Combined use of micelle containing oxidized platinum compound and immune checkpoint inhibitor, and method for producing micelle containing oxidized platinum compound

Abstract

In the present invention, a block copolymer containing a biocompatible polymer block and a polyamino acid block, and a micelle containing an oxidized platinum compound exhibit significantly lower distribution of platinum to bone marrow than a reduced platinum compound. In other words, myelosuppression, which is one side effect, can be prevented, and thus white blood cell production is not inhibited. Further, by using the micelle and an immune checkpoint inhibitor in combination, the activity of T cells, which are a type of white blood cells, is maintained, and thus a drug combining the two is useful in the treatment and / or prevention of cancer.

Description

Micelles containing oxidized platinum compounds and their use in combination with immune checkpoint inhibitors, and methods for producing micelles containing oxidized platinum compounds

[0001] The present invention relates to a pharmaceutical combination of a micelle containing an oxidized platinum compound and an immune checkpoint inhibitor, and the use of the micelle in combination with an immune checkpoint inhibitor for the treatment or prevention of cancer. The present invention also relates to a method for producing a micelle containing a block copolymer including a biocompatible polymer block and a polyamino acid block and the oxidized platinum compound Bis(acetato-O)(1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum (IV), and a cancer therapeutic and / or preventive agent that controls the release of platinum from the micelle. This application claims priority to Japanese Patent Application No. 2024-102788 filed in Japan on June 26, 2024, and Japanese Patent Application No. 2024-102795 filed in Japan on June 26, 2024, the contents of which are incorporated herein by reference.

[0002] Platinum-containing compounds such as nedaplatin, cisplatin, carboplatin, dahplatin, and oxaliplatin are widely used as anticancer drugs because they bind to the double helix structure of DNA and inhibit DNA replication. However, because they are distributed nonspecifically throughout the body, they frequently cause side effects such as kidney damage, bone marrow suppression, nausea, vomiting, diarrhea, and stomatitis.

[0003] For example, Patent Document 1 and Non-Patent Documents 1 and 2 disclose micelles of cisplatin or DACH-platin and a block copolymer of a hydrophilic polymer and a hydrophobic polymer.

[0004] Furthermore, Patent Document 2 discloses a transition metal-encapsulating micelle that contains a complex of a block copolymer of a hydrophilic polymer and an anionic polymer with a transition metal including platinum, in which the transition metal is in an oxidized form.

[0005] Immune checkpoint inhibitors block the binding of immune checkpoint molecules to their receptors, thereby promoting the activation of T cells and enhancing the anti-tumor responsiveness of these T cells, thereby eliminating cancer cells.

[0006] Immune checkpoint inhibitors such as ipilimumab, an anti-CTLA-4 (cytotoxic T lymphocyte-associated antigen-4) antibody, and nivolumab and pembrolizumab, anti-PD-1 (programmed cell death-1) antibodies, have already been approved in Japan and overseas and are being used in cancer treatment.

[0007] However, the response rate of immune checkpoint inhibitor therapy is not particularly high, and it is difficult to observe the effect of immune checkpoint inhibitors alone, especially in solid cancers such as colorectal cancer. On the other hand, oxaliplatin is known to have the effect of activating the immune system by inducing immunogenic cell death in cancer cells, and it is known that the therapeutic effect of chemotherapy containing oxaliplatin is improved when used in combination with immune checkpoint inhibitors (see, for example, Non-Patent Documents 3 and 4).

[0008] International Publication No. WO 2002 / 026241 International Publication No. WO 2018 / 038240

[0009] Cabral H., et al., Preparation and biological properties of dichloro(1,2-diaminocyclohexane)platinum(II) (DACHPt)-loaded polymeric micelles, J. Control. Release, 101: 223-232, 2005. Mochida Y., et al., Polymeric micelles for targeted tumor therapy of platinum anticancer drugs, Expert. Opin. Drug Deliv., 14: 1423-1438, 2017.Zhao X. and Subramanian S., Intrinsic Resistance of Solid Tumors to Immune Checkpoint Blockade Therapy, Cancer Res. 77: 817-822, 2017.Janjigian YY, et al., First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomized, open-label, phase 3 trial, Lancet 398: 27-40, 2021.

[0010] The present invention aims to provide a pharmaceutical composition that can exert a superior therapeutic effect even against cancers for which the therapeutic effect of an immune checkpoint inhibitor alone is insufficient. Another object of the present invention is to provide a cancer therapeutic agent that has fewer side effects associated with platinum.

[0011] As a result of extensive investigations to solve the above problems, the inventors discovered that the combined use of micelles containing an oxidized platinum compound with one or more immune checkpoint inhibitors is advantageous, and thus completed the present invention.

[0012] The inventors also found that micelles containing a block copolymer containing a biocompatible polymer block and a polyamino acid block, and the oxidized platinum compound Bis(acetato-O)(1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum(IV), release platinum from the micelles and activate it in cancer tissues.

[0013] That is, the present invention includes the following aspects. [1-1] A combination drug of a block copolymer containing a biocompatible polymer block and a polyamino acid block, a micelle containing an oxidized platinum compound, and one or more immune checkpoint inhibitors. [1-2] The biocompatible polymer is poly(C １－３ alkylene glycol), polylactic acid, polyglycolic acid, polycaprolactone, polydioxanone, lactic acid / glycolic acid copolymer, polyvinyl alcohol, poly(N-vinylpyrrolidone), poly(2-hydroxyethyl methacrylate), poly(2-C １－３ [1-3] The combination pharmaceutical according to [1-1], wherein the biocompatible polymer is selected from the group consisting of poly(C １－３ [1-4] The combination drug according to [1-1], wherein the poly(C １－３The combination pharmaceutical according to [1-2] or [1-3], wherein the poly(alkylene glycol) is poly(ethylene glycol). [1-5] The combination pharmaceutical according to any of [1-1] to [1-4], wherein the amino acid constituting the polyamino acid block is an acidic amino acid. [1-6] The combination pharmaceutical according to [1-5], wherein the acidic amino acid is glutamic acid and / or aspartic acid. [1-7] The combination pharmaceutical according to [1-5], wherein the acidic amino acid is glutamic acid. [1-8] The combination pharmaceutical according to [1-5], wherein the acidic amino acid is aspartic acid. [1-9] The combination pharmaceutical according to any of [1-1] to [1-8], wherein the biocompatible polymer is a biocompatible polymer having a degree of polymerization of 5 to 20,000. [1-10] The combination pharmaceutical according to any of [1-1] to [1-9], wherein the polyamino acid block is a polyamino acid having a degree of polymerization of 2 to 20,000. [1-11] The combination pharmaceutical according to any one of [1-1] to [1-10], wherein the oxidized platinum compound is selected from the group consisting of nedaplatin, cisplatin, carboplatin, DACH-platin, oxaliplatin, their prodrugs, and oxides of pharmaceutically acceptable salts thereof. [1-12] The combination pharmaceutical according to any one of [1-1] to [1-10], wherein the oxidized platinum compound is Bis(acetato-O)(1,2-cyclohexanediamine-N,N')(dihydroxy)platinum (IV). [1-13] The combination pharmaceutical according to any one of [1-1] to [1-12], wherein the immune checkpoint inhibitor is one or more selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, an anti-CTLA-4 antibody, and an anti-LAG-3 antibody. [1-14] The combination pharmaceutical according to any of [1-1] to [1-12], wherein the immune checkpoint inhibitors are a combination of an anti-PD-L1 antibody and an anti-CTLA-4 antibody. [1-15] The combination pharmaceutical according to [1-13], wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, or cemiplimab. [1-16] The combination pharmaceutical according to [1-13] or [1-14], wherein the anti-PD-L1 antibody is atezolizumab, durvalumab, or avelumab.[1-17] The combination drug according to [1-13] or [1-14], wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab. [1-18] The combination drug according to [1-13], wherein the anti-LAG-3 antibody is leratolimab.

[0014] [2-1] A combination drug of an immune checkpoint inhibitor and a micelle containing a block copolymer including a biocompatible polymer block and a polyamino acid block, and an oxidized platinum compound, the combination drug comprising: (Step 2) a step of producing micelles from a block copolymer including a biocompatible polymer and a polyamino acid block copolymer, and a reduced platinum compound; and (Step 3) a step of oxidizing the micelles produced in Step 2. [2-2] The biocompatible polymer is poly(C １－３ alkylene glycol), polylactic acid, polyglycolic acid, polycaprolactone, polydioxanone, lactic acid / glycolic acid copolymer, polyvinyl alcohol, poly(N-vinylpyrrolidone), poly(2-hydroxyethyl methacrylate), poly(2-C １－３ [2-3] The biocompatible polymer is selected from the group consisting of poly(C １－３ [2-4] The combination drug according to [2-1], wherein the poly(C １－３The combination pharmaceutical according to [2-2] or [2-3], wherein the poly(alkylene glycol) is poly(ethylene glycol). [2-5] The combination pharmaceutical according to any of [2-1] to [2-4], wherein the amino acid constituting the polyamino acid block is an acidic amino acid. [2-6] The combination pharmaceutical according to [2-5], wherein the acidic amino acid is glutamic acid and / or aspartic acid. [2-7] The combination pharmaceutical according to [2-5], wherein the acidic amino acid is glutamic acid. [2-8] The combination pharmaceutical according to [2-5], wherein the acidic amino acid is aspartic acid. [2-9] The combination pharmaceutical according to any of [2-1] to [2-8], wherein the biocompatible polymer is a biocompatible polymer having a degree of polymerization of 5 to 20,000. [2-10] The combination pharmaceutical according to any of [2-1] to [2-9], wherein the polyamino acid is a polyamino acid having a degree of polymerization of 2 to 20,000. [2-11] The combination pharmaceutical according to any one of [2-1] to [2-10], wherein the oxidation treatment is an oxidation treatment using a peroxide. [2-12] The combination pharmaceutical according to [2-11], wherein the peroxide is selected from the group consisting of hydrogen peroxide, benzoyl peroxide, acetone peroxide, and butanone peroxide. [2-13] The combination pharmaceutical according to [2-11], wherein the peroxide is hydrogen peroxide. [2-14] The combination pharmaceutical according to any one of [2-1] to [2-13], wherein the immune checkpoint inhibitor is one or more selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody. [2-15] The combination pharmaceutical according to any one of [2-1] to [2-13], wherein the immune checkpoint inhibitor is a combination of an anti-PD-L1 antibody and an anti-CTLA-4 antibody. [2-16] The combination pharmaceutical according to [2-14], wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, or cemiplimab. [2-17] The combination pharmaceutical according to [2-14] or [2-15], wherein the anti-PD-L1 antibody is atezolizumab, durvalumab, or avelumab. [2-18] The combination pharmaceutical according to [2-14] or [2-15], wherein the anti-CTLA-4 antibody is ipilimumab.[2-19] The combination drug according to [2-14], wherein the anti-LAG-3 antibody is leratolimab.

[0015] [3-1] A combination drug comprising a block copolymer represented by the following formula I, a micelle containing an oxidized platinum compound, and an immune checkpoint inhibitor: (In formula I, R １ is C １－３ is an alkyl group, and R ２ is a hydrogen atom, n is an integer of 5 to 20,000, m is an integer of 2 to 20,000, and p is 1 or 2. [3-2] The combination drug according to [3-1], wherein n is an integer of 5 to 2,000, m is an integer of 2 to 2,000, and p is 1 or 2. [3-3] The combination drug according to [3-1], wherein n is an integer of 10 to 500, m is an integer of 5 to 500, and p is 1 or 2. [3-4] R １ is a methyl group, and R ２ is a hydrogen atom. [3-5] The combination pharmaceutical according to any one of [3-1] to [3-4], wherein the immune checkpoint inhibitor is one or more selected from the group consisting of an anti-PD-1 antibody, an anti-PD-L1 antibody, and an anti-CTLA-4 antibody. [3-6] The combination pharmaceutical according to any one of [3-1] to [3-4], wherein the immune checkpoint inhibitor is a combination of an anti-PD-L1 antibody and an anti-CTLA-4 antibody. [3-7] The combination pharmaceutical according to [3-5], wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, or cemiplimab. [3-8] The combination pharmaceutical according to [3-5] or [3-6], wherein the anti-PD-L1 antibody is atezolizumab, durvalumab, or avelumab. [3-9] The combination pharmaceutical according to [3-5] or [3-6], wherein the anti-CTLA-4 antibody is ipilimumab. [3-10] The combination drug according to [3-5], wherein the anti-LAG-3 antibody is leratolimab.

[0016] [4-1] The combination pharmaceutical according to any one of [1-1] to [3-10], wherein the surface of the micelle containing the block copolymer comprising a biocompatible polymer block and a polyamino acid block, and the oxidized platinum compound is further modified with glucose.

[0017] [11-1] A micelle comprising a block copolymer containing a biocompatible polymer block and a polyamino acid block, and Bis(acetato-O)(1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum(IV). [11-2] The biocompatible polymer is poly(C １－３ alkylene glycol), polylactic acid, polyglycolic acid, polycaprolactone, polydioxanone, lactic acid / glycolic acid copolymer, polyvinyl alcohol, poly(N-vinylpyrrolidone), poly(2-hydroxyethyl methacrylate), poly(2-C １－３ [11-3] The micelle according to [11-1], wherein the biocompatible polymer is selected from the group consisting of poly(C １－３ [11-4] The micelle according to [11-1], wherein the poly(C １－３ The micelle according to [11-3], wherein the poly(alkylene glycol) is poly(ethylene glycol). [11-5] The micelle according to any one of [11-1] to [11-4], wherein the amino acid constituting the polyamino acid block is an acidic amino acid. [11-6] The micelle according to [11-5], wherein the acidic amino acid is glutamic acid and / or aspartic acid. [11-7] The micelle according to [11-5], wherein the acidic amino acid is glutamic acid. [11-8] The micelle according to [11-5], wherein the acidic amino acid is aspartic acid. [11-9] The micelle according to any one of [11-1] to [11-8], wherein the biocompatible polymer has a degree of polymerization of 5 to 20,000. [11-10] The micelle according to any one of [11-1] to [11-9], wherein the polyamino acid block is a polyamino acid having a degree of polymerization of 2 to 20,000.

[0018] [12-1] A micelle comprising a block copolymer containing a biocompatible polymer block and a polyamino acid block, and Bis(acetato-O)(1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum(IV), the micelle being produced by the following steps: (Step 2) producing micelles from a block copolymer containing a biocompatible polymer and a polyamino acid block copolymer, and (SP-4-2) bis(acetato-O)(1,2-cyclohexanediamine-N,N')platinum(II); (Step 3) oxidizing the micelles produced in Step 2 with peroxide. [12-2] A micelle produced by the following steps: (Step 2) producing micelles from a block copolymer containing a biocompatible polymer and a polyamino acid block copolymer, and (SP-4-2) bis(acetato-O)(1,2-cyclohexanediamine-N,N')platinum(II). １－３ alkylene glycol), polylactic acid, polyglycolic acid, polycaprolactone, polydioxanone, lactic acid / glycolic acid copolymer, polyvinyl alcohol, poly(N-vinylpyrrolidone), poly(2-hydroxyethyl methacrylate), poly(2-C １－３ [12-3] The micelle according to [12-1], wherein the biocompatible polymer is selected from the group consisting of poly(C １－３The micelle according to [12-1], wherein the biocompatible polymer is poly(ethylene glycol). [12-4] The micelle according to [12-1], wherein the amino acid constituting the polyamino acid block is an acidic amino acid. [12-5] The micelle according to any one of [12-1] to [12-4], wherein the amino acid constituting the polyamino acid block is glutamic acid and / or aspartic acid. [12-7] The micelle according to any one of [12-1] to [12-3], wherein the amino acid constituting the polyamino acid block is glutamic acid. [12-8] The micelle according to any one of [12-1] to [12-3], wherein the amino acid constituting the polyamino acid block is aspartic acid. [12-9] The micelle according to any one of [12-1] to [12-8], wherein the biocompatible polymer is a biocompatible polymer having a degree of polymerization of 5 to 20,000. [12-10] The micelle according to any one of [12-1] to [12-9], wherein the polyamino acid is a polyamino acid having a degree of polymerization of 2 to 20,000. [12-10] The micelle according to any one of [12-1] to [12-9], wherein the oxidation treatment is an oxidation treatment using a peroxide. [12-11] The micelle according to [12-10], wherein the peroxide is selected from the group consisting of hydrogen peroxide, benzoyl peroxide, acetone peroxide, and butanone peroxide. [12-12] The micelle according to [12-10], wherein the peroxide is hydrogen peroxide.

[0019] [13-1] A micelle represented by the following formula I', wherein the block copolymer according to any one of [11-1] to [12-10] is a block copolymer. (In formula I', R １ and R ２ are each independently a hydrogen atom or C １－３[13-2] The micelle according to [13-1], wherein n is an integer of 5 to 2,000, m is an integer of 2 to 2,000, and p is 1 or 2. [13-3] The micelle according to [13-1], wherein n is an integer of 10 to 500, m is an integer of 5 to 500, and p is 1 or 2. [13-4] R １ is a methyl group, and R ２ is hydrogen, n is an integer of 40 to 500, m is an integer of 5 to 200, and p is 1.

[0020] [14-1] A micelle according to any one of [11-1] to [13-4], wherein the surface of the micelle is further modified with glucose.

[0021] [22-1] A method for treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a block copolymer comprising a biocompatible polymer block and a polyamino acid block according to any one of [1-1] to [4-1], a micelle comprising an oxidized platinum compound, and an effective amount of an immune checkpoint inhibitor. [22-2] The method of [22-1], wherein the cancer is selected from the group consisting of testicular tumor, bladder cancer, renal pelvis / ureter tumor, prostate cancer, ovarian cancer, head and neck cancer, small cell lung cancer, non-small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, osteosarcoma, germ cell tumor (testicular tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, malignant bone tumor, brain tumor, salivary gland cancer, thyroid cancer, biliary tract cancer, small intestine cancer, colon cancer, gastrointestinal stromal tumor, kidney cancer, skin cancer, malignant melanoma, sarcoma, uterine sarcoma, endometrial cancer, relapsed / refractory malignant lymphoma, leukemia, multiple myeloma, pediatric malignant solid tumor (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, primary malignant liver tumor, medulloblastic tumor), and cancer of unknown primary.

[0022] [23-1] Use of a combination of a block copolymer comprising a biocompatible polymer block and a polyamino acid block according to any one of [1-1] to [4-1], a micelle comprising an oxidized platinum compound, and an immune checkpoint inhibitor for the treatment and / or prevention of cancer. [23-2] The use according to [23-1], wherein the cancer is selected from the group consisting of testicular tumor, bladder cancer, renal pelvis / ureter tumor, prostate cancer, ovarian cancer, head and neck cancer, small cell lung cancer, non-small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, osteosarcoma, germ cell tumor (testicular tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, malignant bone tumor, brain tumor, salivary gland cancer, thyroid cancer, biliary tract cancer, small intestine cancer, colon cancer, gastrointestinal stromal tumor, kidney cancer, skin cancer, malignant melanoma, sarcoma, uterine sarcoma, endometrial cancer, relapsed / refractory malignant lymphoma, leukemia, multiple myeloma, pediatric malignant solid tumor (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, primary malignant liver tumor, medulloblastic tumor), and cancer of unknown primary.

[0023] [24-1] A combination pharmaceutical comprising a block copolymer containing the biocompatible polymer block and polyamino acid block according to any one of [1-1] to [4-1], a micelle containing an oxidized platinum compound, and an immune checkpoint inhibitor, for use in the treatment and / or prevention of cancer. [24-2] The combination pharmaceutical according to [24-1], wherein the cancer is selected from the group consisting of testicular tumor, bladder cancer, renal pelvis / ureter tumor, prostate cancer, ovarian cancer, head and neck cancer, small cell lung cancer, non-small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, osteosarcoma, germ cell tumor (testicular tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, malignant bone tumor, brain tumor, salivary gland cancer, thyroid cancer, biliary tract cancer, small intestine cancer, colon cancer, gastrointestinal stromal tumor, kidney cancer, skin cancer, malignant melanoma, sarcoma, uterine sarcoma, endometrial cancer, relapsed / refractory malignant lymphoma, leukemia, multiple myeloma, pediatric malignant solid tumor (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, primary malignant liver tumor, medulloblastic tumor), and cancer of unknown primary.

[0024] [31-1] A pharmaceutical composition comprising the micelle according to any one of [11-1] to [14-1] and a pharmaceutically acceptable carrier and / or excipient.

[0025] [32-1] A therapeutic and / or preventive agent for cancer, comprising the micelle according to any one of [11-1] to [14-1] and a pharmaceutically acceptable carrier and / or excipient. [32-2] The agent for treating and / or preventing cancer according to [32-1], wherein the cancer is selected from the group consisting of testicular tumor, bladder cancer, renal pelvis / ureter tumor, prostate cancer, ovarian cancer, head and neck cancer, small cell lung cancer, non-small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, osteosarcoma, germ cell tumor (testicular tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, malignant bone tumor, brain tumor, salivary gland cancer, thyroid cancer, biliary tract cancer, small intestine cancer, colon cancer, gastrointestinal stromal tumor, kidney cancer, skin cancer, malignant melanoma, sarcoma, uterine sarcoma, endometrial cancer, relapsed / refractory malignant lymphoma, leukemia, multiple myeloma, pediatric malignant solid tumor (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, primary malignant liver tumor, medulloblastic tumor), and cancer of unknown primary.

[0026] [33-1] A pharmaceutical composition for treating and / or preventing cancer, comprising the micelle according to any one of [11-1] to [14-1]. [33-2] The pharmaceutical composition according to [33-1], wherein the cancer is selected from the group consisting of testicular tumor, bladder cancer, renal pelvis / ureter tumor, prostate cancer, ovarian cancer, head and neck cancer, small cell lung cancer, non-small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, osteosarcoma, germ cell tumor (testicular tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, malignant bone tumor, brain tumor, salivary gland cancer, thyroid cancer, biliary tract cancer, small intestine cancer, colon cancer, gastrointestinal stromal tumor, kidney cancer, skin cancer, malignant melanoma, sarcoma, uterine sarcoma, endometrial cancer, relapsed / refractory malignant lymphoma, leukemia, multiple myeloma, pediatric malignant solid tumor (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, primary malignant liver tumor, medulloblastic tumor), and cancer of unknown primary.

[0027] [34-1] A method for treating and / or preventing cancer, comprising administering an effective amount of the micelle according to any one of [11-1] to [14-1] to a subject in need thereof. [34-2] The method for treating and / or preventing cancer according to [34-1], wherein the cancer is selected from the group consisting of testicular tumor, bladder cancer, renal pelvis / ureter tumor, prostate cancer, ovarian cancer, head and neck cancer, small cell lung cancer, non-small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, osteosarcoma, germ cell tumor (testicular tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, malignant bone tumor, brain tumor, salivary gland cancer, thyroid cancer, biliary tract cancer, small intestine cancer, colon cancer, gastrointestinal stromal tumor, kidney cancer, skin cancer, malignant melanoma, sarcoma, uterine sarcoma, endometrial cancer, relapsed / refractory malignant lymphoma, leukemia, multiple myeloma, pediatric malignant solid tumor (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, primary malignant liver tumor, medulloblastic tumor), and cancer of unknown primary.

[0028] [35-1] Use of the micelle according to any one of [11-1] to [14-1] for the treatment and / or prevention of cancer. [35-2] The use according to [35-1], wherein the cancer is selected from the group consisting of testicular tumor, bladder cancer, renal pelvis / ureter tumor, prostate cancer, ovarian cancer, head and neck cancer, small cell lung cancer, non-small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, osteosarcoma, germ cell tumor (testicular tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, malignant bone tumor, brain tumor, salivary gland cancer, thyroid cancer, biliary tract cancer, small intestine cancer, colon cancer, gastrointestinal stromal tumor, kidney cancer, skin cancer, malignant melanoma, sarcoma, uterine sarcoma, endometrial cancer, relapsed / refractory malignant lymphoma, leukemia, multiple myeloma, pediatric malignant solid tumor (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, primary malignant liver tumor, medulloblastic tumor), and cancer of unknown primary.

[0029] [36-1] The micelle according to any one of [11-1] to [14-1] for use in the treatment and / or prevention of cancer. [36-2] The micelle according to [36-1], wherein the cancer is selected from the group consisting of testicular tumor, bladder cancer, renal pelvis / ureter tumor, prostate cancer, ovarian cancer, head and neck cancer, small cell lung cancer, non-small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, osteosarcoma, germ cell tumor (testicular tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, malignant bone tumor, brain tumor, salivary gland cancer, thyroid cancer, biliary tract cancer, small intestine cancer, colon cancer, gastrointestinal stromal tumor, kidney cancer, skin cancer, malignant melanoma, sarcoma, uterine sarcoma, endometrial cancer, relapsed / refractory malignant lymphoma, leukemia, multiple myeloma, pediatric malignant solid tumor (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, primary malignant liver tumor, medulloblastic tumor), and cancer of unknown primary.

[0030] [37-1] Use of the micelle according to any one of [11-1] to [14-1] for producing a medicament for treating and / or preventing cancer. [37-2] Use of the micelle according to [37-1], wherein the cancer is selected from the group consisting of testicular tumor, bladder cancer, renal pelvis / ureter tumor, prostate cancer, ovarian cancer, head and neck cancer, small cell lung cancer, non-small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, osteosarcoma, germ cell tumor (testicular tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, malignant bone tumor, brain tumor, salivary gland cancer, thyroid cancer, biliary tract cancer, small intestine cancer, colon cancer, gastrointestinal stromal tumor, kidney cancer, skin cancer, malignant melanoma, sarcoma, uterine sarcoma, endometrial cancer, relapsed / refractory malignant lymphoma, leukemia, multiple myeloma, pediatric malignant solid tumor (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, primary malignant liver tumor, medulloblastic tumor), and cancer of unknown primary.

[0031] [41-1] A method for producing micelles comprising a block copolymer comprising a biocompatible polymer block and a polyamino acid block, and Bis(acetato-O)(1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum(IV), comprising: (Step 2) producing micelles from a block copolymer comprising a biocompatible polymer block and a polyamino acid block, and (SP4-2) bis(acetato-O)(1,2-cyclohexanediamine-N,N')platinum(II), and (Step 3) treating the micelles produced in Step 2 with peroxide. [41-2] A method for producing micelles according to [41-1], further comprising: (Step 1) producing a block copolymer comprising a biocompatible polymer block and a polyamino acid block from the biocompatible polymer block and the polyamino acid block. [41-3] The method for producing micelles according to [41-1], wherein the oxidation treatment is an oxidation treatment using a peroxide. [41-4] The method for producing micelles according to [41-3], wherein the peroxide is selected from the group consisting of hydrogen peroxide, benzoyl peroxide, acetone peroxide, and butanone peroxide. [41-5] The method for producing micelles according to [41-3], wherein the peroxide is hydrogen peroxide.

[0032] [51-1] A kit comprising the block copolymer comprising a biocompatible polymer block and a polyamino acid block according to any one of [1-1] to [4-1], a micelle containing an oxidized platinum compound, and an immune checkpoint inhibitor. [51-2] The kit according to [51-1], further comprising instructions for use.

[0033] [52-1] A kit for use in treating and / or preventing cancer in a subject, the kit comprising: a block copolymer comprising a biocompatible polymer block and a polyamino acid block according to any one of [1-1] to [4-1]; a micelle comprising an oxidized platinum compound; and an immune checkpoint inhibitor. [52-2] The kit according to [52-1], wherein the cancer is selected from the group consisting of testicular tumor, bladder cancer, renal pelvis / ureter tumor, prostate cancer, ovarian cancer, head and neck cancer, small cell lung cancer, non-small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, osteosarcoma, germ cell tumor (testicular tumor, ovarian tumor, extragonadal tumor), malignant pleural mesothelioma, biliary tract cancer, malignant bone tumor, brain tumor, salivary gland cancer, thyroid cancer, biliary tract cancer, small intestine cancer, colon cancer, gastrointestinal stromal tumor, kidney cancer, skin cancer, malignant melanoma, sarcoma, uterine sarcoma, endometrial cancer, relapsed / refractory malignant lymphoma, leukemia, multiple myeloma, pediatric malignant solid tumor (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, primary malignant liver tumor, medulloblastic tumor), and cancer of unknown primary.

[0034] According to the present invention, it is possible to provide a pharmaceutical composition that can exert a superior therapeutic effect even against cancers for which the therapeutic effect of an immune checkpoint inhibitor alone is insufficient.

[0035] The micelles containing the oxidized platinum compound of the present invention migrate to the bone marrow to a significantly lesser extent than the reduced platinum compound. This means that bone marrow suppression, one of the side effects of platinum, can be prevented, and white blood cell production is not suppressed. Furthermore, because the immune checkpoint inhibitor maintains the activity of T cells, a type of white blood cell, these combination drugs are useful for cancer treatment.

[0036] Furthermore, a micelle containing a block copolymer of the present invention containing a biocompatible polymer block and a polyamino acid block, and Bis(acetato-O)(1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum (IV) can suppress the distribution of platinum, particularly in the bone marrow, and therefore can prevent the suppression of white blood cell and platelet production by platinum.

[0037] Fig. 1 is a graph showing the results of measuring the amount of platinum complex in each organ in a living body in Experimental Example 1. Fig. 2 is a graph showing the results of measuring the number of blood components in Experimental Example 2. Fig. 3 is a graph showing the results of measuring the change in tumor volume over time in Experimental Example 3. Fig. 4 is a graph showing the results of measuring the change in tumor volume over time in Experimental Example 4. Fig. 5 is a graph showing the change in survival rate of mice over time in Experimental Example 4.

[0038] The terms and phrases used in this specification are explained in detail below.

[0039] As used herein, a "block copolymer comprising a biocompatible polymer block and a polyamino acid block" refers to a block copolymer comprising a biocompatible polymer block and a polyamino acid block as components. The biocompatible polymer block and the polyamino acid block may be bonded via a linker. The block copolymer comprising a biocompatible polymer block and a polyamino acid block may be in a free form or in the form of a salt. Examples of salts include pharmaceutically acceptable salts. The block copolymer comprising a biocompatible polymer block and a polyamino acid block may have substituents (e.g., methyl groups, methoxy groups, etc.) at both ends, as long as they do not affect the micellization of the block copolymer.

[0040] In the present specification, the "biocompatible polymer block" is not particularly limited as long as it is a biocompatible polymer, but specifically includes poly(C １－３ alkylene glycol), polylactic acid, polyglycolic acid, polycaprolactone, polydioxanone, lactic acid / glycolic acid copolymer, polyvinyl alcohol, poly(N-vinylpyrrolidone), poly(2-hydroxyethyl methacrylate), poly(2-C １－３ alkyl-2-oxazoline).

[0041] As used herein, "poly(C １－３The "alkylene glycol" is a poly(alkylene glycol) composed of a linear or branched alkylene having 1 to 3 carbon atoms, and specific examples thereof include poly(ethylene glycol) and poly(propylene glycol).

[0042] As used herein, "poly(2-C １－３ The "alkyl-2-oxazoline" is an oxazoline having a linear or branched alkyl group having 1 to 3 carbon atoms as a substituent, and specific examples thereof include poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline), poly(2-propyl-2-oxazoline), and poly(2-isopropyl-2-oxazoline).

[0043] In this specification, the "polyamino acid block" may be a natural amino acid or a non-natural amino acid as long as the constituent amino acids are acidic amino acids, and examples thereof include amino acids whose side chain terminals are carboxylic acids, specifically glutamic acid or aspartic acid.

[0044] In this specification, "C １－３ The "alkyl group" is a straight-chain or branched-chain alkyl group having 1 to 3 carbon atoms, and specific examples thereof include a methyl group, an ethyl group, an n-propyl group, and an isopropyl group.

[0045] In this specification, the reduced platinum compound refers to nedaplatin, cisplatin, carboplatin, dahaplatin, oxaliplatin, and their prodrugs or pharmaceutically acceptable salts. When a compound has an asymmetric carbon, it includes racemic modifications and optically active substances thereof. Further examples include (SP4-2)bis(acetato-O)(1,2-cyclohexanediamine-N,N')platinum(II) and (SP4-2)bis(acetato-O)((1R,2R)-1,2-cyclohexanediamine-N,N')platinum(II).

[0046] In this specification, the oxidized platinum compound is a compound obtained by oxidizing a reduced platinum compound, and is an oxide of nedaplatin, cisplatin, carboplatin, DACH-platin, oxaliplatin, their prodrugs, or their pharmaceutically acceptable salts. When an asymmetric carbon is present, the compound includes a racemic modification and each optically active substance. Further examples include Bis(acetato-O)(1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum(IV) and Bis(acetato-O)((1R,2R)-1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum(IV).

[0047] In this specification, "(SP4-2)bis(acetato-O)(1,2-cyclohexanediamine-N,N')platinum(II)" refers to the following compound II (CAS No. 63037-19-4), and includes racemic and optically active compounds. A specific example of the optically active compound is the following compound IIa (SP4-2)bis(acetato-O)((1R,2R)-1,2-cyclohexanediamine-N,N')platinum(II)) (CAS No. 781572-97-2).

[0048]

[0049] In this specification, "Bis(acetato-O)(1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum(IV)" refers to the following compound III, and includes racemic and optically active compounds. A specific example of an optically active compound is the following compound IIIa (Bis(acetato-O)((1R,2R)-1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum(IV)) (CAS No. 2573255-69-1).

[0050]

[0051] As used herein, "oxidation treatment" can be carried out by contacting a block copolymer of a biocompatible polymer block and a polyamino acid block, and a micelle containing a reduced platinum compound, with a peroxide. For example, oxidation treatment can be carried out by contacting a block copolymer of a biocompatible polymer block and a polyamino acid block, and a micelle containing (SP4-2)bis(acetato-O)(1,2-cyclohexanediamine-N,N')platinum(II), with a peroxide. The peroxide may be either an organic peroxide or an inorganic peroxide having a peroxy structure, and specific examples include hydrogen peroxide, benzoyl peroxide, acetone peroxide, and butanone peroxide. Hydrogen peroxide is available as an aqueous solution of hydrogen peroxide.

[0052] As used herein, "treatment" refers to an intervention intended to prevent the onset of symptoms, inhibit the development, or modify the pathology. As used herein, "treatment" is used to encompass both therapeutic and prophylactic treatment. As used herein, "treatment" is used to encompass slowing the rate of progression of symptoms, preventing progression, alleviating symptoms, and eliminating symptoms.

[0053] As used herein, a "subject" may be an animal. Examples of animals include vertebrates, such as mammals and birds. Examples of mammals include primates such as humans, rodents such as mice and rats, and domestic mammals such as cows, horses, sheep, donkeys, ewes, goats, llamas, and camels. Examples of birds include chickens.

[0054] As used herein, the term "pharmaceutically acceptable salt" is not particularly limited as long as it is a pharmaceutically acceptable salt, and examples thereof include salts with inorganic bases, organic bases, inorganic acids, organic acids, and amino acids. Examples of salts with inorganic bases include salts with alkali metals such as lithium, sodium, and potassium, salts with alkaline earth metals such as magnesium and calcium, and ammonium salts. Examples of salts with organic bases include salts with alkanolamines such as monoethanolamine, diethanolamine, and triethanolamine, and salts with heterocyclic amines such as morpholine and piperidine. Examples of salts with inorganic acids include salts with hydrohalic acids (hydrochloric acid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitric acid, phosphoric acid, etc. Examples of salts with organic acids include salts with monocarboxylic acids such as formic acid, acetic acid, and propanoic acid; salts with saturated dicarboxylic acids such as oxalic acid, malonic acid, malic acid, and succinic acid; salts with unsaturated dicarboxylic acids such as maleic acid and fumaric acid; salts with tricarboxylic acids such as citric acid; and salts with keto acids such as α-ketoglutaric acid. Examples of salts with amino acids include salts with lysine, arginine, aspartic acid, and glutamic acid. These salts may each be a hydrate (hydrated salt).

[0055] As used herein, the term "pharmaceutically acceptable carrier and / or excipient" includes any adjuvant, carrier, excipient, glidant, sweetener, diluent, preservative, dye, colorant, flavor enhancer, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, etc.

[0056] As used herein, the term "immune checkpoint inhibitor" is not particularly limited as long as it has the effect of suppressing excessive immune responses and suppressing the onset of autoimmune diseases and the like, and examples thereof include anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, and anti-LAG-3 antibodies, and specific examples thereof include nivolumab, bembrolizumab, spartalizumab, cemiplimab, avelumab, atezolizumab, durvalumab, ipilimumab, tremelimumab, leratolimab, etc.

[0057] In one aspect of the present invention, a biocompatible polymer block (poly(C １－３alkylene glycol), polylactic acid, polyglycolic acid, polycaprolactone, polydioxanone, lactic acid / glycolic acid copolymer, polyvinyl alcohol, poly(N-vinylpyrrolidone), poly(2-hydroxyethyl methacrylate), poly(2-C １－３ A micelle is provided which comprises a block copolymer containing a polyamino acid block (glutamic acid and / or aspartic acid) and Bis(acetato-O)(1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum (IV).

[0058] In another aspect of the present invention, there is provided micelles produced by the following steps: (Step 1) producing a block copolymer comprising a biocompatible polymer block and a polyamino acid block from a biocompatible polymer block and a polyamino acid block; (Step 2) producing a micelle comprising the block copolymer comprising the biocompatible polymer block and the polyamino acid block, and (SP4-2)bis(acetato-O)(1,2-cyclohexanediamine-N,N')platinum(II); and (Step 3) oxidizing the micelle with a peroxide.

[0059] In another aspect of the present invention, (Step 1) a biocompatible polymer block (poly(C １－３ alkylene glycol), polylactic acid, polyglycolic acid, polycaprolactone, polydioxanone, lactic acid / glycolic acid copolymer, polyvinyl alcohol, poly(N-vinylpyrrolidone), poly(2-hydroxyethyl methacrylate), poly(2-C １－３(Step 1) producing a block copolymer comprising a biocompatible polymer block and a polyamino acid block from a biocompatible polymer block (a biocompatible polymer block) and a polyamino acid block (glutamic acid and / or aspartic acid); (Step 2) producing a micelle comprising the block copolymer comprising the biocompatible polymer block and the polyamino acid block, and a reduced platinum compound; and (Step 3) oxidizing the micelle with peroxide (hydrogen peroxide, benzoyl peroxide, acetone peroxide, and / or butanone peroxide), and the micelle is combined with an immune checkpoint inhibitor (anti-PD-1 antibody (nivolumab, pembrolizumab, or cemiplimab), anti-PD-L1 antibody (atezolizumab, durvalumab, or avelumab), anti-CTLA-4 antibody (ipilimumab or tremelimumab), and / or anti-LAG-3 antibody (leratolimab)).

[0060] In another embodiment of the present invention, the biocompatible block and the polyamino acid block may be bonded via a linker, such as a methylene group, an ethylene group, a propylene group, an amide group, an ester group, a urethane bond, or a carbonate ester.

[0061] In another aspect of the present invention, the terminals of the block copolymer comprising a biocompatible polymer block and a polyamino acid block may be modified, for example, C １－３ Examples include alkyl groups (for example, methyl, ethyl, n-propyl, and isopropyl groups).

[0062] In another embodiment of the invention, the biocompatible polymer block is polyethylene glycol and the polyamino acid block is a polyaspartic acid block.

[0063] In another aspect of the present invention, a combination pharmaceutical comprising an immune checkpoint inhibitor and a micelle obtained by oxidizing a block copolymer of a biocompatible polymer block and a polyamino acid block and a micelle containing a reduced platinum compound can be further used in combination with a pharmaceutically acceptable reducing agent (ascorbic acid, cysteine, glutathione) or a pharmaceutically acceptable salt thereof. The oxidized platinum compound in the micelle can be reduced by the reducing agent or a pharmaceutically acceptable salt thereof, which destabilizes the micelle and may release the encapsulated reduced platinum compound from the micelle.

[0064] In another aspect of the present invention, a pharmaceutical composition containing micelles obtained by oxidizing a block copolymer of a biocompatible polymer block and a polyamino acid block, and micelles containing (SP4-2)bis(acetato-O)(1,2-cyclohexanediamine-N,N')platinum(II), can be used in combination with a pharmaceutically acceptable reducing agent (ascorbic acid, cysteine, glutathione) or a pharmaceutically acceptable salt thereof. The oxidized platinum compound in the micelles can be reduced by the reducing agent or a pharmaceutically acceptable salt thereof, which destabilizes the micelles and may release the encapsulated platinum compound from the micelles.

[0065] In one embodiment of the present invention, the block copolymer of a biocompatible polymer block and a polyamino acid block is represented by Formula I below:

[0066]

[0067] R in Formula I １ is hydrogen or C １－３ It is an alkyl group, preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group or an isopropyl group, and more preferably a methyl group.

[0068] R in Formula I ２ is a hydrogen atom or C １－３ It is an alkyl group, preferably a hydrogen atom, a methyl group, an ethyl group, an n-propyl group or an isopropyl group, and more preferably a hydrogen atom.

[0069] In formula I, n is an integer of 5 to 20,000, preferably an integer of 5 to 2,000, more preferably an integer of 10 to 500, and even more preferably an integer of 40 to 500.

[0070] In formula I, m is an integer of 2 to 20,000, preferably an integer of 2 to 2,000, more preferably an integer of 5 to 500, and even more preferably an integer of 5 to 200.

[0071] In formula I, p is 1 or 2, preferably 1.

[0072] In one embodiment, the particle size of the micelles containing the oxidized platinum compound is 5 to 200 nm, preferably 10 to 100 nm, and more preferably 10 to 60 nm, as measured by dynamic light scattering (He / Ne laser, 173°C, 25°C). The particle size measured by dynamic light scattering can be measured, for example, with a Zetasizer Nano ZS (Malvern Instruments).

[0073] In one embodiment, the particle size of the micelles is 5 to 200 nm, preferably 10 to 100 nm, and more preferably 10 to 60 nm, as measured by dynamic light scattering (He / Ne laser, 173°C, 25°C). The particle size measured by dynamic light scattering can be measured using a Zetasizer Nano ZS (Malvern Instruments).

[0074] In one embodiment, the ratio of the total number of oxidized platinum compounds and reduced platinum compounds to the number of amino acid residues constituting the polyamino acid block is 10 to 100%, preferably 20 to 90%, more preferably 40 to 80%, and in another embodiment, 50 to 100%, preferably 60 to 100%, even more preferably 70 to 100%.

[0075] In one embodiment, the ratio of the oxidized platinum compound to the reduced platinum compound contained in the micelles containing the oxidized platinum compound is 10:90 to 100:0, preferably 20:80 to 100:0, and more preferably 40:60 to 100:0, and in another embodiment, it is 20:80 to 100:0, preferably 30:70 to 80:20, and more preferably 40:60 to 70:30.

[0076] In one embodiment, the ratio of the total number of Bis(acetato-O)(1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum(IV) and (SP-4-2)bis(acetato-O)(1,2-cyclohexanediamine-N,N')platinum(II) to the total number of amino acid residues constituting the polyamino acid block is 10 to 100%, preferably 20 to 90%, and more preferably 40 to 80%. In another embodiment, it is 50 to 100%, preferably 60 to 100%, and even more preferably 70 to 100%.

[0077] In one embodiment, the ratio of Bis(acetato-O)(1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum(IV) to (SP-4-2)bis(acetato-O)(1,2-cyclohexanediamine-N,N')platinum(II) contained in the micelles is 10:90 to 100:0, preferably 20:50 to 80:0, and more preferably 40:60 to 100:0. In another embodiment, the ratio is 20:80 to 100:0, preferably 30:70 to 80:20, and more preferably 40:60 to 70:30.

[0078] In another embodiment, the surface of the micelle may be further modified, for example, with glucose, folic acid, a peptide, an antibody or an antigen-binding fragment thereof, or the like.

[0079] In one aspect, the present invention provides a pharmaceutical composition comprising the above-described micelles and a pharmaceutically acceptable carrier and / or excipient.

[0080] In another aspect, the present invention provides an agent for treating and / or preventing various cancers, comprising the above-mentioned micelle and a pharmaceutically acceptable carrier and / or excipient.

[0081] In yet another aspect, the present invention provides a pharmaceutical composition for treating and / or preventing various cancers, comprising the above-mentioned micelle and a pharmaceutically acceptable carrier and / or excipient.

[0082] In yet another aspect, the present invention provides a method for treating and / or preventing various cancers, comprising administering an effective amount of the above-described micelles to a subject in need thereof.

[0083] In yet another aspect, the present invention provides the above-described micelles for treating and / or preventing various cancers.

[0084] In yet another aspect, the present invention provides use of the above-mentioned micelles for the manufacture of a medicament for treating and / or preventing various cancers.

[0085] In each of these aspects, the various types of cancer are selected from the group consisting of testicular tumors, bladder cancer, renal pelvis / ureter tumors, prostate cancer, ovarian cancer, head and neck cancer, small cell lung cancer, non-small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, osteosarcoma, germ cell tumors (testicular tumors, ovarian tumors, extragonadal tumors), malignant pleural mesothelioma, biliary tract cancer, malignant bone tumors, brain tumors, salivary gland cancer, thyroid cancer, biliary tract cancer, small intestine cancer, colon cancer, gastrointestinal stromal tumors, kidney cancer, skin cancer, malignant melanoma, sarcoma, uterine sarcoma, endometrial cancer, relapsed / refractory malignant lymphoma, leukemia, multiple myeloma, pediatric malignant solid tumors (rhabdomyosarcoma, neuroblastoma, hepatoblastoma, primary malignant liver tumor, medulloblastic tumor), and cancer of unknown primary origin.

[0086] Next, a pharmaceutical composition containing the above-mentioned micelle as an active ingredient will be described.

[0087] The pharmaceutical composition is a formulation of micelles containing an oxidized platinum compound in the form of a conventional pharmaceutical composition, and is prepared using the above-mentioned micelles and a pharmaceutically acceptable carrier and / or excipient.

[0088] The form of such a pharmaceutical composition can be selected from various forms depending on the purpose of treatment, and examples include injections (liquids, emulsions, suspensions, etc.), oral liquids, suppositories, orally disintegrating tablets, inhalants, etc.

[0089] When prepared as an injection, the solution, emulsion, or suspension is preferably sterilized and isotonic with blood. The injection may contain sufficient salt or other ingredients to prepare an isotonic injection, and may also contain analgesics or other pharmaceuticals. Furthermore, the injection may be prepared immediately upon use, and in such cases, the solution may be diluted to the desired concentration using an injection solution, physiological saline, or glucose injection as a diluent.

[0090] As a carrier used for forming the suppository, a wide variety of known carriers can be used, for example, cacao butter.

[0091] The above-mentioned combination drug comprises a copolymer of a biocompatible polymer block and a polyamino acid block represented by the above formula I, a micelle containing an oxidized platinum compound, and an immune checkpoint inhibitor. Therefore, in a regimen comprising a reduced platinum compound and an immune checkpoint inhibitor, the reduced platinum compound can be replaced with a micelle containing an oxidized platinum compound.

[0092] The above-mentioned combination medicine is useful for the treatment and / or prevention of various cancers, which are the same as those described above.

[0093] The micelles described above are useful for treating and / or preventing various cancers, the various cancers being the same as those described above.

[0094] In another aspect, the present invention provides a method for producing micelles, comprising: (Step 1) producing a block copolymer comprising a biocompatible polymer block and a polyamino acid block from a biocompatible polymer block and a polyamino acid block; (Step 2) producing micelles comprising the block copolymer comprising the biocompatible polymer block and the polyamino acid block, and (SP4-2)bis(acetato-O)(1,2-cyclohexanediamine-N,N')platinum(II); and (Step 3) oxidizing the micelles with a peroxide (hydrogen peroxide, benzoyl peroxide, acetone peroxide, and / or butanone peroxide).

[0095] The dosage of the above-mentioned combination drug may be appropriately selected depending on the method of use, the age and sex of the patient, the severity of the disease, and other conditions. Generally, the dosage is 100mg / kg / day for 1 m of body surface area. ２ For the above-mentioned patient, 1 to 300 mg of the platinum compound and 1 to 2,000 mg of the immune checkpoint inhibitor may be administered once or in several divided doses. The platinum compound and the immune checkpoint inhibitor may be administered simultaneously or consecutively. Furthermore, they may be administered at intervals. The order of administration of the platinum compound and the immune checkpoint inhibitor is not limited, and the intervals may be 10 minutes, 20 minutes, 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 1 week after the completion of administration of the previous drug. The combination drug may be administered daily, or may be administered continuously for 1, 2, 3, 4, 5, 6 days, 7, or 8 days, followed by a break of 1, 2, 3, 4, 5, 6 days, 1 week, 2 weeks, 3 weeks, or 4 weeks, which constitutes one course of administration.

[0096] The dosage of the above-mentioned micelles or pharmaceutical composition may be appropriately selected depending on the method of use, the age and sex of the patient, the severity of the disease, and other conditions. Generally, the dosage is about 100 mg / kg of body surface area per day. ２For the treatment of rheumatoid arthritis, 1 to 300 mg of (SP4-2)bis(acetato-O)(1,2-cyclohexanediamine-N,N')platinum (II) may be administered once or in divided doses. The drug may be administered daily, or may be administered continuously for 1, 2, 3, 4, 5, 6, 7, or 8 days, followed by a drug break for 1, 2, 3, 4, 5, 6 days, 1 week, 2 weeks, 3 weeks, or 4 weeks, which constitutes one course of administration.

[0097] In one aspect, the present invention provides a kit comprising the above-described block copolymer comprising a biocompatible polymer block and a polyamino acid block, a micelle comprising an oxidized platinum compound, and an immune checkpoint inhibitor.

[0098] In one aspect, the above-mentioned kit may further include instructions describing the use of the above-mentioned block copolymer comprising a biocompatible polymer block and a polyamino acid block, a micelle comprising an oxidized platinum compound, and an immune checkpoint inhibitor in combination.

[0099] The disclosures of all patent and non-patent publications cited herein are hereby incorporated by reference in their entirety.

[0100] The present invention will be described in detail with reference to the following examples, but these are not intended to limit the present invention, and may be modified within the scope of the present invention.

[0101] In the present invention, the following abbreviations may be used.

[0102]

[0103] [Production Example 1] (Platinum Micelle (DACHPt(OAc) ２ / m) Preparation of DACHPt(OAc) ２ and PEG-PGlu were mixed in water ([Pt] = [Glu] = 5 mM) and reacted at 37°C for 120 hours. The resulting solution was purified by ultrafiltration (MWCO: 30 kDa) and filtration (0.22 μm PVDF) to obtain the micelles of Preparation Example 1 (DACHPt(OAc) ２ / m) was obtained.

[0104] (Measurement of drug loading amount) DACHPt(OAc) ２ 90% nitric acid was added to the solution, which was then heated to 180°C and evaporated to dryness. The solution was resuspended in 1% nitric acid, and the diluted solution was subjected to ICP-MS to quantify the Pt content. ２ The amount of carboxyl groups in PEG-PGlu was obtained from the frozen weight of PEG-PGlu / m and the Pt content, and the drug loading amount ([Pt] / [Glu]) was calculated. The drug loading amount is shown in Table 2 below.

[0105] (Measurement of Pt(IV) content) DACHPt(OAc) ２ The freeze-dried powder of 1000 sachets was irradiated with soft X-rays using a BL37XU SPring-8 microscope, and X-ray absorption near edge structure (XANES) measurements were performed in the range of 11.60 to 11.53 keV. The Pt(IV) content (%Pt(IV)) was calculated from the ratio of the absorbance at the absorption edge of the obtained spectrum to that at the subsequent continuous band. The Pt(IV) content results are shown in Table 2 below.

[0106] Example 1: Oxidized platinum micelles (O-DACHPt(OAc) ２ / m) DACHPt(OAc) produced in Production Example 1 ２ To the solution, hydrogen peroxide (100 equivalents) was added and the mixture was allowed to react for 24 hours at room temperature under light-shielded conditions. The mixture was purified by dialysis (MWCO: 6-8 kDa), ultrafiltration (MWCO: 30 kDa), and filtration (0.22 μm PVDF) to obtain the micelles (O-DACHPt(OAc)) of Example 1. ２ / m) was obtained.

[0107] (Measurement of drug loading amount) O-DACHPt(OAc) ２ The drug loading amount per 1000 mg / m was calculated in the same manner as in Production Example 1. The drug loading amounts are shown in Table 2 below.

[0108] (Measurement of Pt(IV) content) O-DACHPt(OAc) ２ The Pt(IV) content at 1000 nm / m was measured in the same manner as in Production Example 1. The measurement results of the Pt(IV) content are shown in Table 2 below.

[0109]

[0110] [Experimental Example 1] (Study of biodistribution) BALB / c mice (6 weeks old, female) were inoculated with mouse colon cancer cells (Colon-26) at 1 × 10 ６ The mice were then subcutaneously implanted into the mice. Five days later, the micelles of Example 1 and the micelles of Preparation Example 1 were each administered at a dose of 5 mg / kg via the tail vein (n=5). 24, 48, 72, and 96 hours later, blood, tumor, liver, spleen, kidney, lung, and lymph node samples were collected and weighed. Blood was centrifuged to obtain plasma. 90% nitric acid was added to each of the collected organs, which were then evaporated to dryness. After redissolution in 1% nitric acid, the amount of platinum complex was quantified using ICP-MS (7700x ICP-MS, Agilent).

[0111] 1 is a graph showing the results of measuring the amount of platinum complex in each organ. Compared with the liver, spleen, kidney, and lung, it was shown that both the micelles of Example 1 and Preparation Example 1 accumulated in tumor tissue. It was also shown that the micelles of Preparation Example 1 accumulated in bone marrow, but the micelles of Example 1 did not.

[0112] Experimental Example 2 (Toxicity Test) The micelles of Example 1, the micelles of Production Example 1, oxaliplatin as a positive control, or phosphate-buffered saline (PBS) as a negative control were administered to BALB / c mice (6 weeks old, female) via the tail vein (n=6). After 7 days, blood was collected from the inferior vena cava, and the liver, spleen, kidney, and thymus were recovered. The numbers of red blood cells, white blood cells, platelets, lymphocytes, and non-lymphocytes (monocytes and granulocytes) in the blood were measured using a multi-parameter automated hematology analyzer (pocH-100iV Diff, Sysmex).

[0113] 2 is a graph showing the results of counting the number of each blood component. When oxaliplatin and the micelles of Preparation Example 1 were administered, a decrease in white blood cells and platelets was observed. On the other hand, when the micelles of Example 1 were administered, no effect on either white blood cells or platelets was observed.

[0114] [Experimental Example 3] (Study of Antitumor Effect 1) BALB / c mice (6-week-old, female) and BALB / c nu / nu mice (6-week-old, female) were inoculated with mouse colon cancer cells (Colon-26) at 1 × 10 ５After 5 days, the micelles of Example 1, the micelles of Production Example 1, oxaliplatin, or PBS was administered via the tail vein (n=8). The major axis (a) and minor axis (b) of the tumor were measured over time, and the tumor volume (V=ab ２ The tumor size (g / 2) was calculated. At the same time, the weight of each mouse was measured. Mice with an average tumor diameter of more than 15 mm were euthanized.

[0115] 3 is a graph showing the results of measuring the change in tumor volume over time, which shows that administration of the micelles of Example 1 inhibited tumor growth.

[0116] [Experimental Example 4] (Study of Antitumor Effect 2) The antitumor effect of a combination of micelles and an immune checkpoint inhibitor was studied. BALB / c mice (6 weeks old, female) were inoculated with mouse colon cancer cells (Colon-26) at a concentration of 1 × 10 ５ After 5 days, the micelles (O-DACHPt(OAc) ２ Anti-PD-1 antibody (Bio X Cell, BE0273, 5 mg / kg), anti-PD-L1 antibody (Bio X Cell, BE0101, 5 mg / kg), or anti-CTLA-4 antibody (Bio X Cell, BE0164, 5 mg / kg) was administered intraperitoneally via the tail vein (n=8). The long diameter (a) and short diameter (b) of the tumor were measured over time, and tumor volume (V = ab ２ The mean tumor diameter (mm) was calculated. Animals with an average tumor diameter of more than 15 mm were euthanized.

[0117] Figure 4 is a graph showing the results of measuring the change in tumor volume over time. ２ / m), regardless of the combination of any immune checkpoint inhibitor, the change in tumor volume was significantly small. ２ / m) in combination with two immune checkpoint inhibitors, anti-PD-L1 antibody and anti-CTLA-4 antibody, showed almost no change in tumor volume.

[0118] Figure 5 is a graph showing the change in the survival rate of mice over time. It was shown that the survival rate was significantly extended in the group administered with the micelles of Example 1, regardless of the combination with any immune checkpoint inhibitor. In particular, the micelles of Example 1 (O-DACHPt(OAc) ２ In the group that received a combination of IFN-γ / m and two immune checkpoint inhibitors, anti-PD-L1 antibody and anti-CTLA-4 antibody, approximately 90% of the mice were still alive at the end of the observation period.

[0119] A micelle containing a block copolymer containing a biocompatible polymer block and a polyamino acid block, which has controlled platinum release, and Bis(acetato-O)(1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum(IV) is useful for the treatment and / or prevention of cancer. Furthermore, the combined use of a block copolymer containing a biocompatible polymer block and a polyamino acid block, a micelle containing an oxidized platinum compound, and an immune checkpoint inhibitor is useful for the treatment and / or prevention of cancer.

Claims

1. A combination drug comprising a block copolymer containing a biocompatible polymer block and a polyamino acid block, a micelle containing an oxidized platinum compound, and one or more immune checkpoint inhibitors.

2. The biocompatible polymer is poly(C １－３ alkylene glycol), polylactic acid, polyglycolic acid, polycaprolactone, polydioxanone, lactic acid / glycolic acid copolymer, polyvinyl alcohol, poly(N-vinylpyrrolidone), poly(2-hydroxyethyl methacrylate), polyoxazoline, poly(2-C １－３ 2. The pharmaceutical combination of claim 1, wherein the compound is selected from the group consisting of benzodiazepines (benzodiazepines), ... and benzodiazepines (benzodiazepines).

3. The biocompatible polymer is poly(C １－３ 2. The pharmaceutical combination according to claim 1, wherein the hydroxybenzoate is an alkylene glycol.

4. The poly(C １－３ The pharmaceutical combination according to claim 3, wherein the alkylene glycol is poly(ethylene glycol).

5. The combination drug according to any one of claims 1 to 4, wherein the amino acids constituting the polyamino acid block are acidic amino acids.

6. The combination drug according to claim 5, wherein the acidic amino acid is glutamic acid and / or aspartic acid.

7. The combination pharmaceutical of claim 5, wherein the acidic amino acid is glutamic acid.

8. The combination pharmaceutical of claim 5, wherein the acidic amino acid is aspartic acid.

9. The combination pharmaceutical according to any one of claims 1 to 4, wherein the block copolymer comprising a biocompatible polymer block and a polyamino acid block is a compound represented by the following formula I: [In formula I, R １ is C １－３ is an alkyl group, and R ２ is a hydrogen atom, n is an integer of 5 to 20,000, m is an integer of 2 to 20,000, and p is 1 or 2.

10. The pharmaceutical combination according to any one of claims 1 to 4, wherein the oxidized platinum compound is selected from the group consisting of oxides of nedaplatin, cisplatin, carboplatin, dahaplatin, oxaliplatin, their prodrugs, and pharmaceutically acceptable salts thereof.

11. The combination pharmaceutical according to any one of claims 1 to 4, wherein the oxidized platinum compound is Bis(acetato-O)(1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum (IV).

12. The combination pharmaceutical according to any one of claims 1 to 4, wherein the immune checkpoint inhibitor is one or more antibodies selected from the group consisting of anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-CTLA-4 antibodies, and anti-LAG-3 antibodies.

13. The combination drug of claim 12, wherein the anti-PD-1 antibody is nivolumab, pembrolizumab, or cemiplimab.

14. The combination drug of claim 12, wherein the anti-PD-L1 antibody is atezolizumab, durvalumab, or avelumab.

15. The combination pharmaceutical of claim 12, wherein the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

16. The pharmaceutical combination of claim 12, wherein the anti-LAG-3 antibody is leratolimab.

17. The combination drug according to any one of claims 1 to 4, wherein the immune checkpoint inhibitor is a combination of an anti-PD-L1 antibody and an anti-CTLA-4 antibody.

18. A micelle comprising a block copolymer comprising a biocompatible polymer block and a polyamino acid block, and Bis(acetato-O)(1,2-cyclohexanediamine-N,N')(dihydroxydo)platinum(IV).

19. The biocompatible polymer is poly(C １－３ alkylene glycol), polylactic acid, polyglycolic acid, polycaprolactone, polydioxanone, lactic acid / glycolic acid copolymer, polyvinyl alcohol, poly(N-vinylpyrrolidone), poly(2-hydroxyethyl methacrylate), polyoxazoline, poly(2-C １－３ 19. The micelle of claim 18, wherein the micelle is selected from the group consisting of alkyl-oxazolines.

20. The micelle of claim 18, wherein the biocompatible polymer is poly(ethylene glycol).

21. A micelle according to any one of claims 18 to 20, wherein the amino acids constituting the polyamino acid block are glutamic acid and / or aspartic acid.

22. A micelle according to any one of claims 18 to 20, wherein the amino acid constituting the polyamino acid block is glutamic acid.

23. A micelle according to any one of claims 18 to 20, wherein the amino acid constituting the polyamino acid block is aspartic acid.

24. A combination pharmaceutical composition according to any one of claims 1 to 4 for use in the treatment and / or prevention of cancer.

25. The combination pharmaceutical of claim 24, wherein the cancer is selected from the group consisting of testicular tumor, bladder cancer, renal pelvis / ureter tumor, prostate cancer, ovarian cancer, head and neck cancer, small cell lung cancer, non-small cell lung cancer, esophageal cancer, cervical cancer, neuroblastoma, gastric cancer, osteosarcoma, germ cell tumor, malignant pleural mesothelioma, biliary tract cancer, malignant bone tumor, brain tumor, salivary gland cancer, thyroid cancer, biliary tract cancer, small intestine cancer, colon cancer, gastrointestinal stromal tumor, kidney cancer, skin cancer, malignant melanoma, sarcoma, uterine sarcoma, endometrial cancer, relapsed / refractory malignant lymphoma, leukemia, multiple myeloma, pediatric malignant solid tumor, and cancer of unknown primary.

Images