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Antidote-mediated control of an anticoagulant aptamer in vivo

Nature Biotechnology volume 22, pages 1423–1428 (2004)Cite this article

Abstract

Patient safety and treatment outcome could be improved if physicians could rapidly control the activity of therapeutic agents in their patients. Antidote control is the safest way to regulate drug activity, because unlike rapidly clearing drugs, control of the drug activity is independent of underlying patient physiology and co-morbidities. Until recently, however, there was no general method to discover antidote-controlled drugs. Here we demonstrate that the activity and side effects of a specific class of drugs, called aptamers, can be controlled by matched antidotes in vivo. The drug, an anticoagulant aptamer, systemically induces anticoagulation in pigs and inhibits thrombosis in murine models. The antidote rapidly reverses anticoagulation engendered by the drug, and prevents drug-induced bleeding in surgically challenged animals. These results demonstrate that rationally designed drug-antidote pairs can be generated to provide control over drug activities in animals.

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Figure 1: Anticoagulant activity and antidote neutralization of Ch-9.3t in human and animal plasmas.
Figure 2: In vivo drug and antidote activity in swine.
Figure 3: Aptamer Ch-9.3t is an antithrombotic in mice.
Figure 4: Antidote prevents bleeding induced by drug treatment and surgical trauma.

References

  1. Ebbesen, J. et al. Drug-related deaths in a department of internal medicine. Arch. Intern. Med. 161, 2317–2323 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Levine, M.N., Raskob, G., Landefeld, S. & Kearon, C. Hemorrhagic complications of anticoagulant treatment. Chest 119, 108S–121S (2001).

    Article  CAS  PubMed  Google Scholar 

  3. Hebert, P.C. et al. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N. Engl. J. Med. 340, 409–417 (1999).

    Article  CAS  PubMed  Google Scholar 

  4. Bracey, A.W. et al. Lowering the hemoglobin threshold for transfusion in coronary artery bypass procedures: effect on patient outcome. Transfusion 39, 1070–1077 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Engoren, M.C. et al. Effect of blood transfusion on long-term survival after cardiac operation. Ann. Thorac. Surg. 74, 1180–1186 (2002).

    Article  PubMed  Google Scholar 

  6. Moscucci, M. Frequency and costs of ischemic and bleeding complications after percutaneous coronary interventions: rationale for new antithrombotic agents. J. Invasive Cardiol. 14 Suppl B, 55B–64B (2002).

    PubMed  Google Scholar 

  7. Moscucci, M. et al. Predictors of major bleeding in acute coronary syndromes: the Global Registry of Acute Coronary Events (GRACE). Eur. Heart J. 24, 1815–1823 (2003).

    Article  CAS  PubMed  Google Scholar 

  8. Rao, S.V. et al. The relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. J. Am. Med. Assoc. (in the press) (2004).

  9. Al Suwaidi, J. et al. Prognostic implications of abnormalities in renal function in patients with acute coronary syndromes. Circulation 106, 974–980 (2002).

    Article  PubMed  Google Scholar 

  10. Rusconi, C.P. et al. RNA aptamers as reversible antagonists of coagulation factor IXa. Nature 419, 90–94 (2002).

    Article  CAS  PubMed  Google Scholar 

  11. Willis, M.C. et al. Liposome-anchored vascular endothelial growth factor aptamers. Bioconjug. Chem. 9, 573–582 (1998).

    Article  CAS  PubMed  Google Scholar 

  12. High, K.A. & Roberts, H.R. Coagulation Factor IX. in Molecular Basis of Thrombosis and Hemostasis (eds. High, K.A. & Roberts, H.R.) 215–237 (Marcel Dekker, New York, 1995).

    Google Scholar 

  13. White, R. et al. Generation of species cross-reactive aptamers using “toggle” SELEX. Mol. Ther. 4, 567–573 (2001).

    Article  CAS  PubMed  Google Scholar 

  14. Lin, H.F., Maeda, N., Smithies, O., Straight, D.L. & Stafford, D.W. A coagulation factor IX-deficient mouse model for human hemophilia B. Blood 90, 3962–3966 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Drolet, D.W. et al. Pharmacokinetics and safety of an anti-vascular endothelial growth factor aptamer (NX1838) following injection into the vitreous humor of rhesus monkeys. Pharm. Res. 17, 1503–1510 (2000).

    Article  CAS  PubMed  Google Scholar 

  16. Carr, J.A. & Silverman, N. The heparin-protamine interaction. A review. J. Cardiovasc. Surg. (Torino) 40, 659–666 (1999).

    CAS  Google Scholar 

  17. Kurz, K.D., Main, B.W. & Sandusky, G.E. Rat model of arterial thrombosis induced by ferric chloride. Thromb. Res. 60, 269–280 (1990).

    Article  CAS  PubMed  Google Scholar 

  18. Zhu, Y., Carmeliet, P. & Fay, W.P. Plasminogen activator inhibitor-1 is a major determinant of arterial thrombolysis resistance. Circulation 99, 3050–3055 (1999).

    Article  CAS  PubMed  Google Scholar 

  19. Dejana, E., Villa, S. & de Gaetano, G. Bleeding time in rats: a comparison of different experimental conditions. Thromb. Haemost. 48, 108–111 (1982).

    Article  CAS  PubMed  Google Scholar 

  20. Fay, W.P., Parker, A.C., Ansari, M.N., Zheng, X. & Ginsburg, D. Vitronectin inhibits the thrombotic response to arterial injury in mice. Blood 93, 1825–1830 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Spanier, T.B. et al. Selective anticoagulation with active site-blocked factor IXA suggests separate roles for intrinsic and extrinsic coagulation pathways in cardiopulmonary bypass. J. Thorac. Cardiovasc. Surg. 116, 860–869 (1998).

    Article  CAS  PubMed  Google Scholar 

  22. Choudhri, T.F. et al. Targeted inhibition of intrinsic coagulation limits cerebral injury in stroke without increasing intracerebral hemorrhage. J. Exp. Med. 190, 91–99 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Feuerstein, G.Z. et al. Antithrombotic efficacy of a novel murine antihuman factor IX antibody in rats. Arterioscler. Thromb. Vasc. Biol. 19, 2554–2562 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Schoenhagen, P. & Nissen, S.E. Coronary atherosclerotic disease burden: an emerging endpoint in progression/regression studies using intravascular ultrasound. Curr. Drug Targets Cardiovasc. Haematol. Disord. 3, 218–226 (2003).

    Article  CAS  PubMed  Google Scholar 

  25. Hoffman, M. & Monroe, D.M., III. A cell-based model of hemostasis. Thromb. Haemost. 85, 958–965 (2001).

    Article  CAS  PubMed  Google Scholar 

  26. Rosenberg, R.D. Vascular-bed-specific hemostasis and hypercoagulable states: clinical utility of activation peptide assays in predicting thrombotic events in different clinical populations. Thromb. Haemost. 86, 41–50 (2001).

    Article  CAS  PubMed  Google Scholar 

  27. Minnema, M.C. et al. Activation of clotting factors XI and IX in patients with acute myocardial infarction. Arterioscler. Thromb. Vasc. Biol. 20, 2489–2493 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Samama, M.M., Gerotziafas, G.T., Elalamy, I., Horellou, M.H. & Conard, J. Biochemistry and clinical pharmacology of new anticoagulant agents. Pathophysiol. Haemost. Thromb. 32, 218–224 (2002).

    Article  CAS  PubMed  Google Scholar 

  29. Reed, M.D. & Bell, D. Clinical pharmacology of bivalirudin. Pharmacotherapy 22, 105S–111S (2002).

    Article  CAS  PubMed  Google Scholar 

  30. DeAnda, A., Jr. et al. Pilot study of the efficacy of a thrombin inhibitor for use during cardiopulmonary bypass. Ann. Thorac. Surg. 58, 344–350 (1994).

    Article  PubMed  Google Scholar 

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Acknowledgements

We thank K.A. High for plasma from factor IX-deficient mice. We thank B. Harrington, R. Califf, J. Alexander and B. Anderson for their continued intellectual support of the development of antidote-controlled anticoagulant and antithrombotic agents. This work was supported by grants from the American Heart Association to C.P.R. and the National Institutes of Health to B.A.S. and W.P.F.

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  1. Christopher P Rusconi

    Present address: Regado Biosciences, Inc., PO Box 14688, Research Triangle Park, North Carolina, 27709, USA

Authors and Affiliations

  1. Department of Surgery, Center for Translational Research, Duke University Medical Center, Campus Box 2601, Durham, 27710, North Carolina, USA

    Christopher P Rusconi, George A Pitoc, Shahid M Nimjee, Rebekah R White, George Quick Jr, Elizabeth Scardino & Bruce A Sullenger

  2. Department of Internal Medicine, University of Michigan Medical Center, 7301 MSRB III, 1150 W. Medical Center Drive, Ann Arbor, 48109, Michigan, USA

    Joseph D Roberts & William P Fay

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Correspondence to Christopher P Rusconi or Bruce A Sullenger.

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Competing interests

C.P.R. and B.A.S. have equity in Regado Biosciences, Inc., a biotechnology company spun out of Duke University to commercialize drug-antidote pairs.

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Rusconi, C., Roberts, J., Pitoc, G. et al. Antidote-mediated control of an anticoagulant aptamer in vivo. Nat Biotechnol 22, 1423–1428 (2004). https://doi.org/10.1038/nbt1023

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