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1. (WO2014198330) COMBINATION OF CD37 ANTIBODIES WITH CHLORAMBUCIL
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CLAIMS

1. A CD37 antibody for use in a method for the treatment of a patient suffering from a CD37-positive malignancy, preferably a B-cell malignancy, most preferably chronic lymphocytic leukemia (CLL) or B-cell non-Hodgkin' s lymphoma (B-NHL), in combination with chlorambucil, whereby the CD37 antibody comprises:

a variable heavy chain comprising CDRs have the SEQ ID NOs: 15, 16 or 21, and 17, and

a variable light chain comprising CDRs having the SEQ ID NOs: 18, 19 and 20.

2. The CD37 antibody of claim 1, wherein the patient receives at least one dose of the CD37 antibody and at least one dose of chlorambucil during a treatment cycle, whereby a treatment cycle is a time period of about 1 to 6 weeks, preferably 3 to 4 weeks, most preferably 4 weeks.

3. The CD37 antibody of claim 1 or 2, wherein the patient additionally receives at least one dose of a CD20 antibody such as Rituximab.

4. The CD37 antibody of claim 1 to 3, whereby the CD37 antibody is administered to said patient simultaneously with the administration of chlorambucil.

5. The CD37 antibody of claim 1 to 3, whereby the CD37 antibody is administered to said patient after the administration of chlorambucil, preferably within 24hrs or within 36hrs after the administration of chlorambucil, preferably the CD37 antibody is administered to said patient after a 2 day consecutive application of chlorambucil, preferably within 24hrs or within 36hrs after the administration of the second chlorambucil dosage.

6. The CD37 antibody of claim 1 to 3, whereby the CD37 antibody is administered to said patient before the administration of chlorambucil, preferably within 24hrs or within 36hrs before the administration of chlorambucil, preferably the CD37 antibody is administered to said patient before a 2 day consecutive application of chlorambucil,

preferably within 24hrs or within 36hrs before the administration of the first chlorambucil dosage.

7. The CD37 antibody of claims 1 to 6, whereby the CD37 antibody is additionally administered at least one more time during a treatment cycle, preferably in the middle of the treatment cycle at about 2 weeks or once weekly.

8. The CD37 antibody of claims 1 to 7, whereby the said CD37 antibody is administered in a dose of about l(^g/kg to 40mg/kg or in a dose of about 1mg to 2800 mg per patient.

9. The CD37 antibody of claims 1 to 8, whereby the estimated weekly dose of CD37 antibody for a 70 kg human is in the range of 1mg to 2800mg, preferably in the range of 1mg to 400mg weekly or 2 mg to 800 mg every 2 weeks, whereby the CD37 antibody preferably comprises SEQ ID NOs: 5 and 6.

10. The CD37 antibody of claims 1 to 8, whereby the estimated weekly dose of CD37 antibody for a 70 kg human is in the range of 1mg to 2800mg, preferably in the range of 1mg to 1000mg, most preferably in the range of 100 mg to 385 mg weekly or 200 mg to 770mg every two weeks, whereby the CD37 antibody preferably comprises SEQ ID NOs: 11 and 12.

11. The CD37 antibody of claims 1 to 10, whereby the dose for chlorambucil ranges between 50-150 mg/m2 body surface, preferably the chlorambucil dose ranges between 70-120mg/m2 body surface or between 100 - 150 mg/m2 body surface or between 60 - 70 mg/m2 body surface.

12. The CD37 antibody of claims 1 to 11, whereby the patient is a patient suffering from CLL and whereby chlorambucil is preferably administered at a dosage of 100mg/m2 body surface preferably on days 1 and 2 of the treatment cycle, which is preferably 3-4 weeks long, most preferably 4 weeks.

13. The CD37 antibody of claims 1 to 11, whereby the patient is a patient suffering from B-NHL and whereby chlorambucil is preferably administered at a dosage of 120mg/m2 body surface preferably on days 1 and 2 of the treatment cycle , which is preferably 3-4 weeks, most preferably 3 weeks.

14. The CD37 antibody of claim 1 to 3, whereby chlorambucil is administered as a one-time administration per treatment cycle preferably with a dose of 70-400mg/m2 body surface.

15. The CD37 antibody of claims 1 to 14, whereby the combination of the CD37 antibody and chlorambucil is administered as first line treatment.

16. The CD37 antibody of claims 1 to 14, whereby the combination of the CD37 antibody and chlorambucil is administered as second or later line treatment.

17. A method of reducing CD37-positive cells comprising:

a) Exposing CD37-positive cells to a CD37 antibody and

b) Exposing CD37-positive cells to chlorambucil,

whereby said CD37 antibody of step a) comprises:

i) a variable heavy chain comprising CDRs have the SEQ ID NOs: 15, 16 or 21, and 17, and

ii) a variable light chain comprising CDRs having the SEQ ID NOs: 18, 19 and 20.

18. The method of claim 17, whereby the CD37-positive cells are additionally exposed to a CD20 antibody such as Rituximab.

19. The method of claim 17 or 18, whereby the CD37-positive cells are exposed to the CD37 antibody and chlorambucil simultaneously, or

whereby the CD37-positive cells are exposed to the CD37 antibody after they are exposed to chlorambucil, preferably within 24hrs or within 36hrs after they are exposed to chlorambucil, or

whereby the CD37-positive cells are exposed to the CD37 antibody before they are exposed to chlorambucil, preferably within 24hrs or within 36hrs before they are exposed to chlorambucil.

20. A kit for reducing CD37-positive cells comprising:

a) a container comprising a CD37 antibody, whereby said CD37 antibody comprises:

i) a variable heavy chain comprising CDRs having the SEQ ID NOs: 15, 16 or 21, and 17, and

ii) a variable light chain comprising CDRs having the SEQ ID NOs: 18, 19 and 20, and

b) a protocol for using the kit to reduce CD37-positive cells by administration of the CD37 antibody of step a) in combination with chlorambucil and/or c) optionally a protocol for using the kit to reduce CD37-positive cells by administration of the CD37 antibody of step a) in combination with chlorambucil and a CD20 antibody such as Rituximab.

21. A kit for reducing CD37-positive cells comprising:

a) a first container comprising a CD37 antibody, whereby said CD37 antibody comprises:

i) a variable heavy chain comprising CDRs have the SEQ ID NOs: 15, 16 or 21, and 17, and

ii) a variable light chain comprising CDRs having the SEQ ID NOs: 18, 19 and 20, and

b) a second container comprising chlorambucil, and

c) optionally a third container comprising a CD20 antibody like Rituximab, and

d) a protocol for using the kit to reduce CD37-positive cells.

22. The kit according to claim 20 or 21, whereby the protocol indicates to administer the CD37 antibody and ben chlorambucil damustine simultaneously, or

whereby the protocol indicates to administer the CD37 antibody before chlorambucil, preferably within 24hrs or within 36hrs before the administration of chlorambucil, or whereby the protocol indicates to administer the CD37 antibody after chlorambucil, preferably within 24hrs or within 36hrs after the administration of chlorambucil.

23. The kit according to claim 20 to 22, whereby the protocol indicates to administer the kit components to a patient suffering from a CD37-positive malignancy, preferably a B-cell malignancy, preferably chronic lymphocytic leukemia (CLL) or B-NHL, most preferably CLL.

24. An article of manufacture comprising a CD37 antibody and chlorambucil and a label indicating a method according to claims 17-19, whereby the CD37 antibody comprises:

a) a variable heavy chain comprising CDRs have the SEQ ID NOs: 15, 16 or 21, and 17, and

b) a variable light chain comprising CDRs having the SEQ ID NOs: 18, 19 and 20.

25. A pharmaceutical composition comprising a CD37 antibody, chlorambucil, and a pharmaceutically acceptable carrier, whereby the CD37 antibody comprises:

a) a variable heavy chain comprising CDRs have the SEQ ID NOs: 15, 16 or 21, and 17, and

b) a variable light chain comprising CDRs having the SEQ ID NOs: 18, 19 and 20.

26. A method of treating a CD37-positive malignancy, preferably a B-cell malignancy, comprising administrating a therapeutically effective amount of i) a CD37 antibody and ii) chlorambucil and optionally iii) a CD20 antibody such as Rituximab to a patient in need thereof, whereby the CD37 antibody comprises:

a) a variable heavy chain comprising CDRs have the SEQ ID NOs: 15, 16 or 21 , and 17, and

b) a variable light chain comprising CDRs having the SEQ ID NOs: 18, 19 and 20.

27. The CD37 antibody of claims 1 to 16, the method according to claims 17 to 19, the kit according to claims 20 to 23, the article of manufacture according to claim 24, the pharmaceutical composition of claim 25, and the method of treatment according to claim 26, whereby the CD37 antibody is a chimeric antibody defined by

a) a variable heavy chain comprising the amino acid sequence shown in SEQ ID NO: 2, and

b) a variable light chain comprising the amino acid sequence shown in SEQ ID NO:4,

whereby the constant heavy and light chains are preferably of human origin.

28. The CD37 antibody of claims 1 to 16, the method according to claims 17 to 19, the kit according to claims 20 to 23, the article of manufacture according to claim 24, the pharmaceutical composition of claim 25, and the method of treatment according to claim 26, whereby the antibody has a heavy chain comprising the amino acid sequence of SEQ ID NO: 5 and a light chain comprising the amino acid sequence of SEQ ID NO: 6.

29. The CD37 antibody of claims 1 to 16, the method according to claims 17 to 19, the kit according to claims 20 to 23, the article of manufacture according to claim 24, the pharmaceutical composition of claim 25, and the method of treatment according to claim 26, whereby the antibody has a heavy chain comprising the amino acid sequence of SEQ ID NO: 7 fused to SEQ ID NO:2 and a light chain comprising the amino acid sequence of SEQ ID NO: 8 fused to SEQ ID NO:4.

30. The CD37 antibody of claims 1 to 16, the method according to claims 17 to 19, the kit according to claims 20 to 23, the article of manufacture according to claim 24, the pharmaceutical composition of claim 25, and the method of treatment according to claim 26, whereby the antibody has a heavy chain comprising the amino acid sequence of SEQ ID NO: 9 and a light chain comprising the amino acid sequence of SEQ ID NO: 10.

31. The CD37 antibody of claims 1 to 16, the method according to claims 17 to 19, the kit according to claims 20 to 23, the article of manufacture according to claim 24, the pharmaceutical composition of claim 25, and the method of treatment according to claim 26, whereby said antibody is a humanized antibody defined by frameworks supporting said CDRs that are derived from a human antibody, and wherein the constant heavy and light chains are from a human antibody.

32. The CD37 antibody of claims 1 to 16, the method according to claims 17 to 19, the kit according to claims 20 to 23, the article of manufacture according to claim 24, the pharmaceutical composition of claim 25, and the method of treatment according to claim 26, whereby the antibody has a heavy chain comprising the amino acid sequence of SEQ ID NO: 11 and a light chain comprising the amino acid sequence of SEQ ID NO: 12.

33. The CD37 antibody of claims 1 to 16, the method according to claims 17 to 19, the kit according to claims 20 to 23, the article of manufacture according to claim 24, the pharmaceutical composition of claim 25, and the method of treatment according to claim 26, whereby the antibody has a heavy chain comprising the amino acid sequence of SEQ ID NO: 13 and a light chain comprising the amino acid sequence of SEQ ID NO: 14.

34. The CD37 antibody of claims 1 to 16 and 27 to 33, the method according to claims 17 to 19, the kit according to claims 20 to 23, the article of manufacture according to claim 24, the pharmaceutical composition of claim 25, and the method of treatment according to claim 26, whereby the CD37-positive malignancy is selected from the group consisting of: multiple myeloma, plasmacytoma, T-cell lymphoma, acute lymphoblastic leukemia (ALL), and B-cell malignancies, e.g. B-cell lymphomas, aggressive B-cell lymphoma, Hodgkin's disease, B-cell non-Hodgkin's lymphoma (NHL), lymphomas, Waldenstrom's macroglobulinaemia (also called lymphoplasmacytic lymphoma or immunocytoma), central nervous system lymphomas, leukemias, acute lymphoblastic leukemia (ALL), chronic lymphocytic leukemia (CLL; also termed B-cell chronic lymphocytic leukemia BCLL), hairy cell leukemia, chronic myoblastic leukemia), small lymphocytic lymphoma, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, extra-nodal marginal zone B-cell lymphoma of mucosa-associated (MALT) lymphoid tissue, nodal marginal zone B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, diffuse large B-cell lymphoma, mediastinal (thymic) large B-cell lymphoma,

intravascular large B-cell lymphoma, primary effusion lymphoma, Burkitt' s lymphoma/leukemia, grey zone lymphoma, B-cell proliferations of uncertain malignant potential, lymphomatoid granulomatosis, and post-transplant lymphoproliferative disorder, whereby the B-cell malignancy is preferably B-cell non-Hodgkin's lymphoma, B-cell chronic lymphocytic leukemia, whereby the B-cell malignancy is most preferably chronic lymphocytic leukemia (CLL).