Download PDF
Thromb Haemost 1989; 61(02): 259-261
DOI: 10.1055/s-0038-1646571
Original Article
Schattauer GmbH Stuttgart

Monoclonal Antibodies to Tissue-Type Plasminogen Activator which Prolong its Clearance In Vivo

Thomas M Reilly
The E. I. du Pont de Nemours and Company, Medical Products Department, Experimental Station, Wilmington, Delaware, USA
,
Robert M Knabb
The E. I. du Pont de Nemours and Company, Medical Products Department, Experimental Station, Wilmington, Delaware, USA
,
Andrew T Chiu
The E. I. du Pont de Nemours and Company, Medical Products Department, Experimental Station, Wilmington, Delaware, USA
,
David L Bradfute
The E. I. du Pont de Nemours and Company, Medical Products Department, Experimental Station, Wilmington, Delaware, USA
,
Pieter B M W M Timmermans
The E. I. du Pont de Nemours and Company, Medical Products Department, Experimental Station, Wilmington, Delaware, USA
› Author Affiliations
Further Information

Publication History

Received 16 September 1988

Accepted after revision 06 December 1988

Publication Date:
30 June 2018 (online)

  PDF Download  Permissions and Reprints

Summary

Three murine monoclonal antibodies to tissue-type plasminogen activator (t-PA) were evaluated for their effects on the binding of iodinated t-PA to cultured human hepatoma cells (Hep G2), and on extending the half-life of t-PA injected into rabbits. Two of the antibodies, AE5 and EG2, significantly inhibited t-PA binding in vitro, and extended the in vivo half-life of t-PA four to five-fold. A third antibody, BA10, which had a much smaller inhibitory effect on t-PA binding, had no influence in extending t-PA’s half-life. MOPC-21, a control antibody not directed to t-PA, had no effect on either test. Our results are the first to correlate different compounds’ effects on t-PA binding with their ability to retard t-PA clearance in vivo, and provide additional evidence for the importance of a liver cell receptor in the t-PA clearance process.

Keywords

Tissue-type plasminogen activator - Hep G2 human hepatoma cells
 

  • References

  • 1 Collen D. On the regulation and control of fibrinolysis. Thromb Haemostas 1980; 43: 77-89
    PubMedGoogle Scholar
  • 2 Rijken DC, Collen D. Purification and characterization of the plasminogen activator secreted by human melanoma cells in culture. J Biol Chem 1981; 256: 7035-7041
    PubMedGoogle Scholar
  • 3 Hoylaerts M, Rijken DC, Lijnen HR, Collen D. Kinetics of the activation of plasminogen by human tissue plasminogen activator. J Biol Chem 1982; 257: 2912-2919
    PubMedGoogle Scholar
  • 4 Ranby D. Studies on kinetics of plasminogen activation by tissue plasminogen activator. Biochim Biophys Acta 1982; 704: 461-469
    CrossrefPubMedGoogle Scholar
  • 5 Van de Werf F, Bergman SR, Fox KA A, DeGeest H, Hoyng CF, Sobel BE, Collen D. Coronary thrombolysis with intravenously administered human tissue-type plasminogen activator produced by recombinant DNA technology. Circulation 1984; 69: 605-610
    CrossrefPubMedGoogle Scholar
  • 6 Sobel B. Coronary thrombolysis with tissue-type plasminogen activator (tPA): emerging strategies. J Am Coll Cardiol 1986; 5: 1220-1225
    PubMedGoogle Scholar
  • 7 Kominger C, Stassen JM, Collen D. Turnover of human extrinsic (tissue-type) plasminogen activator in rabbits. Thromb Haemostas 1981; 46: 658-661
    PubMedGoogle Scholar
  • 8 Emeis JJ, van den Hoogen CM, Jense D. Hepatic clearance of tissue- type plasminogen activator in rats. Thromb Haemostas 1985; 54: 661-664
    PubMedGoogle Scholar
  • 9 Verstraete M, Bounameaux H, deCock F, de Werf FV, Collen D. Pharmacokinetics and systemic fibrinogenolytic effects of recombinant human tissue-type plasminogen activator (rt-PA) in humans. J Pharmacol Exp Ther 1985; 235: 506-512
    PubMedGoogle Scholar
  • 10 Fuchs HE, Berger Jr H, Pizzo SV. Catabolism of human tissue plasminogen activator in mice. Blood 1985; 65: 539-544
    PubMedGoogle Scholar
  • 11 Bakhit C, Lewis D, Billings R, Malfroy B. Cellular catabolism of recombinant tissue-type plasminogen activator. J Biol Chem 1987; 262: 8716-8720
    PubMedGoogle Scholar
  • 12 Browne MJ, Carey JE, Chapman CG, Tyrrell AW R, Entwisle C, Lawrence GM P, Reavy B, Dodd I, Esmail A, Robinson JH. A tissue-type plasminogen activator mutant with prolonged clearance in vivo. J Biol Chem 1988; 263: 1599-1602
    PubMedGoogle Scholar
  • 13 Collen D, Stassen JM, Larsen G. Pharmacokinetics and thrombolytic properties of deletion mutants of human tissue-type plasminogen activator in rabbits. Blood 1988; 71: 216-219
    PubMedGoogle Scholar
  • 14 Fu KP, Lee S, Hum WT, Kalyan N, Rappaport R, Hetzel N, Hung PP. Disposition of a novel recombinant tissue plasminogen activator, Δ2-89TPA, in mice. Thromb Res 1988; 50: 33-41
    PubMedGoogle Scholar
  • 15 Parham P, Androlewicz MJ, Brodsky FM, Holmes NJ, Ways JP. Monoclonal antibodies: purification, fragmentation and application to structural and functional studies of class I MHC Antigens. J Immunol Meth 1982; 53: 133-139
    CrossrefPubMedGoogle Scholar
  • 16 Reilly TM, Flint SK, McHugh B, Wilsbach-Volcheck KM, Timmermans PB M W M. Characterization of a panel of monoclonal antibodies against human tissue-type plasminogen activator. Hybridoma 1988; 7: 177-183
    CrossrefPubMedGoogle Scholar
  • 17 Urdén G, Johansson U, Chmielewska J, Brandt J, Wiman B. Monoclonal antibodies towards the fast inhibitor of tissue plasminogen activator from human plasma and serum. Thromb Haemostas 1986; 55: 383-387
    PubMedGoogle Scholar
  • 18 Owensby DA, Sobel BE, Schwartz AL. Receptor-mediated endocytosis of tissue-type plasminogen activator by the human hepatoma cell line Hep G2. J Biol Chem 1988; 263: 10587-10594
    PubMedGoogle Scholar
  • 19 Gaffney PJ, Curtis AD. A collaborative study of a proposed international standard for tissue plasminogen activator (t-PA). Thromb Haemostas 1985; 53: 134-136
    PubMedGoogle Scholar
  • 20 Nilsson S, Einarsson M, Ekvarn S, Haggroth L, Mattson C. Turnover of tissue plasminogen activator in normal and hepatectomized rabbits. Thromb Res 1985; 39: 511-521
    CrossrefPubMedGoogle Scholar
  • 21 Bounameaux H, Stassen JM, Seghers C, Collen D. Influence of fibrin and liver blood flow on the turnover and the systemic fibringenolytic effects of recombinant human tissue-type plasminogen activator in rabbits. Blood 1986; 67: 1493-1497
    PubMedGoogle Scholar