Immunantwort auf rekombinantes Hirudin

G. Huhle; Ursula Hoffmann; X. H. Song; D. L. Heene; J. Harenberg

doi:10.1055/s-0038-1660377

Hämostaseologie, Table of Contents

Hamostaseologie 1999; 19(01): 50-54
DOI: 10.1055/s-0038-1660377

Übersichtsarbeiten/Review Articles

Schattauer GmbH

Immunantwort auf rekombinantes Hirudin

Eine Übersicht

G. Huhle

¹I. Medizinische Klinik (Direktor: Prof D. L. Heene) Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim

,

Ursula Hoffmann

¹I. Medizinische Klinik (Direktor: Prof D. L. Heene) Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim

,

X. H. Song

¹I. Medizinische Klinik (Direktor: Prof D. L. Heene) Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim

,

D. L. Heene

¹I. Medizinische Klinik (Direktor: Prof D. L. Heene) Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim

,

J. Harenberg

¹I. Medizinische Klinik (Direktor: Prof D. L. Heene) Fakultät für Klinische Medizin Mannheim der Universität Heidelberg, Mannheim

› Author Affiliations

Abstract

Zusammenfassung

Rekombinantes Hirudin ist ein potentes, spezifisches Antithrombin-Agens, das in Hefezellen exprimiert wird. Die verschiedenen rekombinanten Hirudine befinden sich nun in der klinischen Prüfung bezüglich einer Anzahl von Indikationen. Die Ergebnisse vorliegender Studien versprechen eine hohe Effektivität und Sicherheit in der Vorbeugung von tiefen Beinvenenthrombosen und Lungenembolien bei Patienten mit elektiver Hüftchirurgie, bei Patienten mit akutem Myokardinfarkt, akutem koronaren Syndrom und der instabilen Angina mit nachfolgender Angioplastie. In diesen Studien waren unter der Therapie mit rekombinantem Hirudin allergische Reaktionen nicht aufgetreten. Rekombinantes Hirudin wurde ebenfalls hinsichtlich seiner Effektivität und Sicherheit bei Patienten mit heparin-induzierter Thrombozytopenie Typ II untersucht. Hier zeigte sich eine Inzidenz von Heparin-Antikörpern in bis zu 50% aller mit Hirudin langzeitbehandelten Patienten. Eine Immunantwort gegen rekombinantes Hirudin konnte ebenfalls in Tierversuchen zur Herstellung von monoklonalen Hirudinantikörpern produziert werden. Die vorliegenden Daten zeigen, daß die Hirudinantikörper teils hirudin-neutralisierende, teils halbwertszeitverlängernde Eigenschaften aufweisen. Die biologische Relevanz der Hirudin-Antikörper bleibt weiteren Studien vorbehalten.

Schlüsselwörter

Rekombinantes Hirudin - Antikörper - Allergie

Full Text

References

Literatur
1 Markwardt F. Hirudin as an inhibitor of thrombin. Meth Enzymol 1970; 19: 924-32.
2 Dodt J, Mueller HP, Seemueller U, and Chang JY. The complete amino acid sequence of hirudin, a thrombin specific inhibitor. FEBS Lett 1984; 165: 180-4.
3 Märki WE, Grossenbacher H, Grütter MG, Liersch MH, Meyhack and Heim J. Recombinant hirudin: genetic engineering and structure analysis. Sem Thromb Hemost 1991; 17: 88-93.
4 Moia M, Schiele F, Walker M, Erikkson H, Camez A, and Lemarie JC. Treatment of acute deep vein thrombosis (DVT) by subcutaneous r-hirudin (HBW 023): a multicen-ter study. Thromb Haemost 1995; 73: 1456.
5 Esslinger HU, Haas S, Maurer R, Lassmann A, Dlibbers K, and Mueller-Peltzer H. Pharm acodynamie and safety results of PEG-hirudin in healthy volunteers. Thromb Haemost 1997; 77: 911-9.
6 Hornberger W, Rübsamen K, and Schweden J. Prolonged antithrombotic action of a new polyethyleneglycol-coupled hirudin (LU 57291) in two rat thrombosis models. Ann Hematol 1993; 66 Suppl I 20.
7 Rübsamen K, Hornberger W, Schweden J, and Kurfürst M. Pharmacological characteristics of a long acting polyethylene glycol-coupled recombinant hirudin. Thromb Haemost 1991; 65: 1291.
8 Markwardt F. The development of hirudin as an antithrombotic drug. Thromb Res 1994; 74: 1-23.
9 Wallis RB. From leeches to man. Sem Thromb Hemost 1996; 22: 185-96.
10 Stringer KA, and Lindenfield J. Hirudins: antithrombin anticoagulants. Ann Pharma-cother 1992; 26: 1535-40.
11 Glusa E. Vascular effects of thrombin. Sem Thromb Hemost 1992; 18: 296-304.
12 Agnelli G, Pascucci C, Cosmi B, and Nenci GG. The comparative effects of recombinant hirudin (CGP 39393) and standard heparin in thrombus growth in rabbits. Thromb Haemost 1990; 63: 204-7.
13 Bucha E, Nowak G, and Markwardt F. Prevention of experimental coronary thrombosis by hirudin. Folia Haematol 1988; 115: 52-8.
14 Agnelli G, and Sonaglia F. Recombinant hirudin in the prevention of venous thromboembolism in patients undergoing elective hip surgery. Sem Thromb Hemost 1997; 22: 143-8.
15 Eriksson BI, Ekman S, Kaelebo P, Zachrisson B, Bach D, and Close P. Prevention of deep-vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996; 347: 635-9.
16 Eriksson BI, Kaelebo P, Ekman S, Lindbratt S, Kerry R, and Close P. Direct thrombin inhibition with rec-hirudin CGP 39393 as prophylaxis of thromboembolic complications after total hip-replacement. Thromb Haemost 1994; 72: 227-31.
17 Zoldhelyi P, Webster MWI, FRA ChB CP, Fuster V, Grill DE, Gaspar D, Edwards SJ, Cabot CF, and Chesebro JH. Recombinant hirudin in patients with chronic, stable coronary artery disease. Circulation 1993; 88: 2015-22.
18 Antman EM. for the TIMI 9B investigators. Hirudin in acute myocardial infarction. Thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9B trial. Circulation 1996; 94: 911-21.
19 The global use of strategies to open occluded coronary arteries (GUSTO) lib investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Eng J Med 1996; 335: 775-82.
20 Topol EJ, Fuster V, Harrington RA, Califf RM, Kleimen NS, Kereiakes DJ, Cohen B, Chapekis A, Gold HK, Tannenbaum MA, Rao AK, Deboway D, Schwartz D, Henis M, and Chesebro J. Recombinant hirudin for unstable angina pectoris. A multicenter randomized angiographic trial. Circulation 1994; 89: 1557-66.
21 Van den Bos AA, Deckers JW, Heyndrickxs GR, Laarman GJ, Suryyapranata H, Zijlstra F, Close P, Rijnerse JJMM, Buller HR, and Serruys PW. Safety and efficacy of recombinant hirudin (CGP 39393) versus heparin in patients with stable angina undergoing coronary angioplasty. Circulation 1993; 88: 2058-66.
22 Schiele F, Lindgaerde F, Eriksson H, Bassand JP, Wallmark A, Hansson PO, Grollier G, Sjo M, Moia M, Camez Smyth V, and Walker M. for the International Multicentre Hirudin Study Group. Subcutaneous recombinant hirudin (HBW 023) versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective dose-ranging randomized trial. Thromb Haemost 1997; 77: 834-8.
23 Parent F, Bridey F, Dreyfus M, Musset D, Grimon G, Duroux P, Meyer D, and Simonneau G. Treatment of severe venous thromboembolism with intravenous hirudin (HBW 023): an open pilot study. Thromb Haemost 1993; 70: 386-8.
24 Markwardt F, Fink E, Kaiser B, Klöcking HP, Nowak G, Richter M, and Stürzebecher J. Pharmacological survey of recombinant hirudin. Pharmazie 1988; 43: 202-7.
25 Markwardt F, Nowak G, Stürzebecher J, and Vogel G. Clinicopharmacological studies with recombinant hirudin. Thromb Res 1988; 52: 393-400.
26 Schiele F, Vuillemenot A, Kramarz P, Kieffer Y, Soria J, Soria C, Camez A, Mirshahi MC, and Bassand JP. A pilot study of subcutaneous recombinant hirudin (HBW 023) in the treatment of deep vein thrombosis. Thromb Haemost 1994; 71: 558-62.
27 Neuhaus KL, v. Essen R, Tebbe U, Jessel A, Heinrichss H, Maurer W, Döring W, Harmjanz D, Kotier V, Kaihammer E, Simon H, and Horacek T. Safety observations from the pilot phase of the randomized r-hirudin for improvement of thrombolysis (HIT III) study. Circulation 1994; 90: 1638-42.
28 Glusa E. Pharmacology and therapeutic applications of hirudin, a new anticoagulant. Kidney Int 1998; 53: 54-6.
29 Close P, Bichler J, Kerry R, Ekman S, Bueller HR, Kienast J, Marbet GA, Schramm W, and Verstraete M. Weak aller-genicity of recombinant hirudin CGP 39393 (Revasc) in immunocompetent volunteers. The European Hirudin in Thrombosis Group (HIT Group). Coron Artery Dis 1994; 5: 943-9.
30 Verstraete M, Nurmohamed M, Kienast J, Siebeck M, Silling-Engelhardt G, Bueller H, Hoet B, Bichler J, Close P. on behalf of the european hirudin in thrombosis group. Biologic effects of recombinant hirudin (CGP 39393) in human volunteers. JACC 1993; 22: 10808.
31 Schenk JF, Glusa E, Radziwon P, Markwardt F, and Breddin HK. A recombinant hirudin (IK-HIR02) in healthy volunteers. I. Effects on coagulation parameters and bleeding time. Haemostasis 1996; 26: 140-9.
32 Schlaeppi JM. Preparation of monoclonal antibodies to the thrombin/hirudin complex. Thromb Res 1991; 62: 459-70.
33 Schlaeppi JM, Vekemans S, Rink H, and Chang JY. Preparation of monoclonal antibodies to hirudin and hirudin peptides. Eur J Biochem 1990; 188: 463-70.
34 Koch C, Whitechurch O, Cordier P, and Roitsch C. Antihirudin monoclonal antibodies directed toward discontinuous epitopes of the amino-terminal and epitopes involving the carboxy-terminal hirudin amino acids. Analyt Biochem 1993; 214: 301-12.
35 Huhle G, Song X, Wang LC, Hoffmann U, and Harenberg J. Generation and disappearance of antihirudin antibodies during treatment with r-hirudin. Fibrinol Proteol 1998; 12 (Suppl. 02) 91-113.
36 Eichler P, Olbrich K, Pötzsch B, and Greinacher A. Antihirudin antibodies in patients treated with recombinant hirudin for more than five days, a prospective study. Thromb Haemost 1997; Suppl (Abstract): 493.
37 Bichler J, Gemmerli R, and Fritz H. Studies for revealing a possible sensitization to hirudin after repeated intravenous injections in baboons. Thromb Res 1991; 61: 39-51.
38 Markwardt F. Pharmacology of hirudin. Biomed Biochim Acta 1985; 44: 1007-14.
39 Gygax D, Botta L, Ehrat M, Graf P, Lefevre G, Orszalan P, and Pfister C. Immunoassays in monitoring biotechnological drugs. Ther Drug Monit 1996; 18: 405-9.
40 Bichler J, Fichtl B, Siebeck M, and Fritz H. Pharmacokinetics and pharmacodynamics of hirudin in man after single subcutaneous and intravenous bolus administration. Drug Res 1988; 38: 704-10.
41 Schiele F, Vuillemenot A, Kramarz P, Kieffer Y, Anguenot T, Bernard Y, and Bassand JP. Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia. Am J Hema-tol 1995; 50: 20-5.
42 Amiral J, Bridey F, Wolf M, Boyer-Neumann C, Fressinaud E, Vissac AM, Peynaud-Debayle E, Dreyfus M, and Meyer D. Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia: a study of 44 cases. Thromb Haemost 1995; 73: 21-8.
43 Cines DB, Tomaski A, and Tannenbaum S. Immune endothelial cell injury in heparin-associated thrombocytopenia. N Engl J Med 1987; 316: 581-9.
44 Chong BH, Castaldi PA, and Berndt MC. Heparin-induced thrombocytopenia: effects of rabbit IgG, and its Fab and Fc fragments on antibody-heparin-platelet interaction. Thromb Res 1989; 55: 291-5.
45 Warkentin TE. Heparin-induced thrombocytopenia: Pathogenesis, Frequency, Avoidance and Management. Drug Safety 1997; 17: 325-34.
46 Marbet GA, Verstraete M, Kienast J, Graf P, Hoet B, Tsakiris DA, Silling-Engelhardt G, and Close P. Clinical Pharmacology of intravenously administered recombinant desul-fatohirudin (CGP 39393) in healthy volun-ters. J Cardiovasc Pharmacol 1993; 22: 364-72.