Treatments for a hematological malignancy

Patent metadata

Field	Value
Publication number	US-2020121815-A1
Application number	US-201816627872-A
Country	US
Kind code	A1
Filing date	Jul 31, 2018
Priority date	Jul 31, 2017
Publication date	Apr 23, 2020
Grant date	—

Abstract

Pharmaceutical compositions comprising a radionuclide labelled monoclonal antibody against CD38, and methods of treating a hematological malignancy, inhibiting growth and/or proliferation of a cell expressing CD38, or treating a disease or disorder involving cells expressing CD38 are disclosed. An exemplary monoclonal antibody includes daratumumab labeled with actinium ( 225 Ac).

First claim

What is claimed is:

1 . A method of treating a disease or disorder involving cells expressing CD38, the method comprising:
administering to a subject an effective amount of a pharmaceutical composition comprising a monoclonal antibody against CD38, wherein the monoclonal antibody is labeled with actinium ( 225 Ac).

2 . The method of claim 1 , wherein the monoclonal antibody comprises a human or humanized immunoglobulin (IgG1) against CD38.

3 . The method of claim 1 , wherein the monoclonal antibody comprises daratumumab, MOR202, SAR650984.

4 . The method of claim 1 , wherein the monoclonal antibody comprises daratumumab.

5 . The method of claim 1 , wherein the cells expressing CD38 are CD38-expressing cancer cells or CD38-expressing T-cells, B-cells, NK cells, or plasma cells.

6 . The method of claim 1 , wherein the cells expressing CD38 comprise solid tumor cells or hematological malignancy cells.

7 . The method of claim 6 , wherein the hematological malignancy cells comprise multiple myeloma cells, acute lymphocytic leukemia cells, acute myeloid leukemia cells, chronic lymphocytic leukemia cells, chronic myeloid leukemia cells, Hodgkin's lymphoma cells, non-Hodgkin's lymphoma cells, T-LGL leukemia cells, NK cell leukemia cells, or hairy cell leukemia cells.

8 . The method claim 1 , wherein the pharmaceutical composition further comprises a non-radiolabeled monoclonal antibody against an epitope of CD38.

9 . The method of claim 1 , wherein the pharmaceutical composition further comprises a non-radiolabeled monoclonal antibody against the same epitope of CD38 as the actinium labelled monoclonal antibody.

10 . The method of claim 9 , wherein the effective amount comprises a dose of 0.1 ug/kg to 1 mg/kg antibody comprising 0.1 uCi/kg to 5 uCi/kg.

11 . The method of claim 9 , wherein the effective amount comprises a dose of 0.1 ug/kg to 50 ug/kg antibody comprising 0.1 uCi/kg to 1 uCi/kg.

12 . The method of claim 10 or 11 , wherein the effective amount is administered as a single dose.

13 . The method of claim 10 or 11 , wherein the effective amount is administered as two equal fractionated doses, wherein a second dose is administered 3 to 8 days after a first dose.

14 . The method of claim 1 , further comprising:
administering one or more further therapeutic agents.

15 . The method of claim 14 , wherein administration of the one or more further therapeutic agents is before or after administration of the pharmaceutical composition.

16 . The method of claim 14 , wherein the one or more further therapeutic agents comprises a chemotherapeutic agent, an anti-inflammatory agent, an immunosuppressive, an immunomodulatory agent, or a combination thereof.

17 . The method of claim 14 , wherein the one or more further therapeutic agents comprises an antimyeloma agent.

18 . The method of claim 14 , wherein the antimyeloma agent is selected from dexamethasone, melphalan, doxorubicin, bortezomib, lenalidomide, prednisone, carmustine, etoposide, cisplatin, vincristine, cyclophosphamide, and thalidomide.

19 . The method of claim 1 , wherein the pharmaceutical composition further comprises one or more further therapeutic agents.

20 . The method of claim 1 , wherein the pharmaceutical composition is administered to the subject in a dosage regime comprising at least one dose.

21 . The method of claim 20 , wherein the at least one dose comprises an amount of the monoclonal antibody against CD38 that is 5-fold lower than a dose in a dosage regime comprising only a control monoclonal antibody; or 10-fold lower than a dose in a dosage regime comprising only a control monoclonal antibody; or 20-fold lower than a dose in a dosage regime comprising only a control monoclonal antibody; or 50-fold lower than the dose in the dosage regime comprising only the control monoclonal antibody; or 100-fold lower than the dose in the dosage regime comprising only the control monoclonal antibody, wherein the control monoclonal antibody comprises an unlabeled monoclonal antibody against the same epitope of CD38 as the actinium labelled monoclonal antibody.

22 . The method of claim 21 , wherein the control monoclonal antibody comprises daratumumab administered at a dose of about 16 mg/kg patient weight.

23 . The method of claim 20 , wherein the dosage regime comprises at least one less dose than a control dosage regime, or at least two fewer doses than a control dosage regime, or at least three fewer doses than a control dosage regime, or at least four fewer doses than a control dosage regime, or at least five fewer doses than a control dosage regime, wherein the control dosage regime includes administration, either alone or in combination with one or more additional therapeutic agents, of an unlabeled monoclonal antibody against the same epitope of CD38 as the actinium labelled monoclonal antibody.

24 . The method of claim 23 , wherein the control dosage regime includes 8 doses, administered at one dose per week for at least 8 weeks.

25 . An article of manufacture comprising (a) a radiolabeled monoclonal antibody against CD38, and (b) a label instructing a user to administer to a subject an amount of the antibody effective to treat a disease or disorder involving cells expressing CD38.

26 . The article of manufacture of claim 25 , wherein the monoclonal antibody is daratumumab labeled with actinium ( 225 Ac).

27 . The article of manufacture of claim 26 , wherein the amount of the antibody effective to treat the disease or disorder involving cells expressing CD38 comprises 10 μCi to 200 uCi of the 225 Ac-labelled daratumumab.

28 . A pharmaceutical composition useful for treatment of a disease or disorder involving cells expressing CD38, the composition comprising:
5 to 50 wt. % of a monoclonal antibody against CD38 labeled with actinium ( 225 Ac); 50 to 95 wt. % of the monoclonal antibody against CD38 unlabeled; and
a pharmaceutically acceptable carrier

29 . The pharmaceutical composition of claim 28 , wherein the radiolabeled monoclonal antibody is 225 Ac-daratumumab, and the unlabeled monoclonal antibody is daratumumab.

Assignees

• Actinium Pharmaceuticals Inc

Inventors

• Seth Sandesh
• Thomas Keisha

Classifications

• A61K39/3955

  against proteinaceous materials, e.g. enzymes, hormones, lymphokines · CPC title

• A61K2039/545

  characterised by the dose, timing or administration schedule · CPC title

• A61K51/1027 Primary

  against receptors, cell-surface antigens or cell-surface determinants · CPC title

• A61P35/00

  Antineoplastic agents · CPC title

• A61K51/0482

  chelates from cyclic ligands, e.g. DOTA · CPC title