Prophylactic and therapeutic agent for diseases caused by type i allergic reaction accompanying administration of anticancer agent

Abstract

The present invention addresses the problem of providing a prophylactic and therapeutic agent for diseases caused by a type I allergic reaction accompanying administration of a platinum preparation and / or a taxane-based anticancer agent.　The present invention relates to a pharmaceutical composition for treating or preventing diseases caused by a type I allergic reaction accompanying administration of a platinum preparation and / or a taxane-based anticancer agent, the pharmaceutical composition containing a lecithinized superoxide dismutase.

Description

Preventive and therapeutic agents for diseases caused by type I allergic reactions associated with the administration of anticancer drugs

[0001] The present invention relates to a preventive and therapeutic agent for diseases caused by type I allergic reactions associated with the administration of anticancer drugs.

[0002] The development of numerous anticancer drugs has dramatically improved the effectiveness of cancer drug therapy. However, the side effects of anticancer drugs have also become clearer. In particular, the incidence of type I allergic reactions associated with the administration of platinum-based and taxane-based anticancer drugs, such as cisplatin, carboplatin, and oxaliplatin, is seen in 10-20% of patients. Symptoms include fever, nausea, chills, headache, rash, itching, swelling, tachycardia, hives, flushing, throat tightness, coughing, and difficulty breathing. In severe cases, anaphylaxis can occur, accompanied by wheezing, loss of consciousness, low blood pressure, and respiratory problems.

[0003] If Type I allergic symptoms are observed following administration of platinum and / or taxane anticancer drugs, platinum and / or taxane anticancer drugs are generally not administered thereafter. Therefore, the occurrence of these side effects makes it impossible to continue effective treatment, resulting in the failure to achieve the therapeutic effects of these anticancer drugs. When premedication is intensified, it is common to add d-chlorpheniramine maleate injection 5 mg and famotidine 20 mg or ranitidine 50 mg, increase the dose of dexamethasone, and slow the administration rate of the target drugs (e.g., take more than twice the time).

[0004] JP 2006-169128 A JP 2008-75706 A JP 2010-215527 A JP 2017-73255 A JP 2001-151695 A WO 2022 / 244757 JP 2001-64199 A JP 6-199895 A WO 2006 / 040980

[0005] As described above, if type I allergic symptoms are observed due to the administration of platinum preparations and / or taxane anticancer drugs, these drugs are generally not administered thereafter, and effective treatment often cannot be continued, so the development of a drug that can suppress or prevent these side effects is desired. Therefore, an object of the present invention is to provide an agent for the prevention and treatment of diseases caused by type I allergic reactions associated with the administration of platinum preparations and / or taxane anticancer drugs.

[0006] Therefore, the present inventors have focused on lecithinized superoxide dismutase (PC-SOD) and investigated its pharmacological actions from various viewpoints. As a result, they have found that PC-SOD strongly suppresses the onset of diseases caused by type I allergic reactions associated with the administration of platinum preparations and / or taxane anticancer drugs, and is highly safe, and have thus completed the present invention.

[0007] That is, the present invention provides the following inventions [1] to

[12] . [1] A pharmaceutical composition containing lecithinized superoxide dismutase for treating or preventing a disease caused by a type I allergic reaction associated with the administration of a platinum preparation and / or a taxane anticancer drug. [2] The pharmaceutical composition of [1], wherein the platinum preparation and / or taxane anticancer drug is one or more selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, docetaxel, and paclitaxel. [3] The pharmaceutical composition of [1] or [2], wherein the disease caused by a type I allergic reaction is one or more selected from fever, nausea, chills, headache, rash, skin eruption, itching, swelling, tachycardia, hives, flushing, throat tightness, coughing, dyspnea, wheezing, loss of consciousness, decreased blood pressure, and anaphylaxis accompanied by respiratory failure. [4] The pharmaceutical composition according to any one of [1] to [3], which is administered in combination with a platinum preparation and / or a taxane anticancer drug. [5] The pharmaceutical composition according to any one of [1] to [4], which is administered before the administration of a platinum preparation and / or a taxane anticancer drug. [6] The pharmaceutical composition according to any one of [1] to [5], wherein the lecithinized superoxide dismutase is lyophilized. [7] The lecithinized superoxide dismutase is a human-derived superoxide dismutase subunit coordinated with copper and / or zinc, in which the mercapto group of cysteine ​​at position 111 is hydroxyethylthioated, and one or more amino groups of the subunit are represented by the following general formula (I):

[0008]

[0009] [wherein R is an alkyl group having 8 to 30 carbon atoms, and n is an integer of 2 to 10], and the lecithinized superoxide dismutase is modified directly or via a linker with a lecithin residue represented by the formula: [wherein R is an alkyl group having 8 to 30 carbon atoms, and n is an integer of 2 to 10], and the lecithinized superoxide dismutase independently has m amino groups in each of the superoxide dismutase molecular subunits [wherein m is an integer of 1 to 4, and the average value of m in the lecithinized superoxide dismutase subunits is 1.5 to 2.4]. [1] to [6]. The pharmaceutical composition according to any one of [1] to [6], comprising a lecithinized superoxide dismutase (A) as a main component, the lecithinized superoxide dismutase subunits being substituted with the lecithin residue, wherein the lecithinized superoxide dismutase subunits constituting the lecithinized superoxide dismutase (A) are 25 to 40 mol % of lecithinized superoxide dismutase subunit (a1) where m = 1, 35 to 50 mol % of lecithinized superoxide dismutase subunit (a2) where m = 2, 10 to 20 mol % of lecithinized superoxide dismutase subunit (a3) ​​where m = 3, and 5 to 15 mol % of lecithinized superoxide dismutase subunit (a4) where m = 4.[8] The pharmaceutical composition according to any one of [1] to [7], wherein the lecithinized superoxide dismutase has PC bound to SOD at the following binding ratios: (1) the binding ratio of PC at the binding site K3, the N-terminus, and T2 is 1 to 10% in total of the amino acid residues; (2) the binding ratio of PC at the binding site K9 is 10 to 30%; (3) the binding ratio of PC at the binding site K23 is 50 to 75%; (4) the binding ratio of PC at the binding site K36 is 30 to 55%; (5) the binding ratio of PC at the binding site K70 or K75 is 10 to 80% in total of the amino acid residues; (6) the binding ratio of PC at the binding site K122 or K128 is 10 to 45% in total of the amino acid residues; (7) The proportion of PC bound at the binding site K136 is 10 to 60%; and the average number of PCs bound to PC-SOD as a sum of (1) to (7) is 1 to 8. [9] The pharmaceutical composition according to any one of [1] to [8], wherein the superoxide dismutase of the lecithinized superoxide dismutase has the amino acid sequence set forth in SEQ ID NO: 1.

[10] Use of lecithinized superoxide dismutase for the manufacture of a pharmaceutical composition for treating or preventing diseases caused by type I allergic reactions associated with the administration of platinum preparations and / or taxane anticancer drugs.

[11] Lecithinized superoxide dismutase for treating or preventing diseases caused by type I allergic reactions associated with the administration of platinum preparations and / or taxane anticancer drugs.

[12] A method for treating or preventing diseases caused by type I allergic reactions associated with the administration of platinum preparations and / or taxane anticancer drugs, comprising administering lecithinized superoxide dismutase.

[0010] PC-SOD used in the present invention is useful for suppressing and preventing one or more diseases selected from the group consisting of fever, nausea, chills, headache, rash, skin eruption, itching, swelling, tachycardia, hives, flushing, throat tightness, cough, dyspnea, wheezing, loss of consciousness, decreased blood pressure, and anaphylaxis accompanied by respiratory disorders, caused by type I allergic reactions associated with the administration of platinum preparations and / or taxane anticancer drugs, and is also highly safe.

[0011]

[0026] Figure 1 shows that the combined use of mFOLFOX6 therapy with PC-SOD suppressed the onset of oxaliplatin allergy compared to placebo (p=0.0274).

[0027] Figure 2 shows changes in IgE antibody levels following oxaliplatin administration.

[0028] Figure 3 shows that PC-SOD has an inhibitory effect on the increase in IgE levels caused by BSA-OXA, while SOD does not.

[0012] One aspect of the present invention is a pharmaceutical composition for treating or preventing a disease caused by a type I allergic reaction associated with the administration of a platinum-based drug and / or a taxane-based anticancer drug, the composition containing lecithinized superoxide dismutase. The active ingredient of the pharmaceutical composition of the present invention is lecithinized superoxide dismutase (PC-SOD).

[0013] As used herein, the terms "lecithinized superoxide dismutase" and "PC-SOD" are synonymous and can be used interchangeably. As used herein, the terms "superoxide dismutase" and "SOD" are synonymous and can be used interchangeably. As used herein, the terms "phosphatidylcholine," "PC," and "lecithin" are synonymous and can be used interchangeably, and can refer to both an aggregate and an individual molecule. As used herein, the term "PC-SOD" refers to an aggregate of PC-SOD molecules. Here, the number and binding sites of PCs bound to individual PC-SOD molecules constituting "PC-SOD" may be the same or different among PC-SOD molecules. Therefore, the number of PCs bound to "PC-SOD" can be expressed as the average binding number. Furthermore, in "PC-SOD," PC binding sites can be identified by amino acid residues in SOD, and the binding ratio of PC can be expressed as the ratio of PCs bound to amino acid residues in SOD. As used herein, the term "PC-SOD subunit" refers to an aggregate of PC-SOD molecular subunits. As used herein, the term "SOD" refers to an aggregate of SOD molecules. As used herein, the term "SOD subunit" refers to an aggregate of SOD molecular subunits.

[0014] As used herein, the term "PC-SOD molecule" refers to a molecule formed by dimerization of PC-SOD molecular subunits, and the term "PC-SOD molecular subunit" refers to a monomer of the dimer that constitutes the PC-SOD molecule. Here, the number of PCs that bind to the PC-SOD molecular subunits that constitute each PC-SOD molecule dimer and the binding sites thereon may be the same or different between the PC-SOD molecular subunits that constitute the dimer. As used herein, the term "SOD molecule" refers to a molecule formed by dimerization of SOD molecular subunits, and the term "SOD molecular subunit" refers to a monomer of the dimer that constitutes the SOD molecule.

[0015] PC-SOD is a substance obtained by modifying SOD with lecithin, and the present applicant has previously reported that it is effective against burns (Patent Document 1), interstitial pneumonia (Patent Document 2), chronic obstructive pulmonary disease syndrome (Patent Document 3), acute respiratory distress syndrome (Patent Document 4), type III allergy (Patent Document 5), and neuropathy associated with the administration of anticancer drugs (Patent Document 6). However, its effect on diseases caused by type I allergic reactions associated with the administration of platinum preparations and / or taxane anticancer drugs is completely unknown.

[0016] PC-SOD is a substance in which SOD is modified with lecithin, and is preferably a substance in which one or more amino acid residues of SOD, preferably amino acid residues containing an amino group or an N-terminal amino acid residue, more preferably a lysine residue, are modified with phosphatidylcholine (PC) directly or via a linker.

[0017] The SOD in PC-SOD is preferably human SOD (SEQ ID NO: 1), and particularly preferably human SOD containing copper and zinc in the active center (human Cu / ZnSOD). This SOD may be any of natural human Cu / ZnSOD produced from human tissue, human Cu / ZnSOD produced by genetic engineering techniques, recombinant human Cu / ZnSOD having substantially the same amino acid sequence as natural human Cu / ZnSOD, or SODs in which some amino acids in the amino acid sequence of these human Cu / ZnSODs have been chemically modified or altered. Preferably, the SOD in PC-SOD is human SOD1, more preferably human SOD1 in which the sulfhydryl group of cysteine ​​at position 111 is protected, and even more preferably human SOD1 in which the sulfhydryl group of cysteine ​​at position 111 is hydroxyethylthiolated.

[0018] In PC-SOD, PC is bound directly or via a linker to one or more free amino or hydroxy groups (preferably amino groups) of the amino acid residues constituting SOD. The amino acid residues to which PC is bound include N-terminal Ala, Lys, Gln, Asn, Arg, Ser, Thr, and Tyr of the SOD molecule, preferably N-terminal Ala, Lys, and Thr, more preferably N-terminal Ala and Lys, and even more preferably Lys.

[0019] Preferably, 1 to 12 PCs are independently bound to each SOD molecular subunit, more preferably 1 to 8, even more preferably 1 to 4, even more preferably 2 to 3, and even more preferably 2. Therefore, preferably, 2 to 24 PCs are bound to a PC-SOD molecule, more preferably 2 to 16, even more preferably 2 to 8, even more preferably 4 to 6, and even more preferably 4. In the case of PC-SOD, the number of bound PCs can be expressed as the average number of PCs bound to SOD as a whole. Therefore, in PC-SOD, the average number of PCs bound to SOD is 2 to 24, preferably 2 to 16, more preferably 2 to 8, even more preferably 4 to 6, and most preferably 4.

[0020] PC may be directly bound to the amino acid residues constituting SOD, but is preferably bound via a linker. Dicarboxylic acids are preferred as linkers, with -C(=O)(CH2)nC(=O)- being particularly preferred (where n is an integer of 2 or greater, preferably 2 to 10, more preferably 2 to 6, even more preferably 2 to 4, and particularly preferably 3). This linker connects the hydroxy group of the glyceryl group of PC with the amino group or hydroxy group (preferably the amino group) of the amino acid residue.

[0021] The number of carbon atoms in the fatty acid residue of PC is preferably 8 to 31, more preferably 10 to 28, even more preferably 14 to 22, and particularly preferably 16 (derived from palmitic acid).

[0022] PC-SOD can be produced by the methods described in, for example, Patent Documents 7, 8 and 9, preferably the method described in Patent Document 9.

[0023] A particularly preferred example of PC-SOD is a PC-SOD in which one or more amino groups of a human superoxide dismutase subunit in which the mercapto group of cysteine ​​at position 111 is hydroxyethylthiolated is represented by the following general formula (I):

[0024]

[0025] [wherein R is an alkyl group having 8 to 30 carbon atoms, and n is an integer of 2 to 10], and the lecithinized superoxide dismutase is modified directly or via a linker with a lecithin residue represented by the formula: [wherein R is an alkyl group having 8 to 30 carbon atoms, and n is an integer of 2 to 10], and the lecithinized superoxide dismutase independently has m amino groups in each of the superoxide dismutase molecular subunits [wherein m is an integer of 1 to 4, and the average value of m in the lecithinized superoxide dismutase subunits is 1.5 to 2.4]. the lecithinized superoxide dismutase (A) comprises, as a main component, a lecithinized superoxide dismutase subunit in which m=1, m=2, m=3, m=4, and m=5, m=5, m=6, m=7, m=8, m=9, m=10, m=11, m=12, m=13, m=14, m=15, m=16, m=17, m=18, m=19, m=20, m=21, m=22, m=23, m=24, m=25, m=26, m=27, m=28, m=29, m=30, m=29, m=31, m=22, m=23, m=24, m=25, m=26, m=32, m=27, m=28, m=29, m=33, m=29, m=25, m=26, m=29, m=34, m=29, m=25, m=26, m=29, m=35, m=29, m=26, m=29, m=32 ...9, m=32, m=29, m=25, m=29, m=32, m=29, m=25, m=29, m=32, m=29, m=25, m=29, m=32, m=29, m=25, m=29, m=32, m=29, m=25, m=29, m=32, m=29, m=

[0026] In the PC-SOD of the present invention, the binding site of PC that binds to SOD and its binding rate are preferably as follows. The number following each single-letter amino acid represents the number of residues from the N-terminus in the SOD molecule. (1) When the binding site is K3, the N-terminus, or T2, the binding rate of PC is preferably 1 to 10%, more preferably 2 to 8%, and even more preferably 5%, of the total of the amino acid residues. (2) When the binding site is K9, the binding rate of PC is preferably 10 to 30%, more preferably 15 to 26%, and even more preferably 23%. (3) When the binding site is K23, the binding rate of PC is preferably 50 to 75%, more preferably 55 to 70%, and even more preferably 63%. (4) When the binding site is K36, the binding rate of PC is preferably 30 to 55%, more preferably 35 to 50%, and even more preferably 43%. (5) When the binding site is K70 or K75, the binding ratio of PC is preferably 10 to 80%, more preferably 30 to 65%, and even more preferably 53%, based on the total of the amino acid residues. (6) When the binding site is K122 or K128, the binding ratio of PC is preferably 10 to 45%, more preferably 20 to 35%, and even more preferably 27%, based on the total of the amino acid residues. (7) When the binding site is K136, the binding ratio of PC is preferably 10 to 60%, more preferably 20 to 45%, and even more preferably 33%. Preferably, as a sum of the above (1) to (7), the average number of PCs bound to PC-SOD is 1 to 8, preferably 2 to 6, more preferably 3 to 5, and most preferably 4.

[0027] As described in the Examples below, the PC-SOD has the effect of treating or preventing diseases caused by type I allergic reactions associated with the administration of platinum preparations and / or taxane anticancer drugs. Furthermore, the present inventors conducted studies to elucidate the mechanism of action of the administration of PC-SOD for treating or preventing diseases caused by type I allergic reactions associated with the administration of platinum preparations and / or taxane anticancer drugs, and found that (1) it suppresses the increase in IgE antibodies associated with the administration of platinum preparations and / or taxane anticancer drugs, and (2) it also suppresses allergic reactions such as increased vascular permeability associated with the administration of platinum preparations and / or taxane anticancer drugs. It was also confirmed that SOD does not suppress the increase in IgE antibodies associated with the administration of platinum preparations and / or taxane anticancer drugs.

[0028] Diseases caused by type I allergic reactions associated with the administration of platinum preparations and / or taxane anticancer drugs include one or more diseases selected from fever, nausea, chills, headache, rash, skin eruption, itching, swelling, tachycardia, hives, flushing, throat tightness, cough, dyspnea, wheezing, loss of consciousness, decreased blood pressure, and anaphylaxis accompanied by respiratory disorders. Platinum preparations include one or more selected from cisplatin, carboplatin, oxaliplatin, and nedaplatin. Taxane anticancer drugs include docetaxel and paclitaxel.

[0029] The pharmaceutical composition of the present invention is preferably administered in cancer chemotherapy using a platinum preparation and / or a taxane-based anticancer drug, such as FOLFOX therapy, XELOX therapy (CapeOX therapy), or TC therapy. FOLFOX is a cancer chemotherapy using folinic acid, fluorouracil, and oxaliplatin in combination. There are variations of FOLFOX, including FOLFOX1 to FOLFOX7 and mFOLFOX6, depending on the dosage of each drug. However, FOLFOX4, FOLFOX6, or mFOLFOX6 is preferred, with mFOLFOX6 being particularly preferred in Japan. XELOX therapy (CapeOX therapy) is a cancer chemotherapy using Xeloda and oxaliplatin (capecitabine and oxaliplatin) in combination. TC therapy is a cancer chemotherapy using paclitaxel and carboplatin in combination.

[0030] The pharmaceutical composition of the present invention can be used to treat cancers for which platinum preparations and / or taxane anticancer agents are applicable, such as ovarian cancer, non-small cell lung cancer, breast cancer, uterine cancer, head and neck cancer, esophageal cancer, leukemia, malignant lymphoma, pediatric tumors, multiple myeloma, malignant astrocytoma, glioma, trophoblastic disease, germ cell tumor, lung cancer, testicular tumor, bladder cancer, renal pelvis tumor, urethral tumor, prostate cancer, cervical cancer, neuroblastoma, small cell lung cancer, osteosarcoma, malignant pleural mesothelioma, malignant bone tumor, kidney cancer, penile cancer, various bone and soft tissue tumors, liver cancer, thyroid cancer, retroperitoneal tumor, bone metastasis, testicular cancer, gallbladder cancer, biliary tract cancer, bile duct cancer, adrenal cancer, hepatoblastoma, hepatoma, and ovarian cancer. It is preferably administered to cancer patients suffering from one or more cancers selected from the group consisting of primary malignant tumors, medulloblastoma, gastric cancer, pancreatic cancer, urothelial carcinoma, extragonadal tumors, Langerhans cell histiocytosis, mantle cell lymphoma, lymphoplasmacytic lymphoma, small intestine cancer, colon cancer, rectal cancer, and large intestine cancer, more preferably administered to cancer patients suffering from one or more cancers selected from the group consisting of gastric cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, and large intestine cancer, and even more preferably administered to cancer patients suffering from one or more cancers selected from the group consisting of colon cancer, rectal cancer, and large intestine cancer.

[0031] In addition, in the present invention, platinum preparations and / or taxane anticancer agents can also be administered to patients who have undergone cancer resection as postoperative adjuvant chemotherapy or to prevent recurrence. That is, platinum preparations and / or taxane anticancer drugs are effective against ovarian cancer, non-small cell lung cancer, breast cancer, uterine cancer, head and neck cancer, esophageal cancer, leukemia, malignant lymphoma, pediatric tumors, multiple myeloma, malignant astrocytoma, glioma, trophoblastic disease, germ cell tumor, lung cancer, testicular tumor, bladder cancer, renal pelvis tumor, urethral tumor, prostate cancer, cervical cancer, neuroblastoma, small cell lung cancer, osteosarcoma, malignant pleural mesothelioma, malignant bone tumor, kidney cancer, penile cancer, various bone and soft tissue tumors, liver cancer, thyroid cancer, retroperitoneal tumor, bone metastasis, testicular cancer, gallbladder cancer, biliary tract cancer, bile duct cancer, adrenal cancer, bladder cancer, gallbladder cancer, hepatoblastoma, hepatoblastoma, primary malignant liver tumor, medulloblastoma, gastric cancer, pancreatic cancer, urothelial cancer, sex It is preferably administered to patients who have a medical history of one or more cancers selected from the group consisting of extraglandular tumor, Langerhans cell histiocytosis, mantle cell lymphoma, lymphoplasmacytic lymphoma, small intestine cancer, colon cancer, rectal cancer, and large intestine cancer and have undergone resection of said cancer, more preferably to patients who have a medical history of one or more cancers selected from the group consisting of gastric cancer, pancreatic cancer, small intestine cancer, colon cancer, rectal cancer, and large intestine cancer and have undergone resection of said cancer, and even more preferably to patients who have a medical history of one or more cancers selected from the group consisting of colon cancer, rectal cancer, and large intestine cancer and have undergone resection of said cancer.

[0032] The pharmaceutical composition of the present invention may contain PC-SOD, but it is preferable to incorporate a pharmaceutically acceptable carrier into various dosage forms. The preferred dosage form for such a pharmaceutical composition is injection, preferably intravenous or local injection, or infusion. When preparing an injection, water, a solubilizer, an aqueous xylitol solution (preferably 5 wt%, 10 wt%, or 20 wt%, more preferably 5 wt%), an aqueous glucose solution (preferably 5 wt%, 10 wt%, or 20 wt%, more preferably 5 wt%), or the like is used. Preferred injections include intravenous, local, subcutaneous, and intramuscular injections. More preferred are intravenous or local injections or infusions. The pharmaceutical composition of the present invention may be formulated in the form of a lyophilized formulation or a powder filler, with lyophilized formulations being preferred. To prepare a lyophilized formulation, it is preferable to incorporate a stabilizer such as sucrose. A formulation can be prepared by lyophilizing an aqueous solution containing PC-SOD and sucrose using a method known in the art. The weight ratio of PC-SOD:sucrose is preferably 1:1 to 1:5, more preferably 1:1 to 1:2. When the amount of PC-SOD is 40 mg, the amount of sucrose is preferably 40 mg to 200 mg, more preferably 40 mg to 80 mg, and even more preferably 67 mg.

[0033] The content of PC-SOD in the pharmaceutical composition of the present invention is not particularly limited, but is usually 1 to 100% by mass, preferably 10 to 80% by mass, and more preferably 25 to 50% by mass, based on the total amount of the composition.

[0034] The dosage of the pharmaceutical composition of the present invention varies depending on the symptoms and age of the patient receiving the anticancer agent. For adults, the dosage is preferably 20 to 160 mg, more preferably 20 to 80 mg, and even more preferably 40 to 80 mg of PC-SOD per day. This dosage can also be administered 1 to 4 times per week, 1 to 4 times per 2 weeks, or 1 to 4 times per 3 weeks, with each administration cycle being repeated 1 to 20 times. Preferably, the pharmaceutical composition of the present invention can be administered according to the administration regimen of FOLFOX therapy or TC therapy. Preferably, when using FOLFOX therapy, the pharmaceutical composition of the present invention is administered once every 2 weeks for 12 cycles. Preferably, when using TC therapy, the pharmaceutical composition of the present invention is administered once every 3 weeks for 8 cycles. When using TC therapy, the pharmaceutical composition of the present invention is administered once every 3 weeks for 6 cycles.

[0035] The pharmaceutical composition of the present invention is preferably administered in combination with a platinum preparation and / or a taxane anticancer drug, preferably before or after administration of the platinum preparation and / or taxane anticancer drug, and more preferably before administration of the platinum preparation and / or taxane anticancer drug. More specifically, it is preferably administered within 3 hours, more preferably within 2 hours, and even more preferably within 1 hour before administration of the platinum preparation and / or taxane anticancer drug. In this case, the pharmaceutical composition of the present invention is preferably administered intravenously, more preferably by intravenous drip infusion.

[0036] Another preferred aspect of the present invention is use of PC-SOD for the manufacture of a pharmaceutical composition for treating or preventing a disease caused by a type I allergic reaction associated with the administration of a platinum preparation and / or a taxane anticancer drug. Another preferred aspect of the present invention is PC-SOD for treating or preventing a disease caused by a type I allergic reaction associated with the administration of a platinum preparation and / or a taxane anticancer drug. Another preferred aspect of the present invention is a method for treating or preventing a disease caused by a type I allergic reaction associated with the administration of a platinum preparation and / or a taxane anticancer drug, which method comprises administering PC-SOD. Preferred embodiments of the pharmaceutical composition and PC-SOD in these other aspects of the present invention are the same as those for the pharmaceutical composition of the present invention described above.

[0037] The present invention will now be described in more detail with reference to the following examples, but the present invention is not limited to these examples. PC-SOD used in these examples was produced according to the method described in Patent Document 9.

[0038] Example 1 [Method] A phase II placebo-controlled double-blind comparative study of PC-SOD was conducted in colorectal cancer patients undergoing mFOLFOX6 therapy as postoperative adjuvant chemotherapy (PC-SOD group: 43 cases, placebo group: 47 cases). 2 and levofolinate 200 mg / m 2 was administered intravenously over 2 hours, followed by fluorouracil 400 mg / m 2 was administered intravenously, followed by 2400 mg / m fluorouracil 2 The mFOLFOX6 regimen was administered by continuous intravenous infusion over 46 hours. This cycle was administered every two weeks for 12 cycles. The study drug (PC-SOD 80 mg or placebo) was administered intravenously before the administration of oxaliplatin in the mFOLFOX6 regimen. Efficacy was evaluated by comparing the difference between treatment groups in the time to the first event (unit time is one cycle of administration of the study drug) using the log-rank test, with oxaliplatin allergy defined as an event.

[0039] [Results] Compared with placebo, the development of oxaliplatin allergy was suppressed by combining mFOLFOX6 therapy with PC-SOD (Fig. 1, p=0.0274).

[0040] Test Example 1 (Effect on Increase in Blood IgE Antibodies Caused by Oxaliplatin Administration) [Method] (1) Preparation of Oxaliplatin-Induced Allergy Model Mice: 6-8 week-old ICR male mice (30-40 g) were used, and 12.5 mg / kg of oxaliplatin (hereinafter abbreviated as OXA) was administered intraperitoneally to the mice. The administration was carried out twice, on days 1 and 11. The control group was similarly administered the OXA solvent, i.e., sterile saline (Otsuka Pharmaceutical). 100 mg of oxaliplatin intravenous infusion solution (Nipro Corporation) was used as OXA. (2) Experiment to Evaluate the Allergy Prevention Effect of the Test Drug: The experimental animals were divided into three groups: a control group, an OXA-administered group, and a group administered OXA and PC-SOD at 1 mg / kg (OXA + PC-SOD-administered group). OXA was administered twice, on days 1 and 11, and PC-SOD was administered daily via tail vein injection for five days starting from day 0 (days 0, 1, 2, 3, and 4). The control group and the OXA-administered group were similarly administered the PC-SOD solvent, i.e., sterile saline (Otsuka Pharmaceutical) diluted to half its original concentration with Milli-Q water. (3) Measurement of IgE Blood was collected from the mice on days 4, 11, and 21, and the amount of IgE in the blood was measured using a Mouse IgE ELISA Kit (Bethyl Laboratories, Inc.).

[0041] [Results and Interpretation] The results of IgE measurement are shown in Figure 2. In the OXA-administered group, the amount of IgE in the blood increased compared to the control group. In contrast, in the OXA+PC-SOD-administered group, PC-SOD suppressed the OXA-induced increase in blood IgE. These results confirmed that PC-SOD has an inhibitory effect on the OXA-induced increase in IgE.

[0042] Test Example 2 (Effect on Increase in IgE Antibodies by Administration of Bovine Serum Albumin-Oxaliplatin Conjugate) [Methods] (1) Preparation of Bovine Serum Albumin-Oxaliplatin Conjugate: Bovine serum albumin (Sigma-Aldrich Co., Ltd.) and oxaliplatin (Tokyo Chemical Industry Co., Ltd.) were dissolved in D-PBS (Fujifilm Wako Pure Chemical Industries, Ltd.) to prepare a 20% BSA solution and a 5% OXA solution. The 20% BSA solution and the 5% OXA solution were mixed to a final concentration of 5% BSA and 0.14% OXA, and the mixture was allowed to stand at 37°C for 72 hours. (2) Preparation of Bovine Serum Albumin-Oxaliplatin Conjugate: The BSA-OXA solution was dialyzed against a sufficient amount of D-PBS. The solution was concentrated by ultrafiltration. (3) Preparation of a BSA-OXA-induced allergy model mouse: 6-8 week-old ICR male mice (30-40 g) were used, and BSA-OXA was administered intraperitoneally to the mice at a dose equivalent to 12.5 mg / kg of OXA. The administration was carried out twice, on days 1 and 11. A 1.87% BSA solution was administered to the control group in the same manner. (4) Experiment to evaluate the allergy prevention effect of the test drug: The experimental animals were divided into four groups: a control group, a BSA-OXA administration group, a BSA-OXA and PC-SOD 1 mg / kg administration group (BSA-OXA + PC-SOD administration group), and a BSA-OXA and SOD 1 mg / kg administration group (BSA-OXA + SOD administration group). OXA was administered twice, on days 1 and 11, and PC-SOD or SOD was administered via tail vein injection daily for 5 days starting from day 0 (days 0, 1, 2, 3, and 4). The control group and the BSA-OXA-administered group were similarly administered the solvent for PC-SOD and SOD, i.e., sterile saline (Otsuka Pharmaceutical) diluted to half concentration with Milli-Q water. (5) Measurement of IgE Blood was collected from the mice on day 11, and the amount of IgE in the blood was measured using a Mouse IgE ELISA Kit (Bethyl Laboratories, Inc.).

[0043] [Results and Interpretation] The results of IgE measurements are shown in Figure 3. In the BSA-OXA administration group, the amount of IgE in the blood increased compared to the control group. In contrast, in the BSA-OXA + PC-SOD administration group, PC-SOD suppressed the increase in blood IgE caused by BSA-OXA. On the other hand, in the BSA-OXA + SOD administration group, the increase in blood IgE caused by BSA-OXA was similar to that in the BSA-OXA administration group. These results confirmed that PC-SOD has an inhibitory effect on the increase in IgE caused by BSA-OXA, while SOD does not exhibit this inhibitory effect.

[0044] Test Example 3 (Passive Cutaneous Anaphylaxis (PCA) Reaction Test) [Method] (1) Sensitization Treatment Five- to six-week-old Hartley male guinea pigs (Kwl:Hartley) (body weight ≥250 g) were used as experimental animals. OXA was subcutaneously administered at 10 mg / kg together with Freund's Complete Adjuvant (FCA) as an adjuvant. Administration was performed three times at 14-day intervals (days 0, 14, and 28). The control group was similarly administered the OXA solvent, i.e., 5% glucose solution. (2) Blood Collection 42 days after sensitization, 12 mg / kg of OXA was administered into the auricular vein of the guinea pigs to obtain serum for the Homo-PCA reaction. Two days later (44 days after sensitization), whole blood was collected from the abdominal aorta under isoflurane anesthesia. The blood was centrifuged at approximately 1,600 × g for 20 minutes to obtain serum, which was used as serum for the Homo-PCA reaction. (3) Homo-PCA reaction On the day before the PCA reaction, the hair on the backs of all animals was clipped with an electric clipper (Daito Electric Industry Co., Ltd.), and, if necessary, shaved with an electric razor (Braun).

[0045] 1) On the day of the PCA reaction, the serum for the Homo-PCA reaction was diluted two-fold with physiological saline. 2) 0.1 mL of the serum diluted in 1) was administered intradermally to one site (site 1) on the back of all animals in each group. 3) After a 3-hour sensitization period, PC-SOD 3 mg / kg or the PC-SOD solvent, i.e., 5% xylitol solution (Fuso Pharmaceutical Industries), was administered in the same manner. 4) Approximately 1 hour later, an elicitor containing Evans blue (OXA 12 mg / ml) was administered into the auricular vein. 5) 30 minutes after the elicitation, the abdominal aorta was cut under deep anesthesia with isoflurane, and the animals were killed by exsanguination. The dorsal skin was then removed. 6) All removed skin samples were photographed using a digital camera.

[0046] [Results and Interpretation] The results of the Homo-PCA reaction are shown in Table 1. In the control group, dye leakage was observed in 50% of individuals, while in the PC-SOD-administered group it was 25%. Dye leakage was suppressed in the PC-SOD-administered group compared to the control group. These results confirmed that PC-SOD has a preventive effect against increased vascular permeability, a type of allergic reaction associated with OXA administration.

[0047]

Claims

1. A pharmaceutical composition for treating or preventing a disease caused by a type I allergic reaction associated with the administration of a platinum preparation and / or a taxane-based anticancer agent, which contains lecithinated superoxide dismutase.

2. The pharmaceutical composition according to claim 1, wherein the platinum preparation and / or the taxane-based anticancer agent is one or more selected from cisplatin, carboplatin, oxaliplatin, nedaplatin, docetaxel, and paclitaxel.

3. The pharmaceutical composition according to claim 1, wherein the disease caused by the type I allergic reaction is one or more diseases selected from fever, nausea, chill, headache, rash, skin eruption, itching, swelling, tachycardia, urticaria, flushing, a feeling of constriction in the throat, cough, dyspnea, wheezing, loss of consciousness, hypotension, and anaphylaxis accompanied by respiratory disorder.

4. The pharmaceutical composition according to claim 1, which is administered in combination with a platinum preparation and / or a taxane-based anticancer agent.

5. The pharmaceutical composition according to claim 1, which is administered before the administration of a platinum preparation and / or a taxane-based anticancer agent.

6. The pharmaceutical composition according to claim 1, wherein the lecithinated superoxide dismutase is lyophilized.

7. The lecithinated superoxide dismutase is a human-derived superoxide dismutase subunit in which the mercapto group of cysteine at position 111, coordinated with copper and / or zinc, is hydroxyethylthiolated, and one or more amino groups thereof are represented by the following general formula (I): [In the formula, R is an alkyl group having 8 to 30 carbon atoms, and n is an integer of 2 to 10.] The lecithinated superoxide dismutase is modified directly or via a linker with a lecithin residue represented by the formula, and the lecithinated superoxide dismutase is composed of lecithinated superoxide dismutase subunits in which m amino groups [m is an integer of 1 to 4, and the average value of m in the lecithinated superoxide dismutase subunit is 1.5 to 2.4.] in each of the superoxide dismutase molecule subunits are substituted with the lecithin residue. The lecithinated superoxide dismutase (A) is the main component, and the lecithinated superoxide dismutase subunit constituting the lecithinated superoxide dismutase (A) is composed of 25 to 40 mol% of the lecithinated superoxide dismutase subunit (a1) where m = 1, 35 to 50 mol% of the lecithinated superoxide dismutase subunit (a2) where m = 2, 10 to 20 mol% of the lecithinated superoxide dismutase subunit (a3) where m = 3, and 5 to 15 mol% of the lecithinated superoxide dismutase subunit (a4) where m = 4. The pharmaceutical composition according to claim 1, comprising the lecithinated superoxide dismutase characterized by the above composition.

8. The pharmaceutical composition according to claim 1, wherein the lecithinated superoxide dismutase has PC bound to SOD at the following binding ratios: (1) The binding ratio of PC at the binding sites of K3, the N-terminus, and T2 is 1 to 10% as the total of the left-mentioned amino acid residues; (2) The binding ratio of PC at the binding site of K9 is 10 to 30%; (3) The binding ratio of PC at the binding site of K23 is 50 to 75%; (4) The binding ratio of PC at the binding site of K36 is 30 to 55%; (5) The binding ratio of PC at the binding sites of K70 or K75 is 10 to 80% as the total of the left-mentioned amino acid residues; (6) The binding ratio of PC at the binding sites of K122 or K128 is 10 to 45% as the total of the left-mentioned amino acid residues; (7) The binding ratio of PC at the binding site of K136 is 10 to 60%; As the total of (1) to (7) above, on PC-SOD, PC is bound at an average number of 1 to 8.

9. The pharmaceutical composition according to claim 1, wherein the superoxide dismutase of the lecithinated superoxide dismutase has the amino acid sequence set forth in SEQ ID NO:

1. Use of lecithinated superoxide dismutase for the manufacture of a pharmaceutical composition for the treatment or prevention of a disease caused by a type I allergic reaction associated with the administration of a platinum preparation and / or a taxane-based anticancer agent. Lecithinated superoxide dismutase for the treatment or prevention of a disease caused by a type I allergic reaction associated with the administration of a platinum preparation and / or a taxane-based anticancer agent. A method for treating or preventing a disease caused by a type I allergic reaction associated with the administration of a platinum preparation and / or a taxane-based anticancer agent, characterized by administering lecithinated superoxide dismutase.

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