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Thromb Haemost 1996; 75(04): 679-684
DOI: 10.1055/s-0038-1650342
Original Article
Schattauer GmbH Stuttgart

Antiplatelet and Antithrombotic Effects of YM337, the Fab Fragment of a Humanized Anti-GPIIb/IIIa Monoclonal Antibody in Monkeys

Seiji Kaku
Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan
,
Tomihisa Kawasaki
Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan
,
Nami Hisamichi
Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan
,
Yumiko Sakai
Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan
,
Yuta Taniuchi
Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan
,
Osamu Inagaki
Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan
,
Shinya Yano
Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan
,
Ken-ichi Suzuki
Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan
,
Chinami Terazaki
Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan
,
Yasuhiko Masuho
Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan
,
Noboru Satoh
Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan
,
Toichi Takenaka
Department of Biomedical Engineering, Institute of Basic Medical Sciences, University of Tsukuba, Tsukuba City, Ibaraki, Japan
,
Kennichi Yanagi
1   The Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, Ibaraki, Japan
,
Norio Ohshima
1   The Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co., Ltd, Ibaraki, Japan
› Author Affiliations
Further Information

Publication History

Received 07 June 1995

Accepted after resubmission 18 December 1995

Publication Date:
10 July 2018 (online)

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Summary

The antiplatelet and antithrombotic effects of the Fab fragment of the humanized antiplatelet glycoprotein (GP) IIb/IIIa monoclonal antibody C4G1 (YM337) were investigated in monkeys. First, the relationship between the inhibition of platelet aggregation and the prolongation of bleeding time was studied in rhesus monkeys. YM337 dose-dependently inhibited ex vivo platelet aggregation, with complete inhibition at doses higher than 0.25 mg/kg intravenous injection or 1.5 μg/kg/min infusion. At 0.25 mg/kg bolus injection followed by 1.5 μg/kg/min infusion, YM337 immediately and continuously inhibited platelet aggregation during the 6-h infusion period with platelet aggregation rapidly returning to over 50% of baseline within 1 h after the cessation of infusion. Template-bleeding time was significantly prolonged during the period of complete inhibition of platelet aggregation.

Second, the antithrombotic effects of YM337 were investigated in a photochemically-induced thrombosis model in squirrel monkeys. YM337 at a dose of 1 mg/kg intravenous injection followed by 6 μg/kg/min infusion for 60 min prevented occlusive thrombus formation in all 4 monkeys. In contrast, time to occlusive thrombus formation did not change on intravenous bolus injection of aspirin 17 mg/kg (11.3 ± 5.2 min) or sodium ozagrel (9.4 ± 3.0 min) compared with saline (13.3 ± 4.0 min). YM337 but not aspirin or sodium ozagrel significantly inhibited ex vivo ADP-induced platelet aggregation, while all drugs completely inhibited arachidonic acid-induced platelet aggregation. However, while aspirin and sodium ozagrel inhibited the thromboxane B2 generation accompanying arachidonic acid-induced platelet aggregation, YM337 had no effect on this variable. Platelet counts and bleeding time showed no significant change in any group in this squirrel monkey model.

These results indicate that YM337, with a short half-life, may be a useful therapeutic agent in patients with thrombotic disorders.

 

  • References

  • 1 Plow EF, Ginsberg MH. Cellular adhesion: GPIIb/IIIa as a prototypic adhesion receptor. Prog Hemost Thromb 1988; 9: 117-156
    PubMedGoogle Scholar
  • 2 Phillips DR, Charo IF, Parise LV, Fitzgerald LA. The platelet membrane glycoprotein Ilb-IIIa complex. Blood 1988; 71: 831-843
    PubMedGoogle Scholar
  • 3 Coller BS, Folts JD, Scudder LE, Smith SR. Antithrombotic effect of a monoclonal antibody to the platelet glycoprotein Ilb/IIIa receptor in an experimental animal model. Blood 1986; 68: 783-786
    PubMedGoogle Scholar
  • 4 Topol EJ, Plow EF. Clinical trials of platelet receptor inhibitors. Thromb Haemost 1993; 70: 94-98
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Bruggemann M, Winter G, Waldmann H, Neuberger MS. The immuno-genicity of chimeric antibodies. J Exp Med 1989; 170: 2153-2157
    CrossrefPubMedGoogle Scholar
  • 6 Co MS, Yano S, Hsu RK, Landolfi NF, Vasquez M, Cole M, Tso JT, Bring-man T, Laird W, Hudson D, Kawamura K, Suzuki K, Furuichi K, Queen C, Masuho Y. A humanized antibody specific for platelet integrin gpIIb/IIIa. J Immunol 1994; 152: 2968-2976
    PubMedGoogle Scholar
  • 7 Iizuka K, Akahane K, Momose D, Nakazawa M, Tanouchi T, Kawamura M, Ohyama I, Kajiwara I, Iguchi Y, Okada T, Taniguchi K, Miyamoto T, Hayashi M. Highly selective inhibitors of thromboxane synthetase. (I) Imi-dazol derivatives. J Med Chem 1981; 24: 1139-1148
    CrossrefPubMedGoogle Scholar
  • 8 Rosenblum WI, El-Sabban F. Platelet aggregation in the cerebral microcirculation, effect of aspirin and other agents. Circ Res 1977; 40: 320-328
    CrossrefPubMedGoogle Scholar
  • 9 Sato M, Ohshima N. Platelet thrombus induced in vivo by filtered light and fluorescent dye in mesenteric microvessels of the rat. Thromb Res 1984; 35: 319-334
    CrossrefPubMedGoogle Scholar
  • 10 Yano S, Suzuki K, Katoh M, Sugita Y, Kaku S, Kawamura K, Masuho Y. Epitopes and biological activities of two monoclonal antibodies to platelet integrin aIIBβ3. J Biochem 1994; 116: 778-786
    CrossrefPubMedGoogle Scholar
  • 11 Harlow E, Lane D. Antibodies: a laboratory manual. Cold Spring Harbor Laboratory Press; New York: 1988: 630-631
    Google Scholar
  • 12 Yamaki K, Ohishi S. Fluorometric high performance liquid chromatographic analysis of prostaglandin (PG) metabolites: Application to the catabolism of PGE2 and PGF2a in rat and rabbit kidney homogenates. J Pharmacobio-Dyn 1989; 12: 74-79
    CrossrefPubMedGoogle Scholar
  • 13 Cox D, Motoyama Y, Seki J, Aoki T, Dohi M, Yoshida K. Pentamidine: A non-peptide GPIIb/IIIa antagonist - In vitro studies on platelets from humans and other species. Thromb Haemost 1992; 68: 731-736
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Cook NS, Zerwes H-G, Tapparelli C, Powling M, Singh J, Mettemich R, Hagenbach A. Platelet aggregation and fibrinogen binding in human, rhesus monkey, guinea-pig, hamster and rat blood: Activation by ADP and a thrombin receptor peptide and inhibition by glycoprotein IIb/IIIa antagonists. Thromb Haemost 1993; 70: 531-539
    Article in Thieme ConnectPubMedGoogle Scholar
  • 15 Rote WE, Nedelman MA, Mu D-X, Manley PJ, Weisman H, Cunningham MR, Lucchesi BR. Chimeric 7E3 prevents carotid artery thrombosis in cynomolgus monkeys. Stroke 1994; 25: 1223-1233
    CrossrefPubMedGoogle Scholar
  • 16 Cook NS, Kottirsch G, Zerwes H-G. Platelet glycoprotein Ilb/IIIa antagonist. Drugs of the Future 1994; 19: 135-159
    PubMedGoogle Scholar
  • 17 Bemardi MM, Califf RM, Kleiman N, Ellis SG, Topol EJ. Lack of usefulness of prolonged bleeding times in predicting hemorrhagic events in patients receiving the 7E3 glycoprotein Ilb/IIIa platelet antibody. Am J Cardiol 1993; 72: 1121-1125
    CrossrefPubMedGoogle Scholar
  • 18 Frink RJ, Rooney Jr PA, Trowbridge JO, Rose JP. Coronary thrombosis and platelet/fibrin microemboli in death associated with acute myocardial infarction. Br Heart J 1988; 59: 196-200
    CrossrefPubMedGoogle Scholar
  • 19 Sato M, Natori T, Ohshima N. Effects of scavengers of active oxygens on the platelet thrombus formation in microvessels induced by photochemical reaction. In: Tsuchiya M. et al (ed) Microcirc Ann Tokyo; Nihon-Igakukan: 1987: 135-136
  • 20 Sato M, Ohshima N. A new experimental model for inducing platelet thrombus in the microvasculature: Basic study on its feasibility. Blood and Vessel 1984; 15: 36-44
    PubMedGoogle Scholar
  • 21 Fukuda T, Sato M, Nakamura Y, Ohshima N, Inagaki Y. Inhibitory effect of trapidil on platelet thrombus formation in the microvessels of rat mesentery. Blood and Vessel 1985; 16: 573-580
    PubMedGoogle Scholar
  • 22 Kawasaki T, Kaku S, Takenaka T, Yanagi K, Ohshima N. Thrombolytic activity of a novel modified tissue-type plasminogen activator, YM866, in a photochemically induced platelet-rich thrombosis model. J Cardiovasc Pharmacol 1994; 23: 884-889
    CrossrefPubMedGoogle Scholar
  • 23 Hennekens CH. Role of aspirin with thrombotic therapy in acute myocardial infarction. Chest 1990; 97: 51s-55s
    CrossrefPubMedGoogle Scholar
  • 24 Koller RL. Prevention of recurrent ischemic stroke. Postgrad Med 1991; 90: 81-84
    PubMedGoogle Scholar
  • 25 Smith JB, Willis AL. Aspirin selectively inhibits prostaglandin production in human platelets. Nature 1971; 231: 235-237
    PubMedGoogle Scholar
  • 26 Naito J, Komatsu H, Ujiie A, Hamano S, Kubota T, Tsubosima M. Effects of thromboxane synthetase inhibitors on aggregation of rabbit platelets. Eur J Pharmacol 1983; 91: 41-48
    CrossrefPubMedGoogle Scholar
  • 27 Hanson SR, Pareti FI, Ruggeri ZM, Marzec UM, Kunicki TJ, Montgomery RR, Zimmerman TS, Harker LA. Effects of monoclonal antibodies against the platelet glycoprotein Ilb/IIIa complex on thrombosis and hemostasis in the baboon. J Clin Invest 1988; 81: 149-158
    CrossrefPubMedGoogle Scholar
  • 28 Kelly A, Marzec U, Harker D, Chao B, Lumsden A, Maraganore J, Harker L. Antithrombotic effects of applaggin, a novel antiplatelet peptide. Circulation 1990; 82: 2625
    PubMedGoogle Scholar