Compositions comprising anti-CD38 antibody and carfilzomib

Abstract

The invention relates to a composition comprising an anti-CD38 antibody and carfilzomib. Compositions and kits comprising an anti-CD38 antibody and a carfilzomib compound are disclosed. Methods and uses for treating cancer, such as multiple myeloma, in a subject using the compositions and kits are also disclosed.

Description

[0001] This invention application is a divisional application of the invention patent application filed on March 13, 2014, with application number 201480024843.3 (international application number PCT / US2014 / 025441) entitled "Composition comprising anti-CD38 antibody and carfilzomib".

[0002] Cross-reference to related applications

[0003] This application claims the benefit of U.S. Application No. 61 / 778,540, filed March 13, 2013, and U.S. Application No. 61 / 778,540, filed April 13, 2013, both of which are incorporated herein by reference in their entirety.

[0004] The sequence list submitted via EFS-WEB is mentioned.

[0005] The contents of the ASCII text file containing the sequence list are included in full by reference. The sequence list, named “20140313_034543_002WO1_seq”, is 56.7 kb in size, was created on March 13, 2014, and is hereby electronically submitted with this application via EFS-Web. Technical Field

[0006] The field of this invention relates to anti-CD38 antibodies, carfilzomib, and cancer treatment. Background Technology

[0007] Multiple myeloma (MM) is a B-cell malignancy. In MM, abnormal plasma cells accumulate in the bone marrow, interfering with the production of normal cells. Current treatments for MM include the administration of protease inhibitors such as bortezomib and carfilzomib, immunomodulatory drugs such as lenalidomide and thalidomide, and chemotherapy such as melphalan and prednisone. While these agents have improved survival in multiple myeloma, resistance inevitably becomes a problem, and patients eventually die from the disease. Therefore, multiple myeloma remains ultimately fatal, with a median survival of only about 3 to 5 years.

[0008] CD38 is expressed in malignant plasma cells. CD38 is a 45kD type II transmembrane glycoprotein with a long C-terminal extracellular domain and a short N-terminal cytoplasmic domain. CD38 protein is a catalytic protein that can catalyze the transfer of NAD+ to the plasma. + It is a bifunctional extracellular enzyme that converts cADPR into cyclic ADP-ribose (cADPR) and also hydrolyzes cADPR into ADP-ribose. CD38 is upregulated and has been involved in many hematopoietic malignancies.

[0009] Therefore, some proposed treatments for MM include the administration of anti-CD38 antibodies. See, for example, WO 2012 / 041800; deWeers et al. (2011) J Immunol 186:1840-1848; and Van der Veer et al. (2011) Haematologica 96(2):284-290. Unfortunately, as with various drugs and chemotherapy therapies, not all antibodies are the same, and not all antibodies against the same antigen exhibit the same activity.

[0010] Therefore, there is a need for new and effective treatments to prolong survival and improve treatment outcomes in multiple myeloma, and more generally in blood cancers. Summary of the Invention

[0011] In some embodiments, the present invention relates to a method of treating cancer in a subject, comprising: administering to the subject one or more anti-CD38 antibodies and one or more carfilzomib compounds. In some embodiments, the cancer is a hematologic malignancy. In some embodiments, the cancer is multiple myeloma. In some embodiments, the cancer is relapsed or refractory multiple myeloma. In some embodiments, the one or more carfilzomib compounds are carfilzomib. In some embodiments, the one or more anti-CD38 antibodies are administered in an effective amount, preferably in a synergistic amount. In some embodiments, the one or more anti-CD38 antibodies and / or the one or more carfilzomib compounds are administered in a therapeutically effective amount. In some embodiments, at least one of the one or more anti-CD38 antibodies is capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). +Cells. In some embodiments, the antibody is hu38SB19. In some embodiments, at least one of the one or more anti-CD38 antibodies comprises one or more complementarity-determining regions having an amino acid sequence selected from the group consisting of: SEQ ID NO: 13, 14, 81, 15, 16, 17, 18, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, and 36. In some embodiments, at least one of the one or more anti-CD38 antibodies is selected from the group consisting of: a) an antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:13, 15 and SEQ ID NO:14 or SEQ ID NO:81, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:16, 17 and 18; b) an antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:25, 26 and 27, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:28, 29 and 30; c) an antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:1, 2 and 3, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:16, 17 and 18; d) An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO: 7, 8, and 9, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO: 10, 11, and 12; e) An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO: 19, 20, and 21, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO: 22, 23, and 24; and f) An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO: 31, 32, and 33, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO: 34, 35, and 36. In some embodiments, the antibody comprises a V as shown in SEQ ID NO: 66. H The heavy chain of the variable region, and having the V shown in SEQ ID NO:62 or SEQ ID NO:64 L Light chains with variable regions. In some embodiments, the antibody comprises V as shown in SEQ ID NO:72.H The heavy chain of the variable region, and having the V shown in SEQ ID NO:68 or SEQ ID NO:70 L The light chain of the variable region. In some embodiments, the one or more anti-CD38 antibodies are administered intravenously. In some embodiments, one or more carfilzomib compounds are administered orally. In some embodiments, the one or more anti-CD38 antibodies and one or more carfilzomib compounds are administered sequentially. In some embodiments, the method further includes administering a dexamethasone compound, preferably dexamethasone, to the subject. In some embodiments, the dexamethasone compound is administered orally. In some embodiments, the dexamethasone compound is administered at a low dose. In some embodiments, the one or more anti-CD38 antibodies, the one or more carfilzomib compounds, and the dexamethasone compound are administered sequentially. In some embodiments, one or more anti-CD38 antibodies and one or more carfilzomib compounds are administered sequentially.

[0012] In some embodiments, the present invention relates to a composition comprising: a) at least one anti-CD38 antibody, preferably said antibody being capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + The invention relates to a composition comprising: a) at least one anti-CD38 antibody; b) at least one carfilzomib compound, preferably carfilzomib; and optionally c) a dexamethasone compound, preferably dexamethasone. In some embodiments, the invention relates to a composition comprising: a) at least one anti-CD38 antibody; b) at least one carfilzomib compound; and optionally i) a dexamethasone compound. In some embodiments, the antibody is capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + Cells. In some embodiments, the antibody is hu38SB19. In some embodiments, the carfilzomib compound is carfilzomib. In some embodiments, the dexamethasone compound is dexamethasone.

[0013] In some embodiments, the present invention relates to a kit comprising: a) a first composition comprising at least one anti-CD38 antibody, preferably said antibody being capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). +Cells; and b) a second composition comprising at least one carfilzomib compound, preferably carfilzomib. In some embodiments, the composition is packaged for sequential administration to a subject. In some embodiments, the antibody is hu38SB19. In some embodiments, the kit further comprises a dexamethasone compound, preferably dexamethasone. In some embodiments, the carfilzomib compound and the dexamethasone compound are packaged for sequential administration to a subject.

[0014] In some embodiments, the present invention relates to a kit comprising the following components packaged together: capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + The kit contains at least one anti-CD38 antibody for cells, and a label having one or more of the following information: the at least one anti-CD38 antibody should be administered in combination with carfilzomib, optionally with dexamethasone. In some embodiments, the antibody is hu38SB19. In some embodiments, the kit further comprises a dexamethasone compound, preferably dexamethasone. In some embodiments, the carfilzomib compound and the dexamethasone compound are packaged for sequential administration to the subject.

[0015] In some embodiments, the present invention relates to combination products of the following: (i) at least one anti-CD38 antibody, preferably said antibody being capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + The invention relates to: (i) cells; and (ii) at least one carfilzomib compound, preferably carfilzomib; and optionally (iii) a dexamethasone compound, preferably dexamethasone. In some embodiments, the invention relates to a combination product comprising: a) at least one anti-CD38 antibody; and b) at least one carfilzomib compound; and optionally i) a dexamethasone compound. In some embodiments, the antibody is capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + Cells. In some embodiments, the antibody is hu38SB19. In some embodiments, the carfilzomib compound is carfilzomib. In some embodiments, the dexamethasone compound is dexamethasone. In some embodiments, the combination product is used sequentially in the treatment of hematologic malignancies, preferably multiple myeloma.

[0016] In some embodiments, the present invention relates to (i) at least one anti-CD38 antibody, preferably an antibody capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). +The invention relates to the use of (i) at least one carfilzomib compound, preferably carfilzomib, and optionally (iii) a dexamethasone compound, preferably dexamethasone, for the treatment of hematologic malignancies, preferably multiple myeloma. In some embodiments, the invention relates to the use of (ii) at least one anti-CD38 antibody; and (iii) at least one carfilzomib compound; and optionally (i) a dexamethasone compound for the treatment of hematologic malignancies, preferably multiple myeloma. In some embodiments, the antibody is capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + Cells. In some embodiments, the antibody is hu38SB19. In some embodiments, the carfilzomib compound is carfilzomib. In some embodiments, the dexamethasone compound is dexamethasone.

[0017] In some embodiments of the invention, the subject to be treated is a mammal. In some embodiments of the invention, the subject to be treated is a test animal, such as a mouse. In some embodiments of the invention, the subject to be treated is a human.

[0018] Specifically, the present invention relates to the following:

[0019] 1. A method for treating cancer in a subject, comprising:

[0020] The subjects were administered one or more anti-CD38 antibodies and one or more carfilzomib compounds.

[0021] 2. The method of item 1, wherein the cancer is hematologic malignancy.

[0022] 3. The method of item 1, wherein the cancer is multiple myeloma.

[0023] 4. The method of item 1, wherein the cancer is relapsed multiple myeloma or refractory multiple myeloma.

[0024] 5. The method of item 1, wherein the one or more carfilzomib compounds are carfilzomib.

[0025] 6. The method of item 1, wherein the one or more anti-CD38 antibodies are administered in an effective amount, preferably in a synergistic amount.

[0026] 7. The method of claim 1, wherein the one or more anti-CD38 antibodies and / or the one or more carfilzomib compounds are administered in a therapeutically effective amount.

[0027] 8. The method of any one of claims 1 to 7, wherein at least one of the one or more anti-CD38 antibodies is capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + cell.

[0028] 9. The method of any one of claims 1 to 7, wherein at least one of the one or more anti-CD38 antibodies comprises one or more complementarity-determining regions having an amino acid sequence selected from the group consisting of: SEQ ID NO: 13, 14, 81, 15, 16, 17, 18, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 and 36.

[0029] 10. The method of any one of claims 1 to 7, wherein at least one of the one or more anti-CD38 antibodies is selected from the group consisting of:

[0030] a) An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:13, 15 and SEQ ID NO:14 or SEQ ID NO:81, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:16, 17 and 18.

[0031] b) An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:25, 26 and 27, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:28, 29 and 30.

[0032] c) An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:1, 2 and 3, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:4, 5 and 6.

[0033] d) An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO: 7, 8 and 9, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO: 10, 11 and 12.

[0034] e) An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO: 19, 20, and 21, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO: 22, 23, and 24; and

[0035] f) An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:31, 32 and 33, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:34, 35 and 36.

[0036] 11. The method of item 10, wherein the antibody comprises having V as shown in SEQ ID NO:66 H The heavy chain of the variable region, and having the V shown in SEQ ID NO:62 or SEQ ID NO:64 L Light chains with variable regions.

[0037] 12. The method of item 10, wherein the antibody comprises having V as shown in SEQ ID NO:72 H The heavy chain of the variable region, and having the V shown in SEQ ID NO:68 or SEQ ID NO:70 L Light chains with variable regions.

[0038] 13. The method of any one of claims 1 to 12, wherein one or more anti-CD38 antibodies are administered intravenously.

[0039] 14. The method of any one of claims 1 to 12, wherein one or more of the carfilzomib compounds are administered intravenously.

[0040] 15. The method of any one of claims 1 to 14, wherein the one or more anti-CD38 antibodies and one or more carfilzomib compounds are administered sequentially.

[0041] 16. The method of any one of claims 1 to 15, further comprising administering a dexamethasone compound, preferably dexamethasone, to the subject.

[0042] 17. The method of item 16, wherein the dexamethasone compound is administered orally.

[0043] 18. The method of any one of claims 16 to 17, wherein the one or more anti-CD38 antibodies, the one or more carfilzomib compounds, and the dexamethasone compound are administered sequentially.

[0044] 19. A composition comprising:

[0045] a) At least one anti-CD38 antibody, preferably said antibody capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + Cells; and

[0046] b) at least one carfilzomib compound, preferably carfilzomib; and optionally

[0047] c) Dexamethasone compounds, preferably dexamethasone.

[0048] 20. A reagent kit comprising:

[0049] a) A first composition comprising at least one anti-CD38 antibody, preferably said antibody being capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + Cells; and

[0050] b) A second composition comprising at least one carfilzomib compound, preferably carfilzomib.

[0051] 21. The kit of item 20, wherein the composition is packaged for sequential administration to a subject.

[0052] 22. The kit of item 20 or item 21, further comprising a dexamethasone compound, preferably dexamethasone.

[0053] 23. The kit of item 22, wherein the dexamethasone compound is packaged for sequential administration to a subject.

[0054] 24. A reagent kit comprising the following items packaged together:

[0055] It can kill CD38 cells through apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + At least one anti-CD38 antibody in cells,

[0056] A label containing one or more of the following information: the at least one anti-CD38 antibody should be administered in combination with carfilzomib, optionally with dexamethasone.

[0057] 25. Combinations of the following items:

[0058] (i) At least one anti-CD38 antibody, preferably said antibody is capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + Cells; and

[0059] (ii) at least one carfilzomib compound, preferably carfilzomib; and optionally

[0060] (iii) A dexamethasone compound, preferably dexamethasone.

[0061] 26. The combination product of item 25, wherein the combination product is used sequentially in the treatment of hematologic malignancies, preferably multiple myeloma. Attached Figure Description

[0062] Both the foregoing general description and the following detailed description are merely illustrative and explanatory, and are intended to provide further explanation of the claimed invention. The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate several embodiments of the invention and, together with the description, serve to explain the principles of the invention.

[0063] The invention can be further understood by referring to the accompanying drawings, in which:

[0064] Figure 1A The growth rate of tumors in a xenograft model (H929 model) implanted with NCI-H929 cells is shown.

[0065] Figure 1B The growth rate of tumors in a xenograft model (RPMI model) implanted with RPMI 8226 cells is shown.

[0066] Figure 2A This displays the tumor volume in the RPMI model after treatment with a specified dose of hu38SB19 at a specified time (arrow).

[0067] Figure 2B The image shows the body weight of the RPMI model after treatment with a specified dose of hu38SB19 at a specified time (arrow).

[0068] Figure 3A This displays the tumor volume in the H929 model after treatment with a specified dose of hu38SB19 at a specified time (arrow).

[0069] Figure 3B The image shows the body weight of the H929 model after treatment with a specified dose of hu38SB19 at a specified time (arrow).

[0070] Figure 4A This displays the tumor volume in the H929 model after treatment with a specified dose of hu38SB19 at a specified time (arrow).

[0071] Figure 4BThe image shows the body weight of the H929 model after treatment with a specified dose of hu38SB19 at a specified time (arrow).

[0072] Figure 5A This displays the tumor volume in the H929 model after treatment with a specified dose of hu38SB19 at a specified time (arrow).

[0073] Figure 5B The image shows the body weight of the H929 model after treatment with a specified dose of hu38SB19 at a specified time (arrow).

[0074] Figure 6A The image shows the tumor volume in the H929 model after treatment with a specified dose of carfilzomib at a specified time (arrow).

[0075] Figure 6B The image shows the body weight of the H929 model after treatment with a specified dose of carfilzomib at a specified time (arrow).

[0076] Figure 7A The image shows the tumor volume in the RPMI model after treatment with a specified dose of carfilzomib at a specified time (arrow).

[0077] Figure 7B The image shows the body weight of the RPMI model after treatment with a specified dose of carfilzomib at a specified time (arrow).

[0078] Figure 8A The image shows the tumor volume in the H929 model after treatment with a specified dose of hu38SB19 at a specified time (top arrow) and with a specified dose of carfilzomib at a specified time (bottom arrow).

[0079] Figure 8B The image shows the body weight of the H929 model after treatment with a specified dose of hu38SB19 at a specified time (top arrow) and with a specified dose of carfilzomib at a specified time (bottom arrow).

[0080] Figure 9A The figure shows the mean wet tumor weight of the H929 model after specified treatment with carfilzomib / or hu38SB19 (mAb).

[0081] Figure 9B The figure shows the median wet tumor weight of the H929 model after specified treatment with carfilzomib / or hu38SB19 (mAb).

[0082] Figure 10AThe image shows the tumor volume in the RPMI-8226 model after treatment with a specified dose of hu38SB19 at a specified time (top arrow) and with a specified dose of carfilzomib at a specified time (bottom arrow).

[0083] Figure 10B The image shows the body weight of the RPMI-8226 model after treatment with a specified dose of hu38SB19 at a specified time (top arrow) and with a specified dose of carfilzomib at a specified time (bottom arrow).

[0084] Figure 11 The figure shows the cell surface density of CD38 in multiple myeloma cell lines.

[0085] Figure 12 The figure shows that hu38SB19 (as the sole active ingredient) resulted in a dose-dependent antitumor effect and radical cure of lateral xenograft tumor growth after NCI-H929. A cumulative four doses of 5 mg / kg twice weekly were sufficient to eliminate palpable tumors in all mice within the group.

[0086] Figure 13 The figure shows that the low-dose combination of carfilzomib and hu38SB19 resulted in near-complete inhibition of tumor growth in the NCI-H929 xenograft. Detailed Implementation

[0087] This invention relates to a method of treating cancer in a subject, comprising administering to the subject one or more anti-CD38 antibodies and one or more carfilzomib compounds. As used herein, “treatment / management” means relief of symptoms, temporary or permanent elimination of the cause of symptoms, or prevention or mitigation of the onset of symptoms of the mentioned condition or condition. As disclosed herein, the potency of carfilzomib compounds is considerably improved when administered in combination with one or more anti-CD38 antibodies according to the invention. In fact, it is believed that CD38 cells exhibit (a) killing by apoptosis, (b) antibody-dependent cell-mediated cytotoxicity (ADCC), and (c) complement-dependent cytotoxicity (CDC). + The administration of one or more anti-CD38 antibodies significantly improves the efficacy of carfilzomib compounds in the treatment of hematologic malignancies, including multiple myeloma, to an unexpectedly greater extent than other anti-CD38 antibodies that do not exhibit all three (a)-(c) activities. Therefore, in some embodiments, one or more anti-CD38 antibodies are capable of killing CD38 cells (a) through apoptosis, (b) antibody-dependent cell-mediated cytotoxicity (ADCC), and (c) complement-dependent cytotoxicity (CDC). +Cells. In some embodiments, one or more anti-CD38 antibodies and / or one or more carfilzomib compounds are administered in a therapeutically effective amount. As used herein, a “therapeutically effective amount” of a substance means the amount of a substance that causes relief, temporary or permanent elimination of symptoms, and / or prevents or reduces the occurrence of symptoms of the mentioned disease or condition in a majority of subjects suffering from and similarly treating the mentioned disease or condition.

[0088] In some embodiments, the cancer is a cancer in which CD38 is expressed by malignant cells. In some embodiments, the cancer is a hematologic malignancy of the blood, bone marrow, and / or lymph nodes. In some embodiments, the cancer is a blood cancer. Blood cancers include myeloma, lymphoma, and leukemia. Blood cancers may be selected, for example, from the group consisting of: multiple myeloma, non-Hodgkin's lymphoma, Hodgkin's lymphoma, hairy cell leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, acute myeloid leukemia, and acute lymphoblastic leukemia. In some embodiments, the cancer is multiple myeloma (MM). In some embodiments, the cancer is relapsed MM or refractory MM. As used herein, relapsed MM refers to clinically active MM after a regression period, and refractory MM refers to progressive or stable disease that is being treated or that is progressive within 3 months of the last dose of previous treatment. See Dimopoulos et al. (2010) Eur J Haematology 88:1-15.

[0089] In some embodiments, the subject is a mammal, preferably a human. In some embodiments, the subject is an adult, for example, at least 18 years of age. In some embodiments, the subject requires treatment for cancer. In some embodiments, the subject has been diagnosed with cancer. In some embodiments, the cancer is in partial or complete remission; however, to reduce the likelihood of recurrence, the subject is administered one or more carfilzomib compounds and one or more anti-CD38 antibodies. In some embodiments, the subject has a Karnofsky performance status equal to or better than 60%. The Karnofsky status runs from 100 to 0, where 100 is “completely” healthy and 0 is death (Karnofsky and Burchenal, 1949, “The Clinical Evaluation of Chemotherapeutic Agents in Cancer.” In: MacLeod CM (ed.), Evaluation of Chemotherapeutic Agents. Columbia Univ Press). In some embodiments, the subject has already undergone at least one or two prior therapies for multiple myeloma, with induction therapy considered a prior therapy. In some implementation schemes, subjects demonstrate cancer progression despite prior therapy, or evidence that prior therapy is refractory to cancer.

[0090] In some embodiments, the anti-CD38 antibody specifically binds to CD38. In some embodiments, the anti-CD38 antibody is generated against CD38 or its epitopes. In some embodiments, the anti-CD38 antibody is a monoclonal antibody. In some embodiments, one or more anti-CD38 antibodies according to the invention are monoclonal antibodies as described in WO 2008 / 047242 (which is incorporated herein by reference in its entirety). In some embodiments, one or more anti-CD38 antibodies are monoclonal antibodies 38SB13, 38SB18, 38SB19, 38SB30, 38SB31, and 38SB39 as described in WO 2008 / 047242 (which is incorporated herein by reference in its entirety). In some embodiments, one or more anti-CD38 antibodies are capable of killing CD38 through three different cytotoxic mechanisms: induction of apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + cell.

[0091] The term “antibody” is used in the broadest sense herein and includes any isotype (such as IgG, IgM, IgA, IgD, and IgE) of monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies, chimeric antibodies, and antibody fragments. As used herein, the prefix “anti” indicates that a given antibody is reactive to a given antigen when binding to it. Antibodies that are reactive to a specific antigen can be generated by synthetic and / or recombinant methods, such as selecting a recombinant antibody library in a phage or similar vector, or by immunizing animals with an antigen or an antigen-encoded nucleic acid.

[0092] A typical IgG antibody consists of two identical heavy chains and two identical light chains linked by disulfide bonds. Each heavy and light chain contains constant and variable regions. Each variable region contains three segments called "complementarity-determining regions" ("CDRs") or "hypervariates," which are primarily responsible for binding antigenic epitopes. Sequentially numbered from the N-terminus, they are commonly referred to as CDR1, CDR2, and CDR3. The more highly conserved portion of the variable region outside the CDRs is called the "framework region." As used herein, "V" H "VH" or "VH" refers to the variable region of the immunoglobulin heavy chain of an antibody (including the heavy chain of Fv, scFv, dsFv, Fab, Fab', or F(ab')2 fragments). Mentioning "V"... L "VL" or "VL" refers to the variable region of the immunoglobulin light chain of the antibody (including light chains of Fv, scFv, dsFv, Fab, Fab', or F(ab')2 fragments).

[0093] For example, the antibodies according to the invention can be mouse, chimeric, and / or humanized antibodies. As used herein, a “chimeric antibody” is an antibody in which a constant region or a portion thereof is altered, replaced, or substituted, such that a variable region is linked to a constant region of a different species or belonging to another antibody class or subclass. A “chimeric antibody” also refers to an antibody in which a variable region or a portion thereof is altered, replaced, or substituted, such that a constant region is linked to a variable region of a different species or belonging to another antibody class or subclass. Methods for generating chimeric antibodies are known in the art. See, for example, Morrison, 1985, Science, 229:1202; Oi et al., 1986, BioTechniques, 4:214; Gillies et al., 1989, J. Immunol. Methods, 125:191-202; U.S. Patent Nos. 5,807,715; 4,816,567; and 4,816,397, which are incorporated herein by reference in their entirety. As used herein, the term "humanized antibody" refers to a chimeric antibody containing a minimal sequence derived from a non-human immunoglobulin. The aim of humanization is to reduce the immunogenicity of a xenobiotic antibody (such as a mouse antibody) for introduction into humans while maintaining the antibody's complete antigen-binding affinity and specificity. Several techniques, such as surface remodeling and CDR grafting, can be used to generate humanized antibodies, or antibodies suitable for non-rejection in other mammals. As used herein, surface remodeling uses a combination of molecular modeling, statistical analysis, and mutagenesis to alter the non-CDR surface of the antibody's variable region to resemble the surface of a known antibody in the target host. CDR grafting involves replacing, for example, the complementarity-determining region of a mouse antibody into a human frame domain, see, for example, WO 92 / 22653. Preferably, the humanized chimeric antibody has a constant region and a variable region, in addition to a complementarity-determining region (CDR) substantially or specifically derived from the corresponding human antibody region, and a CDR substantially or specifically derived from mammals other than humans.

[0094] Strategies and methods for surface remodeling of antibodies, and other methods for reducing the immunogenicity of antibodies in different hosts, are disclosed in U.S. Patent No. 5,639,641, which is incorporated herein by reference in its entirety. A variety of other techniques can be used to humanize antibodies, including CDR grafting (EP 0 239 400; WO 91 / 09967; US Patent Nos. 5,530,101 and 5,585,089), veneering or surface repair (EP 0 592106; EP 0 519 596; Padlan EA, 1991, Molecular Immunology 28(4 / 5):489-498; Studnicka GM et al., 1994, Protein Engineering, 7(6):805-814; Roguska MA et al., 1994, PNAS, 91:969-973), chain tampering (US Patent No. 5,565,332), and identification of flexible residues (PCT / US2008 / 074381). Human antibodies can be generated using a variety of methods known in the art, including phage display methods. See also U.S. Patent Nos. 4,444,887, 4,716,111, 5,545,806, and 5,814,318; and International Patent Application Publications WO 98 / 46645, WO 98 / 50433, WO98 / 24893, WO 98 / 16654, WO 96 / 34096, WO 96 / 33735, and WO 91 / 10741 (all references are incorporated herein by reference in their entirety).

[0095] In some embodiments, one or more anti-CD38 antibodies according to the present invention can kill CD38 cells through apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + Cells. In some embodiments, one or more anti-CD38 antibodies according to the invention are even capable of killing CD38 cells via apoptosis in the absence of stromal cells or stromal-derived cytokines. + Cells. These activities can be assessed, as described in WO 2008 / 047242, which is incorporated herein by reference in its entirety.

[0096] In some embodiments of the invention, one or more anti-CD38 antibodies are selected from the group consisting of 38SB13, 38SB18, 38SB19, 38SB30, 38SB31, 38SB39, and antibodies that cross-compete with 38SB13, 38SB18, 38SB19, 38SB30, 38SB31, and 38SB39. Hybridoma cell lines that generated mouse anti-CD38 antibodies 38SB13, 38SB18, 38SB19, 38SB30, 38SB31, and 38SB39 were deposited on June 21, 2006, at the American Center for Type Culture Collection (10801 University Bld, Manassas, VA, 20110-2209, USA) with accession numbers PTA-7667, PTA-7669, PTA-7670, PTA-7666, PTA-7668, and PTA-7671, respectively (as described in WO 2008 / 047242, which is fully incorporated herein by reference).

[0097] As disclosed herein, reference to SEQ ID NO refers to the sequence listed in the sequence listing submitted herein and also as described in WO 2008 / 047242 (which is incorporated herein in its entirety by reference). In some embodiments, for example, the anti-CD38 antibody according to the invention may comprise a heavy chain and a light chain, the heavy chain comprising three consecutive CDRs having the amino acid sequences shown in SEQ ID NO: 1, 2, and 3, and the light chain comprising three consecutive CDRs having the amino acid sequences shown in SEQ ID NO: 4, 5, and 6. An example of such an antibody is the 38SB13 antibody, which comprises a V sequence having the amino acid sequence shown in SEQ ID NO: 50. H The heavy chain of the variable region, and having the V shown in SEQ ID NO:38 L Light chains with variable regions.

[0098] In some embodiments, for example, the anti-CD38 antibody according to the invention may comprise a heavy chain and a light chain, the heavy chain comprising three consecutive CDRs having the amino acid sequences shown in SEQ ID NO:7, 8, and 9, and the light chain comprising three consecutive CDRs having the amino acid sequences shown in SEQ ID NO:10, 11, and 12. An example of such an antibody is the 38SB18 antibody, which comprises a V... H The heavy chain of the variable region, and having the V shown in SEQ ID NO:40 L Light chains with variable regions.

[0099] In some embodiments, for example, the anti-CD38 antibody according to the invention may comprise a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having the amino acid sequences shown in SEQ ID NO:13, SEQ ID NO:15 and SEQ ID NO:14 or SEQ ID NO:81, and the light chain comprises three consecutive CDRs having the amino acid sequences shown in SEQ ID NO:16, 17 and 18. An example of such an antibody is the 38SB19 antibody, which comprises a V-shaped structure as shown in SEQ ID NO:54. H The heavy chain of the variable region, and having the V shown in SEQ ID NO:42 L The light chain of the variable region. Specific examples of the humanized form of 38SB19 (hu38SB19) include antibodies comprising a heavy chain and a light chain, said heavy chain having a V as shown in SEQ ID NO:66. H The variable region, the light chain having a V as shown in SEQ ID NO:62 or SEQ ID NO:64 L Variable region. hu38SB19 is a humanized anti-CD38 antibody currently undergoing clinical evaluation in CD38-positive hematologic malignancies, including multiple myeloma. Previous and current studies have demonstrated that the anti-myeloma activity associated with this agent involves ADCC and CDC, as well as novel mechanisms of direct apoptosis and anti-ADP-ribosylcyclase activity. See Marie-Cécile Wetzel, Céline Nicolazzi, Vallée, et al. hu38SB19: characterization of a potent phase I humanized anti-CD38antibody for the treatment of multiple myeloma and other hematologicmalignancies. AACR Annual Meeting 2013, Abstract #4735.

[0100] In some embodiments, for example, the anti-CD38 antibody according to the invention may comprise a heavy chain and a light chain, the heavy chain comprising three consecutive CDRs having the amino acid sequences shown in SEQ ID NO:19, 20, and 21, and the light chain comprising three consecutive CDRs having the amino acid sequences shown in SEQ ID NO:22, 23, and 24. An example of such an antibody is the 38SB30 antibody, which comprises a V... H The heavy chain of the variable region, and having the V shown in SEQ ID NO:44 L Light chains with variable regions.

[0101] In some embodiments, for example, the anti-CD38 antibody according to the invention may comprise a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having the amino acid sequences shown in SEQ ID NO:25, 26, and 27, and the light chain comprises three consecutive CDRs having the amino acid sequences shown in SEQ ID NO:28, 29, and 30. An example of such an antibody is the 38SB31 antibody, which comprises a V... H The heavy chain of the variable region, and having the V shown in SEQ ID NO:46 L The light chain of the variable region. Specific examples of the humanized form of 38SB31 (hu38SB31) include antibodies comprising a heavy chain and a light chain, said heavy chain having a V as shown in SEQ ID NO:72. H The variable region, the light chain having a V as shown in SEQ ID NO:68 or SEQ ID NO:70 L Variable region.

[0102] In some embodiments, for example, the anti-CD38 antibody according to the invention may comprise a heavy chain and a light chain, the heavy chain comprising three consecutive CDRs having the amino acid sequences shown in SEQ ID NO:31, 32, and 33, and the light chain comprising three consecutive CDRs having the amino acid sequences shown in SEQ ID NO:34, 35, and 36. An example of such an antibody is the 38SB39 antibody, which comprises a V... H The heavy chain of the variable region, and having the V shown in SEQ ID NO:48 L Light chains with variable regions.

[0103] In some embodiments, the anti-CD38 antibody according to the invention is a humanized antibody composed of two identical heavy chains and two identical light chains, wherein each chain consists of a constant region and a variable region.

[0104] As used herein, “carfilzomib compound” refers to carfilzomib (S)-4-methyl-N-((S)-1-(((S)-4-methyl-1-((R)-2-methylepoxyethylene-2-yl)-1-oxopentan-2-yl)amino)-1-oxo-3-phenylpropan-2-yl)-2-((S)-2-(2-morpholinoacetamido)-4-phenylbutyrylamino)pentanamide and carfilzomib derivatives. As used herein, “carfilzomib derivative” refers to a compound having 2-acetamido-N-(1-((1-(1-methylcyclopropyl)-1-oxopropan-2-yl)amino)-1-oxopropan-2-yl)propanamide (which may or may not be substituted) as part of its structural formula, i.e.

[0105]

[0106] In some embodiments, carfilzomib derivatives include compounds having the following structures (which may or may not be substituted) as part of their structural backbone:

[0107]

[0108] Where X is selected from O, NH and NC. 1-6 Alkyl group, preferably O. Examples of "carfilzomib derivatives" according to the invention include those listed in U.S. Patent Nos. 7,232,818; 7,417,042; 7,491,704; 7,737,112; 8,129,346; 8,207,125; 8,207,126; 8,207,127; and 8,207,297.

[0109] In some embodiments, one or more anti-CD38 antibodies are administered in an effective amount. As used herein, an effective amount of one or more anti-CD38 antibodies is an amount that results in an additive or synergistic effect with one or more carfilzomib compounds. As used herein, "synergistic amount" is an amount that results in a synergistic effect. As used herein, "synergistic effect" refers to an effect where the combination of one or more anti-CD38 antibodies and one or more carfilzomib compounds is greater than its intended additive effect. In some embodiments, one or more anti-CD38 antibodies are administered before, during, and / or after administration of one or more carfilzomib compounds. In some embodiments, one or more anti-CD38 antibodies and one or more carfilzomib compounds are co-administered in the form of a single composition (e.g., as a mixture).

[0110] Therefore, in some embodiments, the present invention relates to a composition comprising a mixture of at least one anti-CD38 antibody and at least one carfilzomib compound. In some embodiments, the mixture comprises at least one anti-CD38 antibody in an amount that, when administered to a subject, results in an additive or synergistic effect with at least one carfilzomib compound. In some embodiments, the at least one anti-CD38 antibody in the mixture is capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + Antibodies against cells; and at least one carfilzomib compound.

[0111] For the purposes of this invention, the methods and compositions of this invention are not limited to those obtained by the physical combination of anti-CD38 antibodies and carfilzomib compounds, but also include those that allow for separate administration (which may be simultaneous or spaced apart over a period of time). Therefore, in some embodiments, this invention relates to a first composition comprising one or more anti-CD38 antibodies, and a second composition comprising one or more carfilzomib compounds. In some embodiments, at least one anti-CD38 antibody is capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + The first composition contains an antibody against the cell; and at least one carfilzomib compound. In some embodiments, the amount of one or more anti-CD38 antibodies provided in the first composition is the amount that, when administered to a subject, results in an additive or synergistic effect with at least one carfilzomib compound in the second composition.

[0112] In some embodiments, the first and second compositions may be packaged in a kit. Therefore, in some embodiments, the present invention relates to a kit comprising a first composition containing one or more anti-CD38 antibodies and a second composition containing one or more carfilzomib compounds. In some embodiments, the first and second compositions may be mixed together prior to administration to a subject. In some embodiments, the first and second compositions may be administered simultaneously or sequentially (i.e., at intervals over a period of time) to obtain the maximum potency, additive effect, synergistic effect, or combination thereof of the combination. In some embodiments, the present invention relates to a kit comprising at least one anti-CD38 antibody packaged together and a label having one or more pieces of information indicating that the anti-CD38 antibody should or may be administered in combination with carfilzomib and optionally dexamethasone. The kit according to the invention may further comprise one or more pieces of information indicating that the antibody should or may be administered to a subject suffering from a blood cancer such as multiple myeloma (e.g., relapsed or refractory multiple myeloma). In some embodiments, one or more anti-CD38 antibodies in the kit of the present invention are capable of killing CD38 cells through apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + Those cells.

[0113] In some embodiments, the compositions of the present invention are pharmaceutical compositions. As used herein, the term "pharmaceutical composition" refers to a composition comprising at least one active ingredient (e.g., an anti-CD38 antibody or a carfilzomib compound) and at least one pharmaceutically acceptable carrier. Pharmaceutically acceptable carriers are well known to those skilled in the art and are generally dependent on the chosen route of administration. Pharmaceutical compositions according to the invention can be provided in any form or formulation suitable for the chosen route of administration, such as a solution, for example, for intravenous administration, or capsules, pills, or tablets, for example, for oral administration, etc.

[0114] Prescribing physicians can choose the dosage regimen of the active ingredients and pharmaceutical compositions described herein based on their technical knowledge, including information released by regulatory agencies. For example, carfilzomib is typically administered intravenously. According to the U.S. Food and Drug Administration (FDA), carfilzomib can be administered intravenously, for example, over 2–10 minutes, for two consecutive days each week for three weeks (days 1, 2, 8, 9, 15, and 16), followed by a 12-day rest period (days 17–28). In some implementations, the recommended cycle 1 dose is 20 mg / m². 2 / day, and if permissible, increase the dose in cycle 2 and subsequent cycles to 27mg / m². 2 / day. In some implementations, the patient is allowed to absorb fluids before and / or after administration. However, due to the additive or synergistic effects resulting from the co-administration of one or more anti-CD38 antibodies and one or more carfilzomib compounds, the dosage of the carfilzomib compound can be adjusted accordingly, for example, by changing the dose and / or modifying the dosing schedule. Of course, the prescribing physician can reconsider which dose and schedule to use based on the patient's condition and disease status, as well as clinical and laboratory findings.

[0115] Because the FDA recommends the use of dexamethasone as a pre-dose medication before all cycle 1 doses, during the first cycle of dose scaling, and in case of or recurrence of infusion reaction symptoms, the methods and compositions of the present invention may further include dexamethasone, a member of the glucocorticoid class of steroid drugs, and acting as an anti-inflammatory and immunosuppressant. Therefore, in some embodiments, the treatment methods of the present invention further include administration of a dexamethasone compound to a subject treated with one or more anti-CD38 antibodies and one or more carfilzomib compounds. Similarly, the compositions and kits of the present invention comprising one or more anti-CD38 antibodies and / or one or more carfilzomib compounds may further comprise a dexamethasone compound. As used herein, “dexamethasone compound” refers to dexamethasone ((8S,9R,10S,11S,13S,14S,16R,17R)-9-fluoro-11,17-dihydroxy-17-(2-hydroxyacetyl)-10,13,16-trimethyl-6,7,8,9,10,11,12,13,14,15,16,17-dodecano-3H-cyclopentan[a]phenanthrene-3-one) and dexamethasone derivatives. As used herein, “dexamethasone derivative” refers to a compound having the following structural formula:

[0116]

[0117] R1-R17 are each independently H, halogen, alkyl, alkoxy, amino, or alkylamine. In some preferred embodiments, R1-R3 are H. In some preferred embodiments, R4-R6 are methyl. In some preferred embodiments, R7 is halogen, preferably fluorine. In some preferred embodiments, R8 is H. In some preferred embodiments, R1-R3 are H, R4-R6 are methyl, R7 is halogen, preferably fluorine, and R8 is H.

[0118] In some embodiments, the dexamethasone compound may be administered orally. In some embodiments, the dexamethasone compound may be administered at the same or lower dose compared to the EMA-recommended dose for dexamethasone.

[0119] The compositions of the present invention can be used as a medicine and / or for the preparation of a medicine. In some embodiments, the compositions of the present invention can be used as a medicine and / or for the preparation of a medicine for treating cancers, such as hematologic malignancies of the blood, bone marrow and / or lymph nodes, preferably hematologic cancers.

[0120] Several references are cited throughout the text of this specification. Each reference (including any journal article or abstract, published or unpublished patent application, announced patent, manufacturer's specification, instructions for use, etc.) is incorporated herein by reference. However, no prior art is acknowledged in connection with this invention for any reference cited herein.

[0121] The following examples are intended to illustrate, but not limit, the invention.

[0122] Example

[0123] HU38SB19 is provided in solution at 5 mg / ml and stored at 4°C. Dilute it in sterile saline to prepare a dose for administration, store at 4°C, and use within 10 days of dilution.

[0124] Carfilzomib (PR-171) was obtained from Chemie Tek (CT-CARF 98). Carfilzomib was prepared in a 2 mg / ml stock solution in 10% (w / v) aqueous solution of sulfobutylether-h-cyclodextrin (Cydex) and 10 mmol / L sodium citrate (pH 3.5), and frozen at -80°C. It was diluted daily with the carrier before injection. Carfilzomib was administered weekly, once daily for 2 x 3 weeks (intravenous (iv)).

[0125] Example 1: Effects of administering anti-CD38 antibody and carfilzomib in a mouse model of MM. These studies under this example were conducted with the approval of UCSF IACUC.

[0126] Subcutaneous multiple myeloma (MM) xenograft mouse models were established using NCI-H929 or RPMI-8226 cell lines. Specifically, 5-6 week old female Balb / c Scid mice were obtained from Jackson Lab. Mice were housed for 7-10 days prior to implantation. Mice were housed in a dedicated room at the UCSF Mt Zion Animal Barrier Facility. NCI-H929 and RPMI-8226 cells were obtained from the German Collection of Microorganisms and Cell Cultures, DSMZ, and cultured in sterile suspension culture in T225 flasks as follows: NCI-H929: RPMI1640 + 20% FBS + 4 mM L-glutamine + 1 mM sodium pyruvate + 50 μM mercaptoethanol. RPMI-8226: RPMI1640 + 10% FBS + 4mM L-glutamine.

[0127] At implantation, mice were shaved on the right side of the body and shoulder area, and anesthetized with avertin ip (medial rectus muscle). Using a 1ml syringe and a 25g needle, a 100μL volume (1x10) of solution was injected. 7 (cells) will be at 1x10 per ml 8 MM cells, suspended in serum-free RPMI 1640 medium diluted 1:1 with Matrigel (BD), were subcutaneously (sc) injected into the right lateral side of the body. Mice were monitored for tumor appearance twice weekly, and body weight and tumor volume were measured twice weekly once a tumor became visible. An electronic balance and diameter measuring device were used, and data were collected directly into the Study Director system. The mean tumor volume reached approximately 150–200 mm. 3 At that time, the mice were divided into treatment groups of 8-10 mice each, and the dosage was started.

[0128] The dosing schedule was 2 times / week for 2 weeks (intravenous (iv), caudal vein) for hu38SB19, and 2 times / week for 3 weeks (intravenous (iv), caudal vein) for carfilzomib (once daily, two days a week for three weeks). The dose levels used in the combination study are as follows:

[0129]

[0130] Data is collected using a research management application called StudyLog (Study Director) with an electronic balance and a diameter gauge. Graphs are obtained directly from the application. Figure 1A-10B The experimental results are provided in the document.

[0131] Based on single-agent results of hu38SB19 and carfilzomib in the RPMI-8226 and NCI-H929 multiple myeloma xenograft models, the H929 model appears to be more sensitive to both agents, while the RPMI model appears to be more resistant even to the highest dose tested. Figure 1A-7B Therefore, in combination studies, suboptimal doses of each agent were selected to evaluate the activity of the combination treatment (carfilzomib + hu38SB19) in the H929 model, while higher doses of carfilzomib and hu38SB19 were tested in the RPMI model.

[0132] Antitumor activity was determined according to NCI criteria based on the ratio of median tumor volume change in the treatment group to the median tumor volume change in the control group, multiplied by 100 (%ΔT / ΔC). Lower ΔT / ΔC values ​​described stronger antitumor activity. Antitumor activity was defined as T / C ≤ 40% at its minimum. ΔT / ΔC < 10% was considered high antitumor activity.

[0133] In the H929 model, hu38SB19 alone at 0.5 mg / kg / injection (twice a week for 2 weeks) was inactive, with a %ΔT / ΔC of 74%. Treatment with 2 mg / kg carfilzomib alone (twice a week for 3 weeks) was inactive (68% ΔT / ΔC). The combination of hu38SB19 (0.5 mg / kg / injection) and carfilzomib (2 mg / kg / injection) showed much higher activity (tumor regression), with a %ΔT / ΔC of -11% (Figure 8). The results are summarized in Table 1.

[0134] Table 1

[0135]

[0136] like Figures 10A-10B The study showed similar results in the RPMI-8226 xenograft model. Specifically, on day 41, carfilzomib (3 mg / kg qdx2 weeks x 3 weeks) resulted in complete regression in 0 / 10 cases; hu38SB19 (3 ​​mg / kg BIW x2 weeks) resulted in complete regression in 2 / 10 cases. Therefore, the expected summation based on the extrapolation of the combination of carfilzomib and hu38SB19 would be 2 / 10 cases of complete regression. However, surprisingly, the combination of carfilzomib and hu38SB19 resulted in complete regression in 5 / 8 cases, more than three times the expected result.

[0137] In both the NCI-H929 and RPMI-8226 xenograft models, the combination treatment inhibited tumor growth to a much greater extent than the single agent alone, indicating that the combination of hu38SB19 and carfilzomib blocks tumor cell growth via a potential synergistic mechanism. Carfilzomib is a second-generation proteasome inhibitor recently approved for the treatment of patients with relapsed and refractory multiple myeloma. Inhibition of proteasome activity by carfilzomib leads to the formation of polyubiquitinated proteins, which can induce cell cycle arrest, apoptosis, and inhibition of tumor growth. Hu38SB19 has been demonstrated to have multiple mechanisms of action, including ADCC, CDC, and direct apoptosis induction.

[0138] Some CD38 antibodies, such as Daratumumab, have been reported to induce apoptosis only after cross-linking with secondary antibodies that do not have much direct effect on themselves. However, in preclinical studies, hu38SB19 demonstrated potent direct pro-apoptotic activity against tumor cells even without cross-linking. Therefore, this unique characteristic of hu38SB19, compared to other CD38 antibodies combined with carfilzomib, can also lead to greater tumor cell killing when combined with carfilzomib.

[0139] Example 2: The effects of administering anti-CD38 antibody and carfilzomib in humans

[0140] As described below, clinical studies can be conducted to evaluate the efficacy of hu38SB19 in combination with carfilzomib in the treatment of relapsed or refractory multiple myeloma.

[0141] The objectives of the research may include:

[0142] • To determine efficacy and maximum permissible dose;

[0143] • To evaluate the safety, including immunogenicity, of hu38SB19 in combination with carfilzomib in relapsed or refractory multiple myeloma, the severity, frequency, and incidence of all toxicities were assessed.

[0144] • To evaluate the pharmacokinetics (PK) of hu38SB19 when administered in combination with carfilzomib and the PK of carfilzomib in combination with hu38SB19 and optionally dexamethasone.

[0145] • To assess the relationship between clinical (adverse events and / or tumor response) effects and pharmacological parameters (PK / pharmacodynamics) and / or biological (relevant laboratory) results;

[0146] • Activity (response rate) was assessed using the response criteria defined by the International Myeloma Working Group for hu38SB19 plus carfilzomib and optional dexamethasone; and

[0147] • To describe overall survival, progression-free survival (PFS), and time before disease progression in patients treated with this combination therapy.

[0148] Patients enrolled must have received at least two prior treatments (including bortezomib and thalidomide and / or lenalidomide) and whose disease has responded to the recent therapy by less than or equal to 25% or has progressed during or within 60 days of the recent therapy. Patients excluded from the trial are those with the following: total bilirubin level ≥2x upper limit of normal (ULN); creatinine clearance <30 mL / min; New York Heart Association Class III or IV congestive heart failure; symptomatic myocardial ischemia; myocardial infarction within the past 6 months; peripheral neuropathy grade 3 or 4, or peripheral neuropathy grade 2 with pain; active infection requiring treatment; and pleural effusion.

[0149] Carfilzomib is administered intravenously over 2 to 10 minutes twice a week for 3 weeks, followed by a 12-day rest period (28-day treatment cycle) until disease progression, unacceptable toxicity, or a maximum of 12 cycles. Patients receive 20 mg / m² per dose in cycle 1. 2 and receiving 27 mg / m² in subsequent cycles2 To reduce the occurrence and severity of fever, rigidity, chills, dyspnea, myalgia, and arthralgia, it can be administered before all carfilzomib doses during the first cycle and at the first dose amplification (27 mg / m²). 2 During the cycle, administer dexamethasone 4 mg orally or intravenously before all carfilzomib doses. If these symptoms recur during subsequent cycles, the dexamethasone pre-dose regimen (4 mg orally or intravenously) can be resumed. The dose of hu38SB19 can be administered on the same day as and / or on different days as the carfilzomib dose. When administered on the same day, hu38SB19 and carfilzomib can be administered as a combination or as two separate combinations concurrently.

[0150] Individual patient study durations include an inclusion screening period of up to 21 days, and at least 4 weeks of treatment followed by up to 60 days of post-treatment follow-up in the absence of serious adverse events, dose-limiting toxicities, or disease progression. The total study duration can be up to 1 year.

[0151] The following parameters can be measured during and / or at the end of the study:

[0152] • The number of patients who experienced adverse events while being treated with hu38SB19 in combination with carfilzomib;

[0153] • Assess partial response, full response, progression-free survival, and survival;

[0154] • Evaluate the following pharmacokinetic parameters: area under the curve (AUC), maximum concentration (Cmax), and plasma half-life (T). 1 / 2 );

[0155] • The number of CD38 receptors occupied by hu38SB19; and

[0156] • The number of anti-SAR antibodies in response to hu38SB19.

[0157] Example 3: Efficacy of anti-CD38 antibody as a single agent or in combination with carfilzomib in an in vivo tumor model of multiple myeloma.

[0158] A. Materials and Methods

[0159] CD38 density: CD38 density was determined using anti-CD38-PE Quantibrite (BD Biosciences; Cat. 342371) according to the manufacturer's recommended protocol.

[0160] Reagents and compounds: hu38SB19 was provided by Sanofi Oncology in solution at 5 mg / ml and stored at 4°C. Hu38SB19 was diluted in sterile saline to prepare a dose for administration and used within 10 days of dilution. Hu38SB19 was administered intravenously twice weekly for 2 weeks. Carfilzomib (PR-171) was obtained from Chemie Tek (CT-CARF 98). Carfilzomib was prepared in 10% (w / v) aqueous solution of sulfobutyl ether-h-cyclodextrin (Cydex) and 10 mmol / L sodium citrate (pH 3.5) to prepare a 2 mg / ml stock solution, which was frozen at -80°C and diluted daily with the mediator before injection. Carfilzomib was administered intravenously (iv) once weekly for 2 x 3 weeks.

[0161] Test animals: 5-6 week old female Balb / c Scid mice were purchased from Jackson Lab. Mice were housed for 7-10 days before implantation with multiple myeloma (MM) cell lines. Mice were housed in a dedicated room at the UCSF Mt Zion Animal Barrier Facility.

[0162] Xenograft model: Mice were shaved on the right side and shoulder at implantation. Using a 1ml syringe and a 25g needle, xenografts were injected into a 100μL volume (1x10⁻¹² g) of solution. 7 (cells) will be at 1x10 per ml 8 MM cells, suspended in serum-free RPMI 1640 medium diluted 1:1 with Matrigel (BD), were subcutaneously (sc) injected into the right lateral side of the body. Mice were monitored for tumor appearance twice weekly, and body weight and tumor volume were measured twice weekly once a tumor became visible. An electronic balance and diameter measuring device were used, and data were collected directly into the Study Director system. The mean tumor volume reached approximately 150–200 mm. 3 At that time, the mice were divided into treatment groups of 8-10 mice each, and the dosage was started.

[0163] B. Summary and Conclusion

[0164] hu38SB19 is a humanized anti-CD38 antibody whose anti-myeloma effect is influenced by ADCC, CDC and direct apoptosis mechanisms. Figure 11The cell surface density of CD38 in multiple myeloma cell lines is shown. See Kim D, Park CY, Medeiros BC, Weissman IL. CD19-CD45 low / -CD38 high / CD138+ plasma cells enrich for human tumorigenic myeloma cells. Leukemia. 2012 Dec, 26(12): 2530-7. CD38-positive multiple myeloma plasma cells demonstrated variable CD38 cell surface density. All cell lines except XG-6 were reported as CD38-positive. See Bataille R, Jégo G, Robillard N, et al. The phenotype of normal, reactive and malignant plasma cells. Identification of "many and multiple myelomas" and of new targets for myeloma therapy. Haematologica. 2006 Sept, 91(9): 1234-40. The binding of hu38SB19 to CD38 also affects the ADPRC enzymatic activity of CD38. In vivo, hu38SB19 has demonstrated potent antitumor effects in multiple myeloma xenografts (a disease largely characterized by newly generated plasma cells expressing CD38). Figure 12 The study showed that single-agent administration of hu38SB19 resulted in dose-dependent inhibition of tumor growth in a lateral model following NCI-H929. At the end of the study, the magnitude and significance of tumor growth inhibition increased with increasing hu38SB19 dose. Figure 13 The combination of hu38SB19 and carfilzomib resulted in significant tumor growth inhibition in an NCI-H929 xenograft model that lacked robust sensitivity to carfilzomib monotherapy. These data demonstrate that hu38SB19 monotherapy inhibits NCI-H929 tumor growth and, in combination with a sub-effective dose of carfilzomib, produces significant inhibition of tumor growth. In conclusion, these data further support the evaluation of hu38SB19, both as a monotherapy and in combination with standard of care, as a potential treatment for multiple myeloma.

[0165] To the extent necessary to understand or complete the disclosure of this invention, all publications, patents and patent applications mentioned herein are expressly incorporated herein by reference as if each were individually included.

[0166] The exemplary embodiments of the invention have thus been described. Those skilled in the art should note that the disclosure is merely illustrative, and various other substitutions, adaptations, and modifications can be made within the scope of the invention. Therefore, the invention is not limited to the specific embodiments shown herein, but is limited to the appended claims.

Claims

1. A method for treating cancer in a subject, comprising: The subjects were administered one or more anti-CD38 antibodies and one or more carfilzomib compounds.

2. The method according to claim 1, wherein the cancer is hematologic malignancy, preferably multiple myeloma, more preferably relapsed or refractory multiple myeloma.

3. The method according to claim 1 or 2, wherein at least one of the one or more anti-CD38 antibodies comprises one or more complementarity-determining regions having an amino acid sequence selected from the group consisting of: SEQ ID NO: 13, 14, 81, 15, 16, 17, 18, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 and 36.

4. The method according to any one of claims 1 to 3, wherein at least one of the one or more anti-CD38 antibodies is selected from the group consisting of: a) An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:13, 15 and SEQ ID NO:14 or SEQ ID NO:81, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:16, 17 and 18. b) An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:25, 26 and 27, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:28, 29 and 30. c) An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:1, 2 and 3, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:4, 5 and 6. d) An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO: 7, 8 and 9, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO: 10, 11 and 12. e) An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO: 19, 20, and 21, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO: 22, 23, and 24; and f) An antibody comprising a heavy chain and a light chain, wherein the heavy chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:31, 32 and 33, and the light chain comprises three consecutive CDRs having an amino acid sequence consisting of SEQ ID NO:34, 35 and 36.

5. The method of claim 4, wherein the antibody comprises having the V shown in SEQ ID NO:66 H The heavy chain of the variable region, and having the V shown in SEQ ID NO:62 or SEQ ID NO:64 L A light chain with a variable region, or containing a V as shown in SEQ ID NO:72 H The heavy chain of the variable region, and having the V shown in SEQ ID NO:68 or SEQ ID NO:70 L Light chains with variable regions.

6. A composition comprising: a) At least one anti-CD38 antibody, preferably said antibody capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + Cells; and b) at least one carfilzomib compound, preferably carfilzomib; and optionally c) Dexamethasone compounds, preferably dexamethasone.

7. A reagent kit comprising: a) A first composition comprising at least one anti-CD38 antibody, preferably said antibody being capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + Cells; and b) A second composition comprising at least one carfilzomib compound, preferably carfilzomib.

8. A reagent kit comprising the following items packaged together: It can kill CD38 cells through apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + At least one anti-CD38 antibody in cells, A label containing one or more of the following information: the at least one anti-CD38 antibody should be administered in combination with carfilzomib, optionally with dexamethasone.

9. Combinations of the following items: (i) At least one anti-CD38 antibody, preferably said antibody is capable of killing CD38 cells via apoptosis, antibody-dependent cell-mediated cytotoxicity (ADCC), and complement-dependent cytotoxicity (CDC). + Cells; and (ii) at least one carfilzomib compound, preferably carfilzomib; and optionally (iii) A dexamethasone compound, preferably dexamethasone.

10. The combination product of claim 9, wherein the combination product is used sequentially in the treatment of hematologic malignancies, preferably multiple myeloma.

Images