Claims for Patent: 8,992,915

Summary for Patent: 8,992,915

Title:	Combination of CD37 antibodies with ICE
Abstract:	The present invention relates to immunotherapies that are based on depletion of CD37-positive cells such as B-cells. The present invention provides methods for reduction of CD37-positive cells such as B-cells in an individual/patient using a combination of CD37 antibody/antibodies and ICE. The combination of CD37 antibodies and ICE is shown to have improved anti-tumor efficacy compared to single agent treatment. The application further provides materials and methods for treatment of diseases involving aberrant B-cell activity.
Inventor(s):	Heider; Karl-Heinz (Stockerau, AT), Baum; Anke (Hinterbruehl, AT), Russell; Charlotte Astrid (Hellerup, DK)
Assignee:	Boehringer Ingelheim International GmbH (Ingelheim am Rhein, DE)
Application Number:	13/894,743
Patent Claims:	1. A method for the treatment of a patient suffering from chronic lymphocytic leukemia (CLL) or B-cell non-Hodgkin's lymphoma (B-NHL), the method comprising administering to the patient (a) a CD37 antibody and (b) a combination chemotherapy regimen comprising ICE (ifosfamide, carboplatin, and etoposide (or etoposide phosphate)), whereby the CD37 antibody comprises: a) a variable heavy chain comprising CDRs having 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. 2. The method of claim 1, wherein the patient receives at least one dose of the CD37 antibody and at least one administration of ICE during a treatment cycle, whereby a treatment cycle is a time period of about 1 to 6 weeks. 3. The method of claim 1, wherein the patient additionally receives at least one dose of a CD20 antibody which is Rituximab. 4. The method of claim 1, whereby the CD37 antibody is administered to said patient simultaneously with the administration of ICE. 5. The method of claim 1, whereby the CD37 antibody is administered to said patient after the administration of ICE. 6. The method of claim 1, whereby the CD37 antibody is administered to said patient before the administration of ICE. 7. The method of claim 2, whereby the CD37 antibody is administered at least twice during the treatment cycle, whereby one of the administrations of the CD37 antibody is in the middle of the treatment cycle at about 2 weeks or once weekly. 8. The method of claim 1, whereby the CD37 antibody is administered in a dose of about 10 .mu.g/kg to 40 mg/kg or in a dose of about 1 mg and 2800 mg per patient. 9. The method of claim 1, wherein the patient is a 70 kg human patient, wherein the said human patient is administered a weekly dose in the range of 1 mg to 2800 mg, whereby the CD37 antibody comprises SEQ ID NOs: 5 and 6. 10. The method of claim 1, wherein the patient is a 70 kg human patient, wherein the said human patient is administered a weekly dose in the range of 1 mg to 2800 mg, whereby the CD37 antibody comprises SEQ ID NOs: 11 and 12. 11. The method of claim 2, whereby doses of each component of ICE are: i) for ifosfamide between 3-7 g/m.sup.2 body surface, whereby the ifosfamide is administered on the 2.sup.nd treatment day of the treatment cycle, ii) for carboplatin between 200-800 mg, whereby the carboplatin is administered on the 2.sup.nd treatment day of the treatment cycle and iii) for etoposide between 50-200 mg/m.sup.2, whereby the etoposide is administered on the 1.sup.st, 2.sup.nd and 3.sup.rd treatment day of the treatment cycle. 12. The method of claim 11, whereby the patient is a patient suffering from B-NHL and whereby the treatment cycle is preferably 2-3 weeks. 13. The method of claim 1, whereby the combination of the CD37 antibody and ICE is administered as first line treatment. 14. The method of claim 1, whereby the combination of the CD37 antibody and ICE is administered as second or later line treatment. 15. A method of reducing CD37-positive cells comprising: a) Exposing CD37-positive cells to a CD37 antibody and b) Exposing CD37-positive cells to ICE (ifosfamide, carboplatin, and etoposide (or etoposide phosphate)), whereby said CD37 antibody of step a) 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. 16. The method of claim 15, whereby the CD37-positive cells are additionally exposed to a CD20 antibody which is Rituximab. 17. The method of claim 15, whereby the CD37-positive cells are exposed to the CD37 antibody and ICE simultaneously, or whereby the CD37-positive cells are exposed to the CD37 antibody after they are exposed to ICE, or whereby the CD37-positive cells are exposed to the CD37 antibody before they are exposed to ICE, preferably within 24 hrs or within 36 hrs before they are exposed to ICE. 18. 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 ICE (ifosfamide, carboplatin, and etoposide (or etoposide phosphate)) 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 ICE and a CD20 antibody which is Rituximab. 19. An article of manufacture comprising a CD37 antibody, ICE (ifosfamide, carboplatin, and etoposide (or etoposide phosphate)), and a label indicating a method according to claim 15, whereby the said CD37 antibody comprises: a) a variable heavy chain comprising CDRs having 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. 20. A pharmaceutical composition comprising a CD37 antibody, ICE (ifosfamide, carboplatin, and etoposide (or etoposide phosphate)), and a pharmaceutically acceptable carrier, whereby the CD37 antibody comprises: a) a variable heavy chain comprising CDRs having 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. 21. A method of treating a CD37-positive malignancy, comprising administrating a therapeutically effective amount of i) a CD37 antibody and ii) ICE (ifosfamide, carboplatin, and etoposide (or etoposide phosphate)) and optionally iii) a CD20 antibody which is 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. 22. The method of treatment according to claim 21, 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 (B-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 B-CLL), 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. 23. The method of claim 22, whereby the B-cell malignancy is B-cell non-Hodgkin's lymphoma, B-cell chronic lymphocytic leukemia, and whereby the B-cell malignancy is B-cell non-Hodgkin's lymphoma.

Details for Patent 8,992,915

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Genentech, Inc.	RITUXAN	rituximab	Injection	103705	11/26/1997		2032-05-16
Idec Pharmaceuticals Corp.	RITUXAN	rituximab	Injection	103737	02/19/2002		2032-05-16
Genentech, Inc.	RITUXAN HYCELA	rituximab and hyaluronidase human	Injection	761064	06/22/2017		2032-05-16