Patent
Anticoagulant antidotes comprising antibodies that bind dabigatran and/or related compounds and methods of use thereof
| العنوان: | Anticoagulant antidotes comprising antibodies that bind dabigatran and/or related compounds and methods of use thereof |
|---|---|
| Patent Number: | 8,821,871 |
| تاريخ النشر: | September 02, 2014 |
| Appl. No: | 13/432296 |
| Application Filed: | March 28, 2012 |
| مستخلص: | The present invention relates to antibody molecules against anticoagulants, in particular dabigatran, and their use as antidotes of such anticoagulants. |
| Inventors: | Van Ryn, Joanne (Warthausen, DE); Canada, Keith (Southbury, CT, US); Copenhaver, Robert (Portland, OR, US); Hauel, Norbert (Schemmerhofen, DE); Litzenburger, Tobias (Mittelbiberach, DE); Sarko, Christopher Ronald (New Milford, CT, US); Singh, Sanjaya (Sandy Hook, CT, US); Waterman, Alisa K. (Weston, CT, US) |
| Assignees: | Boehringer Ingelheim International GmbH (Ingelheim am Rhein, DE) |
| Claim: | 1. An antibody molecule against dabigatran comprising a heavy chain variable domain with a CDR1 of SEQ ID NO: 67, a CDR2 of SEQ ID NO: 68, and a CDR3 of SEQ ID NO: 9, and a light chain variable domain with a CDR1 of SEQ ID NO: 64, a CDR2 of SEQ ID NO: 65, and a CDR3 of SEQ ID NO: 69. |
| Claim: | 2. The antibody molecule of claim 1 comprising a heavy chain variable domain of SEQ ID NO: 92, and a light chain variable domain of SEQ ID NO: 93. |
| Claim: | 3. The antibody molecule of claim 1 comprising a heavy chain variable domain of SEQ ID NO: 92, and a light chain variable domain of SEQ ID NO: 94. |
| Claim: | 4. The antibody molecule of claim 1 comprising a heavy chain of SEQ ID NO: 99, and a light chain of SEQ ID No: 100. |
| Claim: | 5. The antibody molecule of claim 1 comprising a heavy chain of SEQ ID NO: 99, and a light chain of SEQ ID No: 101. |
| Claim: | 6. The antibody molecule of claim 1 , wherein the antibody is a polyclonal antibody, a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, a Fab, Fab', or F(ab') 2 fragment of an antibody, a single chain antibody, a single chain variable fragment (scFv), a Small Modular Immunopharmaceutical (SMIP), or a diabody. |
| Claim: | 7. The antibody molecule of claim 1 for use in medicine. |
| Claim: | 8. Antibody molecule of claim 1 for use in the therapy or inhibition of side effects of dabigatran, and/or for reversal of an overdosing of dabigatran. |
| Claim: | 9. Antibody molecule of claim 8 , wherein the side effect is a bleeding event. |
| Claim: | 10. A kit comprising an antibody of claim 1 or 6 , or a pharmaceutical composition thereof. |
| Claim: | 11. A kit comprising: (a) an antibody of claim 1 or 6 , or a pharmaceutical composition thereof; (b) a container; and (c) a label. |
| Claim: | 12. A kit comprising an antibody of claim 1 or 6 , and dabigatran, dabigatran etexilate, a prodrug of dabigatran or a pharmaceutically acceptable salt thereof. |
| Claim: | 13. Method of manufacturing an antibody molecule of claim 1 or 6 , comprising (a) providing a host cell comprising one or more nucleic acids encoding said antibody molecule in functional association with an expression control sequence, (b) cultivating said host cell, and (c) recovering the antibody molecule from the cell culture. |
| Claim: | 14. Method of treatment or prevention of side effects of anticoagulant therapy, or of an overdosing event in anticoagulant therapy, comprising administering an effective amount of an antibody molecule of claim 1 or 6 to a patient in need thereof. |
| Claim: | 15. A method for neutralizing or partially neutralizing dabigatran or 1-O-acylglucuronide of dabigatran in a patient being treated with dabigatran, dabigatran etexilate, a prodrug of dabigatran or a pharmaceutically acceptable salt thereof, comprising administering an antibody of claim 1 or 6 , or a pharmaceutical composition thereof. |
| Claim: | 16. A method for neutralizing or partially neutralizing dabigatran or 1-O-acylglucuronide of dabigatran in a patient comprising: (a) confirming that a patient was being treated with dabigatran, dabigatran etexilate, a prodrug of dabigatran or a pharmaceutically acceptable salt thereof, and the amount that was taken by the patient; (b) neutralizing dabigatran or 1-O-acylglucuronide with an antibody of claim 1 or 6 prior to performing a clotting or coagulation test or assay wherein dabigatran or the 1-O-acylglucuronide of dabigatran would interfere with the accurate read out of the test or assay results; (c) performing the clotting or coagulation test or assay on a sample taken from the patient to determine the level of clot formation without dabigatran or 1-O -acylglucuronide of dabigatran present; and (d) adjusting an amount of dabigatran, dabigatran etexilate, a prodrug of dabigatran or a pharmaceutically acceptable salt thereof administered to the patient in order to achieve the appropriate balance between clot formation and degradation in a patient. |
| Claim: | 17. A method for reducing the concentration of dabigatran or 1-O-acylglucuronide of dabigatran in plasma of a patient being treated with dabigatran, dabigatran etexilate, a prodrug of dabigatran or a pharmaceutically acceptable salt thereof, comprising the step of administering an antibody of claim 1 or 6 , or a pharmaceutical composition thereof that neutralizes the activity of dabigatran or 1-O -acylglucuronide in the patient. |
| Claim: | 18. A method of reversal of the anticoagulant effect of dabigatran or 1-O-acylglucuronide of dabigatran in a patient being treated with dabigatran, dabigatran etexilate, a prodrug of dabigatran or a pharmaceutically acceptable salt thereof, wherein the patient either has major bleeding considered life-threatening or leading to hemodynamic compromise, or wherein the patient requires emergency medical procedures, comprising the step of administering an antibody of claim 1 or 6 , or a pharmaceutical composition thereof that neutralizes the activity of dabigatran or 1-O -acylglucuronide in the patient. |
| Claim: | 19. A method for reversing or reducing the activity of dabigatran or 1-O-acylglucuronide of dabigatran in a patient experiencing bleeding or at risk for bleeding due to an impaired clotting ability or trauma, comprising the steps of: (d) determining the amount of dabigatran or 1-O-acylglucuronide of dabigatran present in the patient; (e) administering an effective amount of an antibody of claim 1 or 6 , or a pharmaceutical composition thereof to reverse or reduce the activity of dabigatran or 1-O-acylglucuronide of dabigatran determined in the patient; and (f) monitoring a thrombin clotting time of the patient to ensure a reversal or reduction in activity of dabigatran or 1-O-acylglucuronide of dabigatran has been reached. |
| Current U.S. Class: | 4241/331 |
| Patent References Cited: | 5693762 December 1997 Queen et al. 5910573 June 1999 Plückthun et al. 6440417 August 2002 Thibaudeau et al. 6469039 October 2002 Hauel et al. 8486398 July 2013 Van Ryn et al. 2004/0097547 May 2004 Taveras et al. 2009/0098119 April 2009 Lu et al. 2011/0206656 August 2011 Van Ryn et al. 2012/0027780 February 2012 Van Ryn et al. 2 277 949 August 1998 WO-98 37075 August 1998 WO-2011 023653 March 2011 WO-2011 089183 July 2011 |
| Other References: | Harmsen et al., Mol Immunol. Aug. 2000;37(10):579-90. cited by examiner Janeway et al., Immunobiology, 3rd edition, 1997, Garland Press, pp. 3:1-3:11. cited by examiner Rudikoff et al., Proc Natl Acad Sci USA, 1982, 79:1979-1983. cited by examiner Portolano et al., J. Immunol., 1993, 150:880-887. cited by examiner William E. Paul, M.D. ed., Fundamental Immunology, 3d ed. 1993, p. 242. cited by examiner Colburn, W. A. et al., “Specific antibodies and Fab Fragments to Alter the Pharmacokinetics and Reverse the Pharmacologic/ Toxicologic Effects of Drugs,” Drug Metabolism Reviews, 1980, vol. 11, No. 2, pp. 223-262. cited by applicant Eisert, W. G. et al., “Dabigatran: An Oral Novel Potent Reversible Nonpeptide Inhibitor of Thrombin,” Arterioscler Thromb Vasc Biol., 2010, vol. 30, pp. 1885-1889. cited by applicant Hardin, J. S. et al., “Pharmacodynamics of a monoclonal antiphencyclidine Fab with Broad Selectivity for Phencyclidine-Like Drugs,” The Journal of Phamacology and Experiemental Therapeutics, 1998, vol. 285, No. 3, pp. 1113-1122. cited by applicant Herion, P. et al., “Monoclonal Antibodies Against Plasma Protease Inhibitors: Production and Characterization of 15 Monoclonal Antibodies Against Human Antithrombin III. Relation Between Antigenic Determinants and Functional Sites of Antithrombin III.” Blood, May 1965, vol. 65, No. 5, pp. 1201-1207. cited by applicant Hursting, M. J. et al., “Drug-specific Fab Therapy in Drug Overdose,” Arch Pathol Lab Med., Aug. 1987, vol. 111, pp. 693-697. cited by applicant International Search Report for PCT/EP2011/073025 dated Mar. 14, 2012. cited by applicant International Search Report for PCT/EP2012/055397 dated May 30, 2012. cited by applicant Lapostolle, F. et al., “Assessment of digoxin antibody use in patients with elevated serum digoxin following chronic or acute exposure,” Intensive Care Med., 2008, vol. 34, pp. 1448-1453. cited by applicant Prescrire Int., 2009, vol. 101, pp. 97-99. cited by applicant Schlaeppi, J. M. et al., “Preparation of monoclonal antibodies to hirudin and hirudin peptides—A method for studying the hirudin—thrombin interaction,” European Journal of Biochemistry, 1990, vol. 188, No. 2, pp. 463-470. cited by applicant Schulman, S. et al., “Anticoagulants and Their Reversal,” Transfustion Medicine Reviews, Jan. 2007, vol. 21, No. 1, pp. 37-48. cited by applicant Written Opinion for the International Searching Authority for PCT/EP2012/055397 dated May 30, 2012. cited by applicant Written Opinion of the International Searching Authority for PCT/EP2011/073025 dated Mar. 14, 2012. cited by applicant Zikria, J. C. et al., “Oral anticoagulation with factor Xa and thrombin inhibitors: on the threshold of change,” Current Opinion in Hematology, 2009, vol. 16, No. 5, pp. 347-356. cited by applicant Van Ryn, J. et al., “Dabigatran etexilate—novel, reversible, oral direct thrombin inhibitor: interpretation of coagulation assays and reversal of anticoagulant activity,” Thrombosis and Haemostasis, 2011, vol. 105, No. 3, pp. 570. cited by applicant Van Ryn, Joanne, et al; Dabigatran Etexilate—A Novel, Reversible, Oral Direct Thrombin Inhitor: Interpretation of Coagulation Assays and Reversal of Anticoagulant Activity; Thrombosis and Haemostasis (2010) pp. 1116-1127. cited by applicant Van Ryn, Joanne, et al; Dabigatran Anticoagulant Activity is Neutralized by an Antibody Selective to Dabigatran an in vitro an in vivo Models; JACC (2011) vol. 57, No. 14 p. 1. cited by applicant |
| Primary Examiner: | Szperka, Michael |
| Attorney, Agent or Firm: | Morris, Michael P. Petka, Wendy A. |
| رقم الانضمام: | edspgr.08821871 |
| قاعدة البيانات: | USPTO Patent Grants |
| الوصف غير متاح. |