimeric 7E3 Fab) demonstrates equivalent affinity and functional blockade of glycoprotein IIb/IIIa and ανβ3 integrins. Circulation 1998; 98: 1085-91.
    CrossrefPubMedGoogle Scholar
  • 19 Aggrastat package insert, New Jersey: Merck.
    PubMed
  • 20 Integrelin package insert, South San Francisco, California: COR Therapeutics.
    PubMed
  • 21 Phillips D.R, Scarborough R.M. Clinical pharmacology of eptifibatide. Am J Cardiol 1997; 80: 11B-20B.
    CrossrefPubMedGoogle Scholar
  • 22 Mascelli M.A, Lance E.T, Damaraju L, Wagner C.L, Weisman H.F, Jordan R.E. Pharmacodynamic profile of short-term abciximab treatment demonstrates prolonged platelet inhibition with gradual recovery from GPIIb/IIIa receptor blockade. Circulation 1998; 97: 1680-8.
    CrossrefPubMedGoogle Scholar
  • 23 Deedwania P.C, Ferguson J.J, Kereiakes D.J, Fitzgerald D, Anders R.J, Burns D.M. Bryzinski Sustained GPIIb/IIIa blockade with oral Orbifiban. Interim safety and toler-ability results with the SOAR study. 1998; 31: 94A (abstract).
    PubMedGoogle Scholar
  • 24 Heyn Adu P, Lötter M.G, Badenhorst P.N, van Reenen O.R, Pieters H, Minnaar P.C, Retief F.P. Kinetics, distribution and sites of destruction of 111Indium-labeled human platelets. Br J Haematol 1980; 44: 269-80.
    CrossrefPubMedGoogle Scholar
  • 25 Kleiman N.S, Raizner A.E, Jordan R.E, Wang A.L, Norton D, Mace K.F, Joshi A, Coller B.S, Weisman H.F. Differential inhibition of platelet aggregation induced by adenosine triphosphate or a thrombin receptor-activating peptide in patients treated with bolus chimeric 7E3 Fab: implications for inhibition of the internal pool of GPIIb/IIIa receptors. J Am Coll Cardiol 1995; 26: 1665-71.
    CrossrefPubMedGoogle Scholar
  • 26 Tcheng J.E, Harrington R.A, Kottke-Marchante K, Kleiman N.S, Ellis S.G, Kereiakes D.J, Mick M.J, Navetta F.I, Smith J.E, Worley S.J. Multicenter, randomized, double-blind, placebo-controlled dose ranging study of the platelet integrin glycoprotein IIb/IIIa blocker integrelin in elective coronary intervention. Circulation 1995; 91: 2151-7.
    CrossrefPubMedGoogle Scholar
  • 27 Kereiakes D.J, Kleiman N.S, Ambrose J, Cohen M, Rodriguez S, Palabrica T, Herrmann H, Sutton J.M, Weaver W.D, McKee D.B, Fitzpatrick V, Sax F.L. Randomized, double-blind, placebo-controlled dose ranging study of tirofiban (MK-383) platelet IIb/IIIa blockade in high risk patients undergoing coronary angioplasty. Am Coll Cardiol 1996; 27: 536-542.
    CrossrefPubMedGoogle Scholar
  • 28 Wagner C.L, Cunningham M.R, Wyand M.S, Weisman H.F, Coller B.S, Jordan R.E. Reversal of the antiplatelet effects of chimeric 7E3 Fab treatment by platelet transfusion in cynomolgus monkeys [abstract]. Thromb Haemost 1995; 73: 1313.
    PubMedGoogle Scholar
  • 29 Simon D.I, Xu H, Ortlepp S, Rogers C, Rao N.K. 7E3 monoclonal antibody directed against the platelet glycoprotein IIb/IIIa cross-reacts with the leukocyte integrin Mac-1 and blocks adhesion to fibrinogen and ICAM-1. Arterioscler Thromb Vase Biol 1997; 17: 528-35.
    CrossrefPubMedGoogle Scholar
  • 30 Stouffer G.A, Hu Z, Sajid M, Li H, Jin G, Nakada M.T, Hanson S.R, Runge M.S. Beta3 integrins are upregulated after vascular injury and modulate thrombospondin- and thrombin-induced proliferation of cultured smooth muscle cells. Circulation 1998; 97: 907-15.
    CrossrefPubMedGoogle Scholar
  • 31 Conforti G, Dominquez-Jimenez C, Zanetti A, Gimbrone Jr M.A, Cermona O, Marchistio P.C, Dejana E. Human endothelial cells express integrin receptors on the luminal aspect of their membrane. Blood 1992; 80: 437-46.
    PubMedGoogle Scholar
  • 32 Charo I.F, Bekeart L.S, Phillips D.R. Platelet glycoprotein IIb-IIIa-like proteins mediate endothelial cell attachment to adhesive proteins and the extracellular matrix. J Biol Chem 1987; 262: 9935-8.
    PubMedGoogle Scholar
  • 33 Liaw L, Skinner M.P, Raines E.W, Ross R, Cheresh D.A, Schwartz S.M, Giachelli C.M. The adhesive and migratory effects of osteo-pontin are mediated via distinct cell surface integrins. J Clin Invest 1995; 332: 1553-9.
    PubMedGoogle Scholar
  • 34 Srivatsa S.S, Fitzpatrick L.A, Tsao T.W, Reilly T.M, Holmes Jr D.R, Schwartz R.S, Mousa S.A. Selective ανβ3 integrin blockade potently limits neointimal hyperplasia and lumen stenosis following deep coronary arterial stent injury: Evidence for the functional importance of integrin ανβ3 and osteopontin expression during neointima formation. Cardio Res 1997; 36: 408-28.
    CrossrefPubMedGoogle Scholar
  • 35 Choi E.T, Engel L, Callow A.D, Sun S, Trachtenberg J, Santoro S, Ryan U.S. Inhibition of neointimal hyperplasia by blocking ανβ3 integrin with a small peptide antagonist GpenGRDSPCA. J Vase Surg 1994; 19: 125-34.
    CrossrefPubMedGoogle Scholar
  • 36 Matsuno H, Stassen J.M, Vermylen J, Deckmyn H. Inhibition of integrin function by a cyclic RGD-containing peptide prevents neointima formation. Circulation 1994; 90: 2203-6.
    CrossrefPubMedGoogle Scholar
  • 37 Lefkovits J, Plow E.F, Topol E.J. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med 1995; 332: 1553-9.
    CrossrefPubMedGoogle Scholar
  • 38 Marijianowski M.M, Nakada M.T, Sundell B.I, Kelly A.B, Jordan R.E, Jakubowski J.A, Chronos N.A.F, Hanson S.R. Abciximab reduces vascular lesion formation in non-human primates. JACC 1999;33:Abstract 845-1.
    PubMedGoogle Scholar
  • 39 Altieri D.C. Occupancy of CD11b/CD18 (Mac-1) divalent ion binding site(s) induces leukocyte adhesion. J Immunol 1991; 147: 1891-8.
    PubMedGoogle Scholar
  • 40 Altieri D.C, Edgington T.S. A monoclonal antibody reacting with distinct adhesion molecules defines a transition in the functional state of the receptor CDllb/CD18 (Mac-1). J Immunol 1988; 1414: 2656-60.
    PubMedGoogle Scholar
  • 41 Altieri D.C, Morrissey J.H, Edgington T.S. Adhesive receptor Mac-1 coordinates the activation of factor X on stimulated cells of monocytic and myeloid differentiation: an alternative initiation of the coagulation cascade. Proc Natl Acad Sci USA 1988; 85: 7462-6.
    CrossrefPubMedGoogle Scholar
  • 42 Rogers C, Welt F.G.P, Karnovsky M.J, Edelman E.R. Monocyte recruitment and neointimal hyperplasia in rabbits: coupled inhibitory effects of heparin. Art Thromb and Vase Biol 1996; 16: 1312-8.
    PubMedGoogle Scholar
  • 43 Reverter J.C, Béguin S, Kessels H, Kuma R, Hemker H.C, Coller B.S. Inhibition of platelet-mediated, tissue factor-induced thrombin generation by the mouse/human chimeric 7E3 antibody. J Clin Invest 1996; 98: 863-74.
    CrossrefPubMedGoogle Scholar
  • 44 Chronos N, Marciniak S.J, Nakada M.T. Binding specificity and associated effects of platelet GPIIb/IIIa inhibitors. Eur H Journal 1999; 1 supplement E E11-E17.
    PubMedGoogle Scholar
  • 45 Cox A.D, Devine D.V. Factor XIIIa binding to activated platelets is mediated through activation of glycoprotein IIb-IIIa. Blood 1994; 83: 1006-16.
    PubMedGoogle Scholar
  • 46 Cohen I, Burk D.L, White J.G. The effect of peptides and monoclonal antibodies that bind to platelet glycoprotein IIb/IIIa complex on the development of clot tension. Blood 1989; 73: 1880-7.
    PubMedGoogle Scholar
  • 47 Collet J.P, Mishal Z, Soria C, Thomas D, Montalescot G. Pharmacological remodeling of platelet-rich clot architecture by abciximab may explain its dethrombotic efficacy. Circulation 1998; 98: 11120. (abstract).
    PubMedGoogle Scholar
  • 48 Coller B.S. Platelets and thrombolytic therapy. N Eng J Med 1990; 322: 33-42.
    CrossrefPubMedGoogle Scholar