Download PDF
Thromb Haemost 1990; 64(02): 276-280
DOI: 10.1055/s-0038-1647300
Original Article
Schattauer GmbH Stuttgart

Low Incidence of Antibodies to Recombinant Human Tissue-Type Plasminogen Activator in Treated Patients

B R Reed
1   The Departments of Medicinal and Analytical ChemistryGenentech, Inc., South San Francisco, CA, USA
,
A B Chen
1   The Departments of Medicinal and Analytical ChemistryGenentech, Inc., South San Francisco, CA, USA
,
P Tanswell
4   The Department of Biochemistry, Dr. Karl Thomae GmbH, Biberach and der Riss, FRG
,
W S Prince
1   The Departments of Medicinal and Analytical ChemistryGenentech, Inc., South San Francisco, CA, USA
,
R M Wert Jr.
2   The Department of Assay ServicesGenentech, Inc., South San Francisco, CA, USA
,
L Glaesle-Schwarz
4   The Department of Biochemistry, Dr. Karl Thomae GmbH, Biberach and der Riss, FRG
,
E B Grossbard
3   The Department of Clinical ResearchGenentech, Inc., South San Francisco, CA, USA
› Author Affiliations
Further Information

Publication History

Received 28 August 1989

Accepted after revision18 May 1990

Publication Date:
25 July 2018 (online)

  PDF Download  Permissions and Reprints

Summary

Sera from over 1,600 patients who received recombinant human tissue plasminogen activator (rt-PA) during clinical trials were assessed for the presence of antibodies to this therapeutic agent. The rt-PA was administered by a variety of dosage regimens for several different indications. Two different forms of rt-PA were used; one was a predominantly two chain form, and the other was a predominantly one chain form. A sensitive radioimmunoprecipitation assay was used to measure antibodies to rt-PA in patients’ serum before and after treatment. Of 932 patients tested with this assay, 929 were negative for antibodies to t-PA. Three patients developed low titers after treatment. Additional serum samples were obtained from these three patients within 2 years after rt-PA therapy and were negative for antibodies to t-PA. With the limited number of positive samples, no correlation could be found with dose or type of rt-PA, dosing regimen or clinical diagnosis. The virtual absence of antibody formation was confirmed in an additional 754 patients using a novel competitive two-site ELISA. It can be concluded that a single infusion of rt-PA was virtually unassociated with antibody formation, suggesting that repeat treatments could be given when necessary without the risk of immunologic complications as are seen with streptokinase or its derivatives.

 

  • References

  • 1 Collen D, Tiefenbrunn AJ, Gold HK, Weisfeldt ML, Sobel BE, Leinbach RC, Brinker JA, Ludbrook PA, Yasuda I, Bulkley BH, Robison AK, Hutter Jr AM, Bell WR, Spadaro Jr JJ, Khaw BA, Grossbard EB. Coronary thrombolysis with recombinant human tissue-type plasminogen activator: a prospective, randomized, placebo-controlled trial. Circulation 1984; 70: 1012-1017
    CrossrefPubMedGoogle Scholar
  • 2 Williams DO, Borer J, Braunwald E, Chesebro JH, Cohen LS, Dalen J, Dodge HT, Francis CK, Knatterud G, Ludbrook P, Markis JE, Mueller H, Desvigne-Nickens P, Passamani ER, Powers ER, Rao AK, Roberts R, Ross A, Ryan TJ, Sobel BE, Winniford M, Zaret B. Intravenous recombinant tissue-type plasminogen activator in patients with acute myocardial infarction: a report from the NHLBI thrombolysis in myocardial infarction trial. Circulation 1986; 73: 338-346
    CrossrefPubMedGoogle Scholar
  • 3 Verstraete M, Bernard R, Bory M, Brower RW, Collen D, de Bono DP, Erbel R, Huhmann W, Lennane RJ, Lubsen J, Mathey D, Meyer J, Michels HR, Rutsch W, Schartl M, Schmidt W, Uebis R, von Essen R. Randomised trial of intravenous recombinant tissue-type plasminogen activator versus intravenous streptokinase in acute myocardial infarction. Lancet 1985; 1: 842-847
    PubMedGoogle Scholar
  • 4 Chesebro JH, Knatterud G, Roberts R, Borer J, Cohen LS, Dalen J, Dodge HT, Francis CK, Hillis D, Ludbrook P, Markis JE, Mueller H, Passamani ER, Powers ER, Rao AK, Robertson T, Ross A, Ryan TJ, Sobel BE, Willerson J, Williams DO, Zaret BL, Braunwald E. Thrombolysis in Myocardial Infarction (TIMI) Trial, Phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Circulation 1987; 76: 142-154
    CrossrefPubMedGoogle Scholar
  • 5 Verstraete M, Arnold AE R, Brower RW, Collen D, de Bono DP, De Zwaan C, Erbel R, Hillis S, Lennane RJ, Lubsen J, Mathey D, Reid DS, Rutsch W, Schartl M, Schofer J, Serruys PW, Simoons ML, Uebis R, Vahanian A, Verheugt FW A, von Essen R. Acute coronary thrombolysis with recombinant human tissue-type plasminogen activator: initial patency and influence of maintained infusion on reocclusion rate. Am J Cardiol 1987; 60: 231-237
    CrossrefPubMedGoogle Scholar
  • 6 Topol EJ, Morris DC, Smalling RW, Schumacher RR, Taylor CR, Nishikawa A, Liberman HA, Collen D, Tufte ME, Grossbard EB, O’Neill WW. A multicenter, randomized, placebo-controlled trial of a new form of intravenous recombinant tissue-type plasminogen activator (Activase) in acute myocardial infarction. J Am Coll Cardiol 1987; 9: 1205-1213
    CrossrefPubMedGoogle Scholar
  • 7 Topol EJ, George BS, Kereiakes DJ, Candela RJ, Abbottsmith CW, Stump DC, Boswick JM, Stack RS, Califf RM. Comparison of two dose regimens of intravenous tissue plasminogen activator for acute myocardial infarction. Am J Cardiol 1988; 61: 723-728
    CrossrefPubMedGoogle Scholar
  • 8 Mueller HS, Rao AK, Forman SA. Thrombolysis in myocardial infarction (TIMI): comparative studies of coronary reperfusion and systemic fibrinogenolysis with two forms of recombinant tissue-type plasminogen activator. J Am Coll Cardiol 1987; 10: 479-490
    CrossrefPubMedGoogle Scholar
  • 9 Guerci AD, Gerstenblith G, Brinker JA, Chandra NC, Gottlieb SO, Bahr RD, Weiss JL, Shapiro EP, Flaherty JT, Bush DE, Chew PH, Gottlieb SH, Halperin HR, Ouyang P, Walford GD, Bell WR, Fatterpaker AK, Llewellyn M, Topol EJ, Healy B, Siu CO, Becker LC, Weisfeldt ML. A randomized trial of intravenous tissue plasminogen activator for acute myocardial infarction with subsequent radomization to elective coronary angioplasty. N Engl J Med 1987; 317: 1613-1618
    CrossrefPubMedGoogle Scholar
  • 10 O’Rourke M, Baron D, Keogh A, Kelly R, Nelson G, Barnes C, Raftos J, Graham K, Hillman K, Newman H, Woolridge J, Rivers J, White H, Whitlock R, Norris R. Limitation of myocardial infarction by early infusion of recombinant tissue-type plasminogen activator. Circulation 1988; 77: 1311-1215
    CrossrefPubMedGoogle Scholar
  • 11 National Heart Foundation of Australia Coronary Thrombolysis Group. Coronary thrombolysis and myocardial salvage by tissue plasminogen activator given up to 4 hours after onset of myocardial infacrtion. Lancet 1988; 1: 203-208
    PubMedGoogle Scholar
  • 12 Van de Werf F, Arnold AE R. Intravenous tissue plasminogen activator and size of infarct, left ventricular function, and survival in acute myocardial infarction. Br Med J 1988; 297: 1374-1379
    CrossrefPubMedGoogle Scholar
  • 13 Wilcox RG, von der Lippe G, Olsson CG, Jensen G, Skene AM, Hampton JR. Trial of tissue plasminogen activator for mortality reduction in acute myocardial infarction. Lancet 1988; 2: 525-530
    PubMedGoogle Scholar
  • 14 Berson SA, Yalow RS, Bauman A, Rothschild MA, Newerly K. Insulin-I131 metabolism in human subjects: demonstration of insulin binding globulin in the circulation of insulin treated subjects. J Clin Invest 1955; 35: 170-190
    PubMedGoogle Scholar
  • 15 Roth J, Glick SM, Yalow RS, Berson SA. Antibodies to human growth hormone (HGH) in human subjects treated with HGH. J Clin Invest 1964; 43: 1056-1065
    CrossrefPubMedGoogle Scholar
  • 16 Haddad Jr JG, Caldwell JG. Calcitonin resistance: clinical and immunologic studies in subjects with Paget’s disease of bone treated with porcine and salmon calcitonins. J Clin Invest 1972; 51: 3133-1341
    CrossrefPubMedGoogle Scholar
  • 17 Bisset GW, Black A, Hilton PJ, Jones NF, Montgomery M. Polyuria associated with an antibody to vasopressin. Clin Sci Molec Med 1976; 50: 277-283
    PubMedGoogle Scholar
  • 18 Lindner J, McNeil LW, Marney S, Conway M, Rivier J, Vale W, Rabin D. Characterization of human anti-luteinizing hormone-releasing hormone (LRH) antibodies in the serum of a patient with isolated gonadotropin deficiency treated with synthetic LRH. J Clin Endocrinol Metab 1981; 52: 267-270
    CrossrefPubMedGoogle Scholar
  • 19 Musch K, Wolf AS, Lauritzen C. Antibodies to human chorionic gonadotropin in humans. Clin Chim Acta 1981; 113: 95-100
    CrossrefPubMedGoogle Scholar
  • 20 White GC II, McMillan CW, Blatt PM, Roberts HR. Factor VIII inhibitors: a clinical overview. Am J Hematol 1982; 13: 335-342
    CrossrefPubMedGoogle Scholar
  • 21 Fineberg SE, Galloway JA, Fineberg NS, Rathbun MJ, Hufferd S. Immunogenicity of recombinant DNA human insulin. Diabetologia 1983; 25: 465-469
    PubMedGoogle Scholar
  • 22 Kaplan SL, Underwood LE, August GP. et al Clinical studies with recombinant-DNA-derived methionyl human growth hormone in growth hormone deficient children. Lancet 1986; 1: 697-700
    PubMedGoogle Scholar
  • 23 Spiegel RJ, Spicehandler JR, Jacobs SL, Oden EM. Low incidence of serum neutralizing factors in patients receiving recombinant alfa-2b interferon (Intron A). Am J Med 1986; 80: 223-228
    CrossrefPubMedGoogle Scholar
  • 24 Lew AS, Neer T, Rodriguez L, Geft IL, Shah PK, Ganz W. Clinical failure of streptokinase due to an unsuspected high titer of antistreptokinase antibody. J Am Coll Cardiol 1984; 4: 183-5
    CrossrefPubMedGoogle Scholar
  • 25 Sigwart U, Grbic M, Bachmann F. Measurement of antistreptokinase antibodies. J Am Coll Cardiol 1985; 5: 1500
    PubMedGoogle Scholar
  • 26 van Breda A, Katzen BT, Deutsch AS. Urokinase versus streptokinase in local thrombolysis. Radiology 1987; 165: 109-111
    CrossrefPubMedGoogle Scholar
  • 27 Rutsch W, Schmutzler H. Intracoronary thrombolysis: organizational prerequistites, technique, and results. Cardiovasc Intervent Radiol 1986; 9: 245-252
    CrossrefPubMedGoogle Scholar
  • 28 Totty WG, Romano T, Benian GM, Gilula LA, Sherman LA. Serum sickness following streptokinase therapy. Am J Roentgenol 1982; 138: 143-144
    CrossrefPubMedGoogle Scholar
  • 29 Weatherbee TC, Esterbrooks DJ, Katz DA. et al Serum sickness following selective intracoronary streptokinase. Curr Ther Res 1984; 35: 433-438
    PubMedGoogle Scholar
  • 30 Bucknall C, Darley C, Flax J, Vincent R, Chamberlain D. Vasculitis complicating treatment with intravenous anisoylated plasminogen streptokinase activator complex in acute myocardial infarction. Br Heart J 1988; 59: 9-11
    CrossrefPubMedGoogle Scholar
  • 31 McGrath KG, Zeffren B, Alexander J, Kaplan K, Patterson R. Allergic reactions to streptokinase consistent with anaphylactic or antigen-antibody complex-mediated damage. J Allergy Clin Immunol 1985; 76: 453-457
    CrossrefPubMedGoogle Scholar
  • 32 McGrath KG, Patterson R. Anaphylactic reactivity to streptokinase. JAMA 1984; 252: 1314-1217
    CrossrefPubMedGoogle Scholar
  • 33 GISSI. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 1986; 1: 397-402
    PubMedGoogle Scholar
  • 34 AIMS Trial Study Group. Effect of intravenous APS AC on mortality after acute myocardial infarction: preliminary report of a placebo-controlled clinical trial. Lancet 1988; 1: 545-549
    PubMedGoogle Scholar
  • 35 Pennica D, Holmes WE, Kohr WJ, Harkins RN, Vehar GA, Ward CA, Bennett WF, Yelverton E, Seeburg PH, Heyneker HL, Goeddel DV. Cloning and expression of human tissue-type plasminogen activator cDNA in E.coli. Nature 1983; 301: 214-221
    CrossrefPubMedGoogle Scholar
  • 36 Gerloff RK, Hoyer BH, McLaren LC. Precipitation of radiolabeled poliovirus with specific antibody and antiglobulin. J Immunol 1962; 89: 559-570
    PubMedGoogle Scholar
  • 37 Hoyng CF. Tissue plasminogen activator produced by CHO cells: laboratory, clinical and regulatory aspects. In: Therapeutic Agents Produced by Genetic Engineering: The Example of Growth Hormone and its Releasing Factor Joyeaux A, Leygue G, Morre M, Roncucci R, Schmelck PH. (eds) “Quo Vadis?” Symposium, Sanofi Group 29.05.1985. Toulouse-Labege; France:
  • 38 Chen AB, Anicetti VR, Klassen TD, Berthold W, Zahn G, Wert RM, Geier MD, Jones AJ S. A sensitive radioimmunoprecipitation assay for the detection of antibody to recombinant human gamma-interferon: comparison to a bioassay neutralization test. J Interferon Res 1986; 6: 313-320
    CrossrefPubMedGoogle Scholar
  • 39 Seifried E, Tanswell P, Rijken DC, Barrett-Bergshoeff MM, Su CA P F, Kluft C. Pharmacokinetics of antigen and activity of recombinant tissue-type plasminogen activator after infusion in healthy volunteers. Arzneim Forsch/Drug Res 1988; 38: 418-22
    PubMedGoogle Scholar
  • 40 Protzman WP, Jacobs SL, Minnicozzi M, Oden EM, Kelsey DK. A radioimmunologic technique to screen for antibodies to alpha-2 interferon. J Immunol Methods 1984; 75: 317-23
    CrossrefPubMedGoogle Scholar
  • 41 Haggroth L, Mattsson C, Friberg J. Inhibition of the human tissue plasminogen activator in plasma from different species. Thromb Res 1984; 33: 583-594
    CrossrefPubMedGoogle Scholar
  • 42 Maizel AS, Bookstein JJ. Streptokinase, urokinase, and tissue plasminogen activator: pharmacokinetics, relative advantages, and methods for maximizing rates and consistency of lysis. Cardiovasc Intervent Radiol 1986; 9: 236-244
    CrossrefPubMedGoogle Scholar
  • 43 Moran DM, Strandring R, Lavender EA, Harris GS. Assessment of antistreptokinase antibody levels in human sera using a microradioimmunoassay procedure. Thromb Haemostas 1984; 52: 281-287
    PubMedGoogle Scholar