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Details for Patent: 8,486,398

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Details for Patent: 8,486,398

Title:Anticoagulant antidotes comprising antibodies that bind dabigatran and/or related compounds
Abstract: The present invention relates to antibody molecules against anticoagulants, in particular dabigatran, and their use as antidotes of such anticoagulants.
Inventor(s): Van Ryn; Joanne (Warthausen, DE), Park; John Edward (Warthausen, DE), Hauel; Norbert (Schemmerhofen, DE), Kunz; Ulrich (Biberach, DE), Litzenburger; Tobias (Mittelbiberach, DE), Canada; Keith (Southbury, CT), Singh; Sanjaya (Sandy Hook, CT), Waterman; Alisa (Weston, CT)
Assignee: Boehringer Ingelheim International GmbH (Ingelheim am Rhein, DE)
Filing Date:Jan 20, 2011
Application Number:13/010,403
Claims:1. An isolated antibody molecule of capable of binding to and neutralizing the activity of dabigatran, which comprises a heavy chain variable domain with a CDR1 selected from the group consisting of SEQ ID NO: 1 and SEQ ID NO: 2, a CDR2 selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, and a CDR3 selected from the group consisting of SEQ ID NO: 9 and SEQ ID NO: 10, and a light chain variable domain with a CDR1 selected from the group consisting of SEQ ID NO: 11, SEQ ID NO: 12, and SEQ ID NO: 13, a CDR2 of SEQ ID NO: 14, and a CDR3 of SEQ ID NO: 15.

2. The antibody molecule of claim 1 which is capable of neutralizing the activity of dabigatran and 1-O-acylglucuronide of dabigatran.

3. The antibody molecule of claim 1 which comprises a heavy chain variable domain with a CDR1 of SEQ ID NO: 1, a CDR2 selected from the group consisting of SEQ ID NO: 6, SEQ ID NO: 7, and SEQ ID NO: 8, a CDR3 of SEQ ID NO: 10, and a light chain variable domain with a CDR1 of SEQ ID NO: 13, a CDR2 of SEQ ID NO: 14, and a CDR3 of SEQ ID NO: 15.

4. The antibody molecule of claim 1 which comprises a heavy chain variable domain selected from the group consisting of SEQ ID NOs: 16, 18, 20, 22, 24, and 26, and a light chain variable domain selected from the group consisting of SEQ ID Nos: 17, 19, 21, 23, 25, and 27.

5. The antibody molecule of claim 4 which comprises a heavy chain variable domain of SEQ ID NO: 16, and a light chain variable domain of SEQ ID No: 17, or a heavy chain variable domain of SEQ ID NO: 18, and a light chain variable domain of SEQ ID No: 19, or a heavy chain variable domain of SEQ ID NO: 20, and a light chain variable domain of SEQ ID No: 21, or a heavy chain variable domain of SEQ ID NO: 22, and a light chain variable domain of SEQ ID No: 23, or a heavy chain variable domain of SEQ ID NO: 24, and a light chain variable domain of SEQ ID No: 25, or a heavy chain variable domain of SEQ ID NO: 24, and a light chain variable domain of SEQ ID No: 27, or a heavy chain variable domain of SEQ ID NO: 26, and a light chain variable domain of SEQ ID No: 27.

6. The antibody molecule of claim 1 which is a polyclonal antibody, a monoclonal antibody, a human antibody, a humanized antibody, a chimeric antibody, a fragment of an antibody, a single chain antibody, a Small Modular Immunopharmaceutical (SMIP), a or a diabody.

7. The antibody molecule of claim 6 which is a scFv, wherein the heavy chain variable domain and the light chain variable domain are linked to each other through a linker peptide selected from the group consisting of SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, and SEQ ID NO: 31.

8. The antibody molecule of claim 7 which comprises SEQ ID NO: 32, or SEQ ID NO: 33.

9. The antibody molecule of claim 6 having a heavy chain comprising SEQ ID NO: 34 or SEQ ID NO: 40, and a light chain comprising SEQ ID NO: 35, or having a heavy chain comprising SEQ ID NO: 42, and a light chain comprising SEQ ID NO: 43.

10. The antibody of claim 6 which is a Fab molecule having a Fd fragment comprising SEQ ID NO: 36, SEQ ID NO: 38, or SEQ ID NO: 41, and a light chain comprising SEQ ID NO: 37 or SEQ ID NO: 39.

11. The antibody of claim 6, wherein the antibody fragment is a Fab, Fab', or F(ab').sub.2 fragment.

12. The antibody of claim 6, wherein the single chain antibody is a single chain variable fragment (scFv).

13. A kit comprising an antibody of claim 1, or a pharmaceutical composition thereof.

14. A kit comprising: a. an antibody of claim 1, or a pharmaceutical composition thereof; b. a container; and c. a label.

15. A kit comprising an antibody of claim 1, and dabigatran, dabigatran etexilate, a prodrug of dabigatran or a pharmaceutically acceptable salt thereof.

16. The kit according to claim 15, wherein the form of dabigatran, dabigatran etexilate, a prodrug of dabigatran or a pharmaceutically acceptable salt thereof is in the form of a solid, liquid or gel.

17. The kit according to claim 15, wherein the pharmaceutically acceptable salt of dabigatran etexilate is a mesylate salt.

18. The kit according to claim 15 or 17, wherein the strength per dosage unit of the dabigatran, dabigatran etexilate, a prodrug of dabigatran or a pharmaceutically acceptable salt thereof is between 75 mg and 300 mg, either QD or BID.

19. A kit comprising: a. an antibody of claim 1, or a pharmaceutical composition thereof; b. a pharmaceutical composition of dabigatran, dabigatran etexilate, a prodrug of dabigatran or a pharmaceutically acceptable salt thereof; c. a container; and d. a label.

20. The kit according to claim 19, wherein the form of dabigatran, dabigatran etexilate, a prodrug of dabigatran or a pharmaceutically acceptable salt thereof is in the form of a solid, liquid or gel.

21. The kit according to claim 19, wherein the pharmaceutically acceptable salt of dabigatran etexilate is a mesylate salt.

22. The kit according to claim 19 or 21, wherein the strength per dosage unit of the dabigatran, dabigatran etexilate, a prodrug of dabigatran or a pharmaceutically acceptable salt thereof is between 75 mg and 300 mg, either QD or BID.

23. A kit comprising: a. a first pharmaceutical composition comprising dabigatran, dabigatran etexilate, a prodrug of dabigatran or a pharmaceutically acceptable salt thereof; b. a second pharmaceutical composition comprising an antibody of claim 1; c. instructions for separate administration of said first and second pharmaceutical compositions to a patient, wherein said first and second pharmaceutical compositions are contained in separate containers and said second pharmaceutical composition is administered to a patient requiring neutralization or partial neutralization of dabigatran or 1-O-acylglucuronide of dabigatran.

24. A method for preventing or treating 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 to a patient in need thereof , wherein the anticoagulant therapy comprises dabigatran, dabigatran etexilate, a prodrug of dabigatran or a pharmaceutically acceptable salt thereof.

25. The method according to claim 24, wherein the side effect is a bleeding event.

26. A method of manufacturing an antibody molecule of claim 1, 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.

27. 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 a pharmaceutical composition thereof.

28. 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 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.

29. The method according to claim 27 or 28, wherein the amount of antibody to dabigatran or 1-O-acylglucuronide of dabigatran is in the molar ratio of between 0.1 and 100.

30. The method according to claim 29, wherein the amount of antibody to dabigatran or 1-O-acylglucuronide of dabigatran is in the molar ratio of between 0.1 and 10.

31. The method according to claim 28, wherein the accurate read out of the test or assay result is an accurate read out of fibrinogen levels, activated protein C resistance or related tests.
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