WO2017082186A1 - New use for npr-a agonist - Google Patents

Abstract

A drug combining (A) a natriuretic peptide receptor GC-A agonist, with, as (B) an anti-malignant tumor agent, a compound having anti-microtubule action, or a PD-1 pathway inhibitor [(B')]. By administering the drug at least 5 days before administering the (B) anti-malignant tumor agent, the natriuretic peptide receptor GC-A agonist effect is exhibited, and the (B) anti-malignant tumor agent can effectively reach the inside of the tumor cells via the bloodstream, thereby making the drug useful as an anti-malignant tumor treatment drug having a strong effect.

Description

New uses of NPR-A agonists

The present invention relates to a medicine.

Peptides called natriuretic peptides include atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP). These specifically bind to receptors having a guanylate cyclase domain. Specifically, ANP and BNP are natriuretic peptide receptors GC-A (also known as NPR-A), and CNP is a natriuretic peptide. It is known that by binding to the receptor GC-B (also known as NPR-B), the intracellular GMP concentration is increased and various physiological activities are expressed.

ANP is a peptide consisting of 28 amino acids that is produced and secreted by atrial cells, but exhibits diuretic action in the kidney and exerts blood pressure regulating actions such as relaxing and dilating vascular smooth muscle in the blood vessels. , Human type ANP (hANP) is used as a therapeutic agent for acute heart failure. In recent years, there have been many reports on suppression of proliferation and metastasis of cancer cells and suppression of fibrosis of each organ.

For example, in Patent Documents 1 and 2 and Non-Patent Document 1, in addition to ANP, four peptides of Long Acting Natriuretic Peptide, Vessel Dilator, and Kaliuretic Peptide are included in pancreatic cancer, prostate cancer, small cell lung cancer, breast cancer and the like. It has been reported that tumor growth can be suppressed by directly acting on each tumor cell and inhibiting DNA synthesis.

Patent Document 3 focuses on ANP receptors, and inhibits NPR-A activity using siRNA or the like to inhibit NPR-A synthesis or ANP analogs. It is disclosed that diseases such as cancer induced by the ANP cascade can be treated.

Non-Patent Document 2 reports that ANP suppresses the inflammatory reaction of vascular endothelial cells, thereby suppressing the adsorption of cancer cells themselves to vascular endothelial cells and suppressing the metastasis of cancer cells. Yes.

Further, in Patent Document 4, a natriuretic peptide receptor GC-A agonist directly acts on tumor cells expressing GC-A to migrate and infiltrate including epithelial-mesenchymal transition (EMT). In addition to showing the effect (direct effect) of suppressing metastasis by suppressing the acquisition of ability, the signaling substance generated with the increase of intracellular cGMP acts on the endothelial cells of blood vessels and lymph vessels It is disclosed that adhesion / invasion of tumor cells to the vascular endothelium is inhibited and an effect of suppressing tumor metastasis (indirect effect) is also exhibited. Further, it has been described that such a GC-A agonist can suppress metastasis and invasion of tumor cells, and therefore may be used in combination with other antitumor agents. Thus, it is disclosed that cisplatin enhances apoptosis-inducing activity to cancer cells by a GC-A agonist.

In Patent Document 5, a natriuretic peptide receptor GC-B agonist suppresses the production of various factors and cytokines that exacerbate malignant tumors in cancer-associated fibroblasts (CAF), and natriuretic peptide receptor GC- A agonist suppresses the EMT of cancer cells and specifically suppresses the production of each factor and cytokine that exacerbate malignant tumors from cancer cells. By using these in combination, each growth factor that exacerbates malignant tumors It has been reported that the production of inflammatory cytokines and the like is remarkably suppressed, and the EMT of cancer cells is suppressed.

In addition, it has been reported that fibrosis suppression has an improving effect by administering ANP to a model animal of peritoneal fibrosis or renal fibrosis (see Non-Patent Documents 3 and 4). Non-Patent Document 5 discloses that pulmonary fibrosis is suppressed by using ANP and sildenafil in combination.

US6943147 US2005 / 0209139 US2005 / 0272650 gazette WO2012 / 118042 WO2013 / 027680 publication

However, the growth inhibitory effect of malignant tumors by ANP is still unclear. For example, in Patent Document 1, 1 μM ANP shows a decrease in cancer cells of about 34% compared to controls in cell experiments (Patent Document 1, FIG. 2), but many cancer cells survive, The effectiveness as an anticancer agent is not suggested. Patent Document 2 describes that 89% of cancer cells decrease when the concentration of ANP is increased to 1 mM in cell experiments (Patent Document 2, FIG. 3). It is suspected that the cell proliferation is suppressed due to the cytotoxicity. Since ANP has a side effect of lowering blood pressure in clinical practice, it is known as a drug that requires attention to the dose. Therefore, ANP is suppressed because the growth of cancer cells was suppressed at a high concentration in cell experiments. It cannot be said that it can be used as an anticancer agent. In addition, for example, as described in SCIENCE 307, 58-62, (2005), the blood vessel structure in the tumor tissue is made of many immature blood vessels and takes an abnormal structure, so the vessel wall collapses, It is known that a drug is difficult to reach cancer cells in a tumor tissue due to leakage of blood components to surrounding tissues as blood vessel permeability increases. Therefore, even if the tumor growth inhibitory effect of ANP is confirmed in an in vitro experimental system, the action of ANP confirmed in in vivo is unlikely to be due to a direct action on cancer cells. It can be seen that the report that the apoptosis-inducing activity of ANP was enhanced by the cisplatin disclosed in 4 is not sufficient as a mechanism.

Also, regarding the report of fibrosis suppression, it is unlikely that ANP is acting directly because the vascular structure is broken by the progress of fibrosis and the drug is difficult to reach. Further, from FIG. 4 of Non-Patent Document 5, in experiments using human lung fibroblasts, when ANP and sildenafil were used together, suppression of differentiation potential was confirmed, whereas suppression of differentiation potential was not confirmed with ANP alone. However, it is clear that the direct action of ANP is unknown and the mechanism is not sufficient.

An object of the present invention is to provide a medicament capable of effectively treating malignant tumors, pulmonary fibrosis, or interstitial pneumonia or suppressing malignant transformation thereof.

As a result of repeated studies to solve the above-mentioned problems, the present inventors combine a compound having a microtubule inhibitory action with an natriuretic peptide receptor GC-A agonist as an anticancer agent that is difficult to reach the deep part of the tumor. By protecting (maturating) the blood vessels in the tumor tissue with a GC-A agonist, it becomes possible to efficiently reach the cancer cell with a compound having a microtubule inhibitory effect. The inventors have newly found that the tumor effect is more exerted, and have completed the present invention.

That is, the present invention relates to the following [1] to [10].
[1] The (B) anti-malignant tumor agent, which comprises (A) a natriuretic peptide receptor GC-A agonist and is administered 5 days or more before the administration of the (B) antineoplastic agent The therapeutic effect enhancer.
[2] A pharmaceutical comprising a combination of (A) a natriuretic peptide receptor GC-A agonist and (B ′) a compound having a microtubule inhibitory action or a PD-1 pathway inhibitor.
[3] (B) A compound having a microtubule inhibitory action or a PD-1 pathway inhibitor containing a natriuretic peptide receptor GC-A agonist, or an agent for enhancing the therapeutic effect of a malignant tumor.
[4] A pharmaceutical composition for use in combination with (B ′) a compound having a microtubule inhibitory action or a PD-1 pathway inhibitor, comprising (A) a natriuretic peptide receptor GC-A agonist as an active ingredient.
[5] A pharmaceutical composition for use in combination with (A) a natriuretic peptide receptor GC-A agonist, comprising (B ′) a compound having a microtubule inhibitory action or a PD-1 pathway inhibitor as an active ingredient.
[6] A pharmaceutical composition for a patient who is treated with (B ′) a compound having a microtubule inhibitory action or a PD-1 pathway inhibitor, comprising (A) a natriuretic peptide receptor GC-A agonist as an active ingredient object.
[7] (B ′) A pharmaceutical composition for a patient undergoing treatment with a natriuretic peptide receptor GC-A agonist, comprising as an active ingredient a compound having a microtubule inhibitory action or a PD-1 pathway inhibitor object.
[8] A pharmaceutical composition used for the prevention or treatment of pulmonary fibrosis or interstitial pneumonia, comprising a natriuretic peptide receptor GC-A agonist.
[9] A method for preventing or treating pulmonary fibrosis or interstitial pneumonia, comprising administering a natriuretic peptide receptor GC-A agonist.
[10] A natriuretic peptide receptor GC-A agonist for the prevention or treatment of pulmonary fibrosis or interstitial pneumonia.

The medicament of the present invention exhibits an excellent effect of exerting an antitumor effect more strongly than when a compound having a microtubule inhibitory action is taken alone.

In addition, the present invention is based on the concept of efficiently bringing an anticancer drug to cancer cells by protecting (maturating) blood vessels in tumor tissue with a GC-A agonist. Even if it is an anticancer drug other than the compound having an inhibitory action, the same effect is expected for a drug that is difficult to reach cancer cells.

FIG. 1 is a diagram showing a vascular state in a tumor in a breast cancer mouse orthotopic transplantation model. The upper row is the control group, the lower row is the ANP group, the left row is a diagram showing vascular endothelial cells, the middle row is staining the mural cells, and the right row is a combined view of all staining including nuclear staining. . FIG. 2 is a diagram showing the lining rate of wall cells of tumor blood vessels in a breast cancer mouse orthotopic transplantation model. FIG. 3 is a graph showing the cisplatin concentration in a tumor in a breast cancer mouse orthotopic transplantation model. FIG. 4 is a diagram showing the intravascular vascular state in genetically modified mice transplanted with lung cancer at the same site. From top to bottom, WT (wild type) group, EC-GCA-Tg (GC-A overexpression) group, Flox / flox (control) group, EC-GCA-KO (GC-A knockout) group, left column Is a diagram in which vascular endothelial cells are stained, a middle row is a diagram in which mural cells are stained, and a right column is a diagram in which all staining diagrams including nuclear staining are combined. FIG. 5 is a graph showing the lining ratio of tumor vascular wall cells in genetically modified mice transplanted with lung cancer at the same site. FIG. 6 is a diagram showing the cisplatin concentration in the tumor in a lung cancer mouse orthotopic transplantation model. FIG. 7 is a graph showing changes in body weight and blood components in a cisplatin-induced bone marrow suppression model. FIG. 8 is a graph showing the transition of bone marrow components in a cisplatin-induced myelosuppression model. FIG. 9 is a graph showing changes in serum G-CSF concentration in a cisplatin-induced myelosuppression model. FIG. 10 is a graph showing the combined effect after administration of ANP and DTX in a breast cancer mouse orthotopic transplantation model. FIG. 11 is a graph showing changes in tumor volume according to the ANP administration period when ANP and CDDP (cisplatin) are used in combination in a breast cancer mouse orthotopic transplantation model. FIG. 12 is a diagram showing the combined effect of ANP and anti-PD-1 antibody in a breast cancer mouse orthotopic transplantation model. FIG. 13 is a diagram showing a lung fibrosis area by ANP administration in a pulmonary fibrosis mouse model. FIG. 14 is a diagram showing lung fibrosis area in tissue-specific transgenics.

The medicament of the present invention is characterized in that (A) a natriuretic peptide receptor GC-A agonist and (B) an antineoplastic agent are used in combination as active ingredients. Specifically, for example, (A) a combination of a natriuretic peptide receptor GC-A agonist and a platinum preparation, or (A) a natriuretic peptide receptor GC-A agonist and (B ′) a microtubule Examples thereof include those used in combination with compounds having an inhibitory action, and those used in combination with (A) a natriuretic peptide receptor GC-A agonist and (B ′) a PD-1 pathway inhibitor.

<(A) Natriuretic peptide receptor GC-A agonist>
In the present invention, the “natriuretic peptide receptor GC-A agonist” is sometimes referred to as natriuretic peptide receptor GC-A (hereinafter simply “GC-A”) (Chinkers M, etal., Nature 338). 78-83, 1989)) and has the action of activating guanylate cyclase (hereinafter referred to as “GC-A agonist activity”). Sometimes referred to as an “agonist”. Typical GC-A agonists include, for example, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP). The GC-A agonist of the present invention is not particularly limited as long as it has GC-A agonist activity, and ANP, BNP, and variants thereof are used singly or in combination of two or more. Can do.

Examples of the ANP in the present invention include a human-derived ANP (SLRRSSCFGG RMDRIGAQSG LGCNSFRY: SEQ ID NO: 1), a rat-derived ANP / mouse-derived ANP (SLRRSSCFGGＩＤRIDRIGAGSGSG LGCNSFRY: SEQ ID NO: 2), and the like. Regarding human-derived ANP, α-hANP described in Biochem. Biophys. Res. Commun., 118, 131, 1984 obtained the marketing approval in Japan under the generic name carperitide and sold ( Product name: Hump, HANP). α-ANP is also commonly known as Human pro-ANP [99-126].

As the BNP in the present invention, human-derived BNP consisting of 32 amino acids (SPKMVQGSGC FGRKMDRISSS SGLGCKVLR RH: SEQ ID NO: 3), porcine-derived BNP (SPKTMRDSGC FGLRLDRIGS LSGLGCCNVLR RY: can be exemplified as SEQ ID NO: 4). In addition, rat-derived BNP consisting of 45 amino acids (SQDSAFRIQE RLRNSKMAHS SSCFFGQKIDR IGAVSLLGCD GLRLF: SEQ ID NO: 5), mouse-derived BNP (SQGSTLLVQQ RPQNSKVTHI SSCFGHKIDRL IGSVRLC) Human-derived BNP has received regulatory approval in the United States, etc., under the general name nesiritide, and is sold under the trade name: Natrecor.

In the present invention, a “variant” of ANP or BNP refers to substitution, deletion, insertion, and / or addition (hereinafter referred to as “one” to several amino acids in one to several amino acid sequences of ANP or BNP). , Collectively referred to as “substitution etc.” and having GC-A agonist activity. "Several places" is usually about 3 places, preferably about 2 places. “Several” is usually about 10, preferably about 5, more preferably about 3, and still more preferably about 2. When substitution is made at a plurality of locations, any one of substitution, deletion, insertion, and addition may be used, or two or more may be combined. The amino acid to be substituted may be a naturally occurring amino acid, a modified product such as an acylated product thereof, or an artificially synthesized amino acid analog.

For example, as long as the ANP mutant has GC-A agonist activity, for example, one to several amino acids are substituted at one to several desired positions in the amino acid sequence shown in SEQ ID NO: 1 or 2. May be. In addition, as long as the BNP mutant has GC-A agonist activity, 1 to several amino acids are substituted at one to several desired positions of the amino acid sequence shown in SEQ ID NO: 3, 4, 5, or 6. May be.

Specific examples of ANP mutants include, for example, rat α-rANP (Biochem. Biophys. Res. Commun., Vol. 121, p. 585, p. 1984) in which the Met at position 12 of hANP has been replaced with Ile. ANP etc. from which N-terminal Ser-Leu-Arg-Arg-Ser-Ser has been deleted. Examples of such ANP or BNP mutants include a series of peptides described in Medicinal Research, Review 10, Vol. 10, p. 115, 1990. In addition, as an example in which one or more amino acids in the amino acid sequence are deleted and one or more amino acids in the amino acid sequence are substituted with other amino acids, for example, mini-ANP (Science, 270 Volume, 1657, 1995).

Furthermore, the ANP or BNP of the present invention may be a derivative or a modified product as long as it has GC-A agonist activity.

A “derivative” of ANP or BNP is a fusion peptide comprising the amino acid sequence of ANP, BNP or a variant thereof, to which another peptide or protein is added, and at least the biological activity of ANP or BNP. It means a fusion peptide that retains a part. A fusion peptide having at least a part of such biological activity (in the present invention, an action of binding to GC-A and activating guanylate cyclase) is also referred to as an ANP or BNP derivative. In the derivative of the present invention, an additional peptide may be fused to either the C-terminal or N-terminal of ANP, BNP or a variant thereof, and the additional peptide is fused to both the C-terminal and the N-terminal. There may be. The peptide to be added is not particularly limited, but a peptide having no physiological activity is preferable. Further, the additional peptide may be directly bonded, or may be bonded via a linker sequence consisting of 1 to several amino acids. Various linker sequences are known, but those containing a large amount of Gly, Ala, Ser and the like are preferably used. Examples of such an additional peptide include an Fc site of immunoglobulin (preferably IgG), serum albumin, C-terminal sequence of ghrelin and the like (for example, a fusion protein in which ANP is bound to an Fc site of immunoglobulin ( US Patent Application Publication No. 2010/0310561, etc.), fusion protein in which GLP-1 is bound to serum albumin (see International Patent Publication No. 2002/046227, etc.)).

The “derivatives” are preferably hANP derivatives and hBNP derivatives. Specifically, for example, a fusion protein in which ANP is bound to an Fc site of an immunoglobulin (see US Patent Application Publication No. 2010/0310561, etc.) improves the retention in blood while retaining the biological activity of ANP. It is known that Moreover, regarding various derivatives of ANP and BNP, for example, a series of peptides described in Medicinal Research Review, Vol. 10, p. 115, 1990 can be mentioned.

Further, specific examples of ANP derivatives include various ANP derivatives disclosed in International Publication No. 2009/142307 (corresponding to US Patent Application Publication No. 2010/305031). Here, it has been reported that in a derivative in which a partial sequence derived from the C-terminal of ghrelin is added to ANP, the retention in blood is improved while maintaining the physiological activity of the original peptide. In this report, GC-A agonist activity is retained in any of various derivatives obtained by adding a partial peptide derived from the C-terminus of ghrelin to either the N-terminus or C-terminus of hANP and both. Medium half-life was extended.

The “modified form” of ANP or BNP is one in which one to several amino acids contained in ANP, BNP or a variant thereof are modified by a chemical reaction with another chemical substance, and ANP or BNP It means that retains at least part of the biological activity of BNP. Any site may be selected as the site to be modified as long as it retains the activity of ANP or BNP. For example, in a modification that adds a somewhat large chemical substance such as a polymer, the modification is preferably performed at a site other than the active site of ANP or BNP or the receptor binding site. In addition, in the case of modification for preventing cleavage by a degrading enzyme, it is also possible to employ a modification in which the portion that undergoes the cleavage is modified. Further, another chemical substance may be directly bonded, or may be bonded through a linker sequence consisting of 1 to several amino acids. Various linker sequences are known, but those containing Gly, Ala, Arg, Lys, etc. are preferably used.

Various methods are known as methods of chemical modification. For example, a method of adding a high molecular polymer (pharmacologically used) used in pharmaceutical technology such as polyethylene glycol (PEG), polyvinyl alcohol (PVA), etc. Further, a method of adding a compound serving as a linker to a side chain amino group such as a Lys residue and binding it to another protein (eg, serum albumin) via the chain is known, but is not limited thereto. Various methods can be employed. Moreover, about the manufacturing method of the modified body of ANP or BNP, it can produce suitably with reference to US Patent application publication 2009/0175821 specification. The modified product is preferably chemically modified by adding a high-molecular polymer used for pharmaceutical use.

For example, the modified ANP may be modified at one or more desired positions in the amino acid sequence of SEQ ID NO: 1 or 2 as long as it has GC-A agonist activity. It contains the amino acid sequence of SEQ ID NO: 1 or 2, and its SEQ ID NO: 7 Xaa10 -Xaa11 -Xaa12 -Arg (where Xaa3 is Met, Leu or Ile) ("ring structure") and at least one amino acid other than the amino acid corresponding to the amino acid is chemically modified More preferably, the amino acid other than the amino acid represented by SEQ ID NO: 7 in the amino acid sequence of SEQ ID NO: 1 or 2 is modified at one to several positions, more preferably SEQ ID NO: 1 or 2. 1 to 6 of the amino acid sequence of And modified at any one to several positions at position 28. Moreover, as long as it has GC-A agonist activity, a variant of BNP is a desired one of the amino acid sequences of SEQ ID NOs: 3 to 6. The amino acid sequence may be modified at a plurality of positions, but preferably contains at least one amino acid other than the amino acid sequence represented by SEQ ID NO: 7 including the amino acid sequence of SEQ ID NO: 3 to 6 in the sequence listing More preferably, the amino acid sequence of SEQ ID NOs: 3 to 6 is modified at one to several positions in an amino acid other than the amino acid represented by SEQ ID NO: 7, More preferably, the amino acid sequence of SEQ ID NO: 3 or 4 is modified at one to several positions of positions 1 to 9, 31 and 32, or the amino acid sequence of SEQ ID NO: 5 or 6 The acid sequence is modified at any one to several positions from positions 1 to 22, 44 and 45. Furthermore, the above-mentioned active fragments, mutants and derivatives of ANP or BNP are modified. Such modified compounds can also be used in the present invention as long as they retain GC-A agonist activity.

Specific examples of such modifications that can be employed as GC-A agonists include, for example, hANP, hBNP, or variants thereof, hydrophilic polymers such as PEG and PVA, and hydrocarbon groups such as alkyl groups and aryl groups. It is known that a representative hydrophobic group retains GC-A agonist activity in various modified forms bound thereto, with or without a linker (US Pat. No. 7,662,773, International Patent). Publication 2009/020934 etc.).

The binding between ANP or BNP and the GC-A receptor is important for the ring structure of ANP and BNP and its C-terminal tail, so that derivatives and modifications in which a sequence or substance of N is bound to its N-terminal are particularly important. The body has little effect on the ring structure by the added peptide or modification, and retains the GC-A agonist activity without inhibiting the binding to the GC-A receptor. This has been demonstrated by many documents mentioned above.

In the present invention, ANP, BNP, and variants thereof may be collected from natural cells or tissues, or may be prepared using genetic engineering or cell engineering techniques, It may be chemically synthesized. Such preparation can be performed according to known techniques.

It should be noted that whether or not a certain substance has a GC-A agonist activity can be easily measured by a person skilled in the art by a conventionally known method. Specifically, for example, it is possible by adding a substance to cultured cells in which GC-A (Chinkers M, et al., Nature 338; 78-83, 1989) is forcibly expressed and measuring intracellular cGMP levels. It is. That a part of the GC-A agonist activity is retained means that the same test system is used, and the GC-A agonist substance and ANP or BNP (the agonist substance was prepared with reference to the sequence of ANP or BNP) When the GC-A agonist activity is measured along with the reference peptide), the peak of cGMP increasing activity by the agonist substance is at least about 10% of the peak of cGMP increasing activity exhibited by ANP or BNP. Usually, it means to hold the above, but preferably means to hold about 30% or more, more preferably about 50% or more, and still more preferably about 70% or more. Even if the increase in activity is not large at the peak, those having a long activity duration when administered to a living body can be used in the present invention.

A preferable GC-A agonist in the present invention is ANP, BNP, or a variant thereof, and more preferably hANP or hBNP.

Also, as the above-mentioned GC-A agonist, a pharmaceutically acceptable salt of the agonist may be used. Pharmaceutically acceptable salts include acid addition salts such as inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, or organic acids such as formic acid, acetic acid, butyric acid, succinic acid, citric acid. Further, it may take the form of a metal salt such as sodium, potassium, lithium or calcium, or a salt with an organic base.

<(B) Antineoplastic agent>
As the antineoplastic agent in the present invention, a platinum preparation, a compound having a microtubule inhibitory action, or a PD-1 pathway inhibitor can be used. In addition, in this specification, an antineoplastic agent may be described as an anticancer agent.

[Platinum preparation]
A platinum preparation (platinum preparation) binds to a double helical structure of DNA to inhibit DNA replication, and also has a function of leading cancer cells to self-destruction (apoptosis).

In the present invention, as the platinum preparation (platinum preparation), a preparation containing an antitumor platinum complex as an active ingredient can be used. Specific examples include cisplatin, carboplatin, oxaliplatin, nedaplatin, xeniplatin, enroplatin, lobaplatin, ormaplatin, loboplatin, seriplatin, miboplatin, and spiroplatin. These can be used alone or in combination of two or more.

[(B′-1) Compound having microtubule inhibitory effect]
Microtubules have an inhibitory effect on microtubules because they form a spindle during cell division and play an important role in maintaining normal cell functions such as the arrangement of organelles and mass transport. It is considered that the growth of tumor cells can be suppressed by acting a compound.

In the present invention, compounds having a microtubule inhibitory action include taxane anticancer agents and bin alkaloid malignant tumor agents. A taxane antineoplastic agent inhibits microtubule depolymerization to form an abnormally shaped tubulin, and specific examples include paclitaxel, docetaxel, cabazitaxel, and the like. Vin alkaloid-based malignant tumor agents inhibit tubulin from depolymerizing to form microtubules, and specific examples include vincristine, vinblastine, vindesine, vinorelbine and the like. Examples of other compounds having a microtubule inhibitory action include eribulin and the like. These can be used alone or in combination of two or more.

[(B′-2) PD-1 pathway inhibitor]
PD-1 is an immune checkpoint protein that is expressed on activated T cells and B cells to limit T cell activation in the periphery and suppress antitumor T cell responses during immune responses to infection Since it has an action, it is considered that a compound that inhibits the PD-1 pathway can induce an immune response and suppress tumor growth.

In the present invention, PD-1 pathway inhibitors include inhibitors against PD-1, PD-L1, PD-L2, etc., and antibodies against PD-1 or PD-1 ligand, PD-1 or A nucleic acid encoding an antibody against PD-1 ligand is exemplified. Specifically, nivolumab, pembrolizumab, atezolizumab and the like are exemplified. These can be used alone or in combination of two or more.

As side effects of anticancer drugs currently on the market, weight loss, bone marrow suppression, kidney damage and the like are well known. In general, cancer treatment is performed by setting a cycle (course or cool) of about 1 to several weeks, which is a combination of a day when treatment is performed and a day when treatment is not performed. If the cancer treatment is prolonged, the dose of the anticancer agent must be reduced, and eventually it becomes difficult to continue using the anticancer agent, and the treatment must be stopped. Therefore, measures for preventing or reducing side effects are important. For example, docetaxel, a compound having an inhibitory action on microtubules, has been used as an antineoplastic agent alone, but severe myelosuppression (pancytopenia, leukopenia, neutropenia (pyrogenic) (Including neutropenia), hemoglobin reduction, thrombocytopenia, etc.) are known to occur frequently, and if abnormalities are observed, appropriate intervals such as prolonged dosing intervals, reduced doses, and withdrawal It is recommended to consider treatment and proper use of G-CSF (granulocyte colony stimulating factor) formulations that suppress febrile neutropenia. However, since many G-CSF preparations have a short blood half-life, it is known that daily administration is necessary until the neutrophil count is recovered, and it is known that the physical and financial burden on the patient is large. Although the detailed mechanism is unknown in the present invention, when used in combination with a natriuretic peptide receptor GC-A agonist, the natriuretic peptide receptor GC-A agonist protects blood vessels in the tumor tissue and suppresses the collapse. Therefore, a compound having a microtubule inhibitory action can be efficiently delivered into tumor cells via the bloodstream, or a PD-1 pathway inhibitor can be efficiently delivered to immune cells present in tumor tissues. Thus, it is considered that the growth of the tumor can be suppressed by increasing the concentration of the compound having a microtubule inhibitory action in the tumor cells or by activating the autoimmune reaction. Furthermore, tumor growth can be efficiently inhibited by efficiently delivering tumor-damaging immune cells induced by cancer peptide vaccines or oncolytic viruses to the tumor tissue via the bloodstream. . In addition, since a compound having a microtubule inhibitory action has a bone marrow inhibitory action as a side effect, the dose of a compound having a microtubule inhibitory action can be reduced by using it together with a natriuretic peptide receptor GC-A agonist. So far, it is considered that the effect that it becomes possible to continue the administration of the anticancer drug to a patient who had to stop the treatment due to a side effect. Furthermore, the present inventors have confirmed that when an anticancer agent was administered to a place where ANP was pre-administered several days ago, leukopenia (myelosuppression), which is the main side effect of the anticancer agent, was not observed, As a mechanism, it has been confirmed that the endogenous serum G-CSF concentration is increased. When used in combination with a natriuretic peptide receptor GC-A agonist, the occurrence of side effects of myelosuppression is reduced, and further, the blood G-CSF concentration is increased. It is thought that the effect that weight reduction is possible or it becomes completely unnecessary is also exhibited.

The pharmaceutical of the present invention is not particularly limited as long as it is a combination of the component (A) and the component (B), and can contain other antitumor components as long as the effects of the present invention are not impaired. Specifically, alkylating agents, antimetabolites, antitumor antibiotics, antitumor plant components, BRM (biological response regulator), hormones, vitamins, antitumor antibodies, molecular targeted drugs, etc. Antitumor agents and the like. These contents are not particularly limited.

More specifically, as the alkylating agent, for example, an alkylating agent such as nitrogen mustard, nitrogen mustard N-oxide or chlorambutyl; an aziridine alkylating agent such as carbocon or thiotepa; dibromomannitol or dibromodarsi Epoxide alkylating agents such as Thor; nitrosourea alkylating agents such as carmustine, lomustine, semustine, nimustine hydrochloride, streptozocin, chlorozotocin or ranimustine; busulfan, improsulfan tosylate, dacarbazine, ifosfamide, cyclophosphami And melphalan or temozolomide.

Examples of various antimetabolites include, for example, purine antimetabolites such as 6-mercaptopurine, 6-thioguanine, thioinosine, nelarabine, fludarabine or pentostatin; fluorouracil, tegafur, tegafur uracil, carmofur, doxyfluridine, broxuridine, cytarabine And pyrimidine antimetabolite such as enositabine, capecitabine or gemcitabine; antifolate antimetabolite such as methotrexate, trimetrexate or pemetrexed.

Examples of antitumor antibiotics include anthracycline antibiotics such as mitomycin C, bleomycin, pepromycin, daunorubicin, aclarubicin, doxorubicin, pirarubicin, THP-adriamycin, 4′-epidoxorubicin, epirubicin, idarubicin or mitoxantrone. Tumor agents; chromomycin A3 or actinomycin D.

Examples of the anti-tumor plant component include taxanes (paclitaxel, docetaxel, etc.) other than the component used as the component (B); vin alkaloids other than the component used as the component (B) (vincristine, vinblastine, vindesine, vinorelbine) Etc.); camptothecin derivatives such as irinotecan and nogitecan; or epipodophyllotoxins such as etoposide, teniposide and sobuzoxane.

Examples of BRM include tumor necrosis factor and indomethacin.

Hormones include, for example, hydrocortisone, dexamethasone, methylprednisolone, prednisolone, plasterone, betamethasone, triamcinolone, oxymetholone, nandrolone, metenolone, phosphaterol, ethinylestradiol, chlormadinone, medroxyprogesterone, tamoxifen, anastrozole, exemestane, Examples include goserelin, bicalutamide, flutamide, leuprorelin, letrozole and the like.

Examples of vitamins include vitamin C and vitamin A.

Antitumor antibodies and molecular targeted drugs include trastuzumab, rituximab, cetuximab, nimotuzumab, denosumab, bevacizumab, infliximab, imatinib mesylate, gefitinib, erlotinib, sunitinib, lapatinib, i Examples include gamicin, dasatinib, tamibarotene, tretinoin, panitumumab, bortezomib and the like.

Other antitumor agents include, for example, platinum preparations other than the component (B) component (cisplatin, carboplatin, oxaliplatin, etc.), L-asparaginase, acecraton, schizophyllan, picibanil, procarbazine, pipobroman, neocartinostatin , Hydroxyurea, krestin and the like. In addition, immunoantibody drugs (anti-PD-1 antibodies other than those used as component (B): nivolumab, pembrolizumab, etc., PD-L1 antibodies: atezolizumab, etc., anti-CTLA4 antibody: ipilimumab, etc.), biologics related (interferon / α , Interferon / β, interferon / γ, interleukin 2, ubenimex dried BCG, lentinan, etc.).

Furthermore, recently, it has been reported that PDE5 inhibitors represented by Viagra (registered trademark) have a suppressive effect on malignant tumors (DasDet al.,. Proc. Natl. Acad. Sci. (2010),) vol / 107, No. 42, pp. 18202-18207), the medicament of the present invention can be used in combination with these PDE5 inhibitors. The PDE5 inhibitor is not particularly limited as long as it is a substance having an activity of inhibiting cGMP degradation by the PDE5 enzyme (for example, M. 薬 剤 P. Govannoni, et al. Curr. Med. Chem. (2010) 17, pp. 2564-2587)). Preferably, sildenafil, vardenafil, tadalafil, udenafil, mirodenafil, SLx-2101, lodenafil, Lodenafil carbonate, Exisulind, and their derivatives, and More preferably, it is sildenafil, vardenafil, tadalafil, udenafil, milodenafil or a pharmacologically acceptable salt thereof, more preferably sildenafil citrate, vardenafil hydrochloride, tadalafil. , Udenafil or mirodenafil, even more preferably sildenafil citrate. About these chemical | medical agents, manufacture and a formulation can be carried out by description of said reference (including the cited reference) and a well-known technique.

In addition, other pharmaceutical ingredients include excipients, binders, disintegrants, lubricants, sweeteners, flavoring agents, preservatives, chelating agents, antioxidants, cooling agents, coating agents, stabilizers, fluids Agent, thickener, solubilizer, thickener, buffer, fragrance, colorant, adsorbent, wetting agent, moisture-proofing agent, antistatic agent, plasticizer, antifoaming agent, surfactant, emulsifier, dilution You may contain additives, such as an agent. These contents are not particularly limited.

The pharmaceutical of the present invention is not particularly limited as long as it is a combination of component (A) and component (B), and can be prepared according to methods known to those skilled in the art. Moreover, the shape and size are not particularly limited, and any dosage form of oral administration and parenteral administration can be employed. In the case of parenteral administration, it is also possible to administer directly to the tumor site. Specifically, in the case of oral administration, tablets (including intraoral quick disintegrating tablets, chewable tablets, effervescent tablets, jelly-like drops, etc.), capsules (including hard capsules and soft capsules), Fine granules, powders, granules, pills, solutions, syrups and the like can be mentioned. In the case of parenteral administration, pulmonary dosage forms (for example, those using a nephriser), nasal dosage forms, transdermal dosage forms (for example, ointments, creams), injection dosage forms and the like can be mentioned. In the case of an injection dosage form, it can be administered systemically or locally by intravenous injection such as infusion, intramuscular injection, intraperitoneal injection, subcutaneous injection or the like. Moreover, when (A) component is included, the formulation design which makes it difficult to be decomposed | disassembled in a digestive tract, or the dosage form which can be absorbed from mucous membranes other than a digestive tract is also possible.

For example, a combination (including kit) of an injection of component (A) and an injection of component (B) may be mentioned. Moreover, the combination (including a kit) etc. which combined the transpulmonary inhalation agent of (A) component, and the injection of (B) component are illustrated.

The medicament of the present invention is characterized by combining the (A) component and the (B) component as active ingredients, and the use form thereof was prepared separately for each of the (A) component and the (B) component. A mode in which a single agent is used at the same time, a mode in which single agents separately prepared for each of the components (A) and (B) are used sequentially, and a unit separately prepared for each of the components (A) and (B). A mode in which the agent is used separately and a mode in which the agent (A) and the component (B) are formulated together and used as a preparation (mixture) prepared by combining them are mentioned. Moreover, the aspect which uses (B) component as an active ingredient for the patient who is receiving treatment with (A) ingredient, or the (A) ingredient is used as an active ingredient for the patient who is receiving treatment with (B) ingredient Embodiments are also included in the present invention. In addition, when using (A) component and (B) component sequentially or separately, whichever may be used first, the interval when using separately depends on the patient's symptoms, etc. Can be appropriately set according to the judgment of the doctor. Particularly when the purpose is to avoid the side effects of component (B), component (A) is administered 1 to 7 days before the administration date of component (B) (for example, 2 to 3 days before, 5 days or more before) May be.

When used as a medicament of the present invention, the dosage of component (A) and component (B) is the dosage form, patient symptoms, age, body weight, sex, or other drugs (if any) to be used in combination. It will depend on the doctor's judgment. Examples include an embodiment in which 0.1 to 1000 mg of component (A) is administered intravenously and 0.1 to 10,000 mg of component (B) is administered intravenously per day for an adult weighing 60 kg, preferably component (A) Of 0.1 to 100 mg intravenously and 0.1 to 1000 mg of component (B) intravenously administered, more preferably 1 to 10 mg of component (A) intravenously and 1 to 500 mg of component (B) intravenously A mode of internal administration is exemplified. Such dose may be administered at once or dividedly, and the administration period is appropriately set for each component. In the case of parenteral administration, for example, intravenous administration, not only bolus administration but also continuous administration using an infusion pump, a catheter or the like may be used.

In the case of administering the component (A), for example, a freeze-dried preparation is dissolved in water for injection and continuously administered (also referred to as continual administration) using a micro infusion pump (a pediatric micro infusion set in the absence). )can do. In the case of continuous administration, the administration period is usually several hours to several days, for example, 1 to 14 days, preferably about 3 to 7 days. In this case, the upper limit of the dose is, for example, a concentration of about 50 μg / kg / min (per day, about 72 mg / kg) or less can be appropriately employed, and about 5 μg / kg / min (per day, about 7. 2 mg / kg) or less, preferably about 0.5 μg / kg / min (per day, about 720 μg / kg) or less, more preferably about 0.2 μg / kg / min or less, Preferably it is about 0.1 μg / kg / min or less, and even more preferably about 0.05 μg / kg / min or less. The lower limit is usually about 0.0001 μg / kg / min (about 0.144 μg / kg per day) or more, preferably about 0.001 μg / kg / min (about 1.44 μg / kg per day). More preferably, it is about 0.01 μg / kg / min (about 14.4 μg / kg per day) or more. These may be constant during the administration period or may be varied in combination as appropriate. As a specific administration method, for example, about 0.025 μg / kg / min can be adopted for about 3 to 4 days. In this case, the daily dose is about 36 μg / kg.

Since the component (A) has the action of relaxing and dilating blood vessels and reducing blood pressure as described above, it is administered at a rate that does not lower blood pressure more than necessary when treating malignant tumors or suppressing or preventing malignant transformation. It is preferable to monitor blood pressure during and immediately after administration. In this case, the administration period of the component (A) is usually several hours or longer, preferably 1 day or longer. During this period, continuous administration is preferable, and the period is usually 1 day or longer, preferably about 1 to 14 days, and more preferably about 1 to 5 days. When a malignant tumor is controlled over a long period of time, the above administration method can be repeated as appropriate, or the dosage and administration period can be appropriately changed according to the patient's condition.

Further, the concentration of component (A) in the blood (for example, about 0.01 ng / mL to about 1.6 ng / mL, preferably about 0.1 ng / mL to about 1 so as to bring about the same effect as the above intravenous injection. (6 ng / mL, more preferably about 0.4 ng / mL to about 1.6 ng / mL) can be used as a sustained-release preparation, such as continuous subcutaneous injection. In the case of using a sustained-release preparation, the dose and administration interval can be appropriately changed according to the preparation and the patient's condition, but it is preferably administered once a week.

Specifically, for example, when ANP is administered intravenously, for example, 1000 μg of hANP (for example, 1000 for Hump Injection (trade name), manufactured by Daiichi Sankyo Co., Ltd.) is dissolved in 10 mL of water for injection, and “weight × about It is preferred to administer at a rate of "0.06 mL / hour" (about 0.1 μg / kg / min) or less. The administration rate is not limited to the above rate, and blood pressure and heart rate are monitored at a rate of about 0.2 μg / kg / min or less (preferably about 0.01 μg / kg / min or more) depending on the medical condition. However, it is preferable to adjust appropriately. In particular, it has been confirmed that even if hANP is continuously administered at a dose of about 0.025 μg / kg / min for about 3 or 4 days, hemodynamics such as blood pressure and heart rate are not greatly changed, and this dosage method is adopted. It is also preferable to do.

When hBNP is administered, for example, intravenously, for example, it is preferable to administer about 0.01 μg / kg / min continuously, and further combined with bolus administration of about 2 μg / kg hBNP before the continuous administration. An administration method can also be adopted. Also in this case, it is preferable to administer the blood pressure at a rate that does not lower the blood pressure more than necessary, and it is recommended to monitor the blood pressure at the time of administration and immediately after administration.

If ANP and BNP do not significantly affect blood pressure, heart rate, etc. at the above administration rate, the administration rate may be further increased.

When using a mutant of ANP or BNP instead of a natural type (hANP, hBNP, etc.), taking into account the characteristics of the substance such as strength of its activity, persistence in the body, molecular weight, The administration rate, administration frequency, etc. can be determined as appropriate. In addition, for hANP or hBNP, by adopting controlled-release preparation technology or sustained-release preparation technology, various mutants, derivatives or modifications that are difficult to undergo peptide degradation, the invention is not limited to continuous administration or bolus administration, It is possible to select an administration method, administration frequency, etc. with less burden on the patient.

Component (B) can be administered with reference to known clinical practice, for example, intravenously administered as a bolus. The dosage and dosing schedule can be varied according to the specific disease symptoms and the overall symptoms of the patient. Depending on the age, symptoms or occurrence of side effects, the medicament of the present invention can protect blood vessels in tumor tissue with the component (A) and allow the component (B) to reach cancer cells efficiently. Therefore, the amount can be reduced as appropriate. When using the medicament of the present invention, (B) component is not particularly limited, adult 0.01 per day - 10000 mg / ^{m 2,} preferably 0.1 ~ 1000 mg / ^{m 2,} more preferably 1 to It is 500 mg / m ² and can be administered usually in 1 to 3 divided doses per day. If the patient experiences excessive toxicity, dose reduction is necessary. Dosage amount and regimen may be varied if one or more additional chemotherapeutic agents are used in addition to the combination therapy of the invention. The dosage regimen can be determined by the physician treating the particular patient.

In the case of cisplatin intravenously, but are not limited to, for example, the dose for adults (body weight 60kg) per day, 0.01 ~ 10000mg / ^{m 2,} preferably 0.1 ~ 1000mg ^{/ m} 2, More preferably, it is 1 to 500 mg / m ² , and further preferably 10 to 150 mg / m ² .

More specifically, when paclitaxel is administered intravenously, it is not particularly limited. For example, the dosage is 0.01 to 10,000 mg / m ² , preferably 0.1 to 1000 mg per day for an adult (body weight 60 kg). / M ² , more preferably 1 to 500 mg / m ² , still more preferably 50 to 250 mg / m ² .

Furthermore, when administering docetaxel intravenously, but are not limited to, for example, the dose for adults (body weight 60kg) per day, 0.01 ~ 10000mg / ^{m 2,} preferably 0.1 ~ 1000mg ^{/ m} 2, More preferably, it is 1 to 500 mg / m ² , still more preferably 50 to 100 mg / m ² .

In addition, when the PD-1 antibody is administered intravenously, it is not particularly limited. For example, the dose is 0.01 to 50 mg / kg (body weight), preferably 0.1 to adult (body weight 60 kg) per day. To 20 mg / kg, more preferably 1 to 10 mg / kg, still more preferably 1 to 5 mg / kg.

The medicament of the present invention has an excellent effect that the anti-malignant tumor effect of the component (B) is enhanced and exerted by the blood vessel protecting action of the component (A) as compared to the case of using the component (B) alone. That is, the pharmaceutical composition of the present invention is used for treatment of malignant tumors or suppression of malignant transformation. The malignant tumor may be a solid cancer or an invasive cancer, such as breast cancer, non-small cell lung cancer, gastric cancer, head and neck cancer, ovarian cancer, esophageal cancer, endometrial cancer, prostate cancer, angiosarcoma, Examples include cervical cancer and germ cell tumor (testicular tumor, ovarian tumor, extragonadal tumor).

Moreover, the medicament of the present invention can be used not only for cancer treatment but also for prevention of recurrence and metastasis after cancer treatment. Accordingly, preferred embodiments of the medicament of the present invention include cancer treatment medicaments, cancer recurrence prevention medicaments, and cancer metastasis restraint medicaments.

The present invention also provides a method for treating a malignant tumor, comprising administering a therapeutically effective amount of the combination of the component (A) and the component (B) to an individual who needs to treat the malignant tumor or suppress the malignant transformation. To do.

In the present specification, an individual who needs to treat a malignant tumor or suppress malignant transformation is preferably a human who needs to reduce or cure the malignant tumor, but may be a pet animal or the like.

Further, in this specification, the therapeutically effective amount means that when the combination of the component (A) and the component (B) is administered to the individual, the growth of malignant tumor is suppressed as compared with the individual not administered. It is a quantity. The specific effective amount is appropriately set according to the administration form, administration method, purpose of use, individual age, weight, symptoms, etc., and is not constant.

In the treatment method of the present invention, the component (A) and the component (B) may be combined and administered to the individual as they are so as to be the therapeutically effective amount, and are administered according to the use form of the medicament of the present invention. be able to.

In addition, the present invention is based on the concept that an anticancer agent can be efficiently reached to cancer cells by protecting (maturating) blood vessels in tumor tissue with a GC-A agonist. Even if it is an anticancer drug other than the component B ′), the same effect is expected for a drug that is difficult to reach cancer cells. Therefore, the medicament of the present invention is a combination of the above-described component (A) and a platinum preparation or component (B ′). However, as the component (B), the other antitumor components described above are used as the component (A). It does not prevent the combination. In addition to the above, there is no particular limitation as long as it is a drug that is present in the blood after administration but is difficult to reach cancer cells. For example, an immune antibody drug (anti-CTLA4 antibody: ipilimumab, etc.) Tim-3 antibody: MBG453 etc., anti-LAG3 antibody: BMS-986016 etc., anti-OX-40 antibody: MEDI-6469 etc., anti-ICOS antibody: GSK-3359609 etc., anti-B7RP-1 antibody: AMG-557 etc., anti-B7 -H3 antibody: enobrituzumab etc., anti-4-1-BB antibody: urelmab etc., anti-GITR antibody: MK-4166 etc., anti-CD27 antibody: valrilumab etc., anti-CSF-1 receptor antibody: emacuzumab etc.), immunoregulatory protein ( Soluble LAG3: IMP-321, etc.), immunoregulatory small molecule (JAK2 inhibitor: paclitinib, etc., Fms / Kit / Flt-3 inhibitor) Agent: Pekidaruchinibu etc.), oncolytic virus (T-VEC, etc.), cancer vaccine (NeuVax, ITK-1, TG-4010, include Shupuraseru -T etc.) and the like. Immune antibody drugs target tumor cells or immune cells such as T cells infiltrating the tumor, and in order to exert an effect, the blood flow in the patient's tumor is improved, and a sufficient amount of T cells In addition, since it is important that the immunoantibody drug reaches the deep part of the tumor, the antitumor effect of the immunoantibody drug is further exhibited by combining with the natriuretic peptide receptor GC-A agonist as in the present invention. It is expected. In addition, for example, in the case of a cancer peptide vaccine which is a kind of cancer vaccine, it promotes the production of cytotoxic T cells by being phagocytosed by immune cells. It is expected that the anti-tumor effect of the vaccine will be exerted more.

The component (A) is preferably administered 1 day or more before the administration date of the component (B), more preferably 2 days or more, more preferably 3 days or more, still more preferably 5 days or more, more preferably 7 days ago. It is desirable to administer daily or a continuous preparation from the day before the day.

Another aspect of the present invention is based on the excellent effect that the anti-malignant tumor effect of the component (B) is enhanced as compared with the case of using the component (B) alone due to the vascular protective action of the component (A). And (B) an agent for enhancing the therapeutic effect of an antineoplastic agent, comprising (A) a natriuretic peptide receptor GC-A agonist. In addition, although the term of the pharmaceutical of this invention can refer to the item of the medicine of this invention, the kind of each component said here, its usage amount, and the usage method, for example, (A) It contains the natriuretic peptide receptor GC-A agonist, (B) An agent for enhancing the therapeutic effect of an antineoplastic agent (B), which is administered 5 days or more before the administration of an antineoplastic agent can be exemplified.

In the enhancer described above, as a preferable example, specifically, the maximum blood concentration of the component (A) is preferably 0.01 ng / mL to 1.6 ng / mL three days before the administration of the component (B). A potentiator characterized in that it is administered at a dose of about 0.1 ng / mL to 1.6 ng / mL, more preferably about 0.4 ng / mL to about 1.6 ng / mL. It is done.

Furthermore, from the viewpoint of the effect that the antineoplastic effect of the component (B) is enhanced as compared with the case of using the component (B) alone due to the vascular protective action of the component (A), the present invention also provides the following: A pharmaceutical composition is provided.
-Pharmaceutical composition for using together with (B) component which contains (A) component as an active ingredient.
-Pharmaceutical composition for using together with (A) component which contains (B) component as an active ingredient.
A medicine for a patient receiving treatment with the component (B) containing the component (A) as an active ingredient. A medicine for a patient receiving treatment with the ingredient (A) containing the component (B) as an active ingredient. Composition.
In addition, the term of the medicine of this invention can be referred for the kind of each component here, the usage-amount, usage method, and the objective.

The present invention is characterized by combining the components (A) and (B) described above. The PD-1 antibody that can be used as the component (B) has pulmonary fibrosis and idiopathic stroma as side effects. It is known to have pneumonia. However, since component (A) specifically acts on vascular endothelial cells and suppresses the production of various growth factors and various inflammatory cytokines from blood vessels, it becomes possible to reduce the occurrence of side effects due to component (B). Thus, it is presumed that it becomes possible to obtain a treatment or improvement effect for pulmonary fibrosis or idiopathic interstitial pneumonia. Therefore, the present invention also provides a pharmaceutical composition for use in the prevention or treatment of pulmonary fibrosis or interstitial pneumonia, which contains (A) a natriuretic peptide receptor GC-A agonist.

The pharmaceutical composition used for the prevention or treatment of pulmonary fibrosis or interstitial pneumonia only needs to contain the above-described component (A). For details of the component (A), For example, the component (A) can be administered usually for several hours to several days, preferably 1 to 14 days, more preferably about 3 to 7 days. In this case, the upper limit of the dose is, for example, a concentration of about 50 μg / kg / min (per day, about 72 mg / kg) or less can be appropriately employed, and about 5 μg / kg / min (per day, about 7. 2 mg / kg) or less, preferably about 0.5 μg / kg / min (per day, about 720 μg / kg) or less, more preferably about 0.2 μg / kg / min or less, Preferably it is about 0.1 μg / kg / min or less, and even more preferably about 0.05 μg / kg / min or less. The lower limit is usually about 0.0001 μg / kg / min (about 0.144 μg / kg per day) or more, preferably about 0.001 μg / kg / min (about 1.44 μg / kg per day). More preferably, it is about 0.01 μg / kg / min (about 14.4 μg / kg per day) or more.

In addition, although it does not specifically limit as target pulmonary fibrosis or interstitial pneumonia, the case where it is a side effect of the (B) component demonstrated by the term of the medicine of this invention is illustrated. Here, the component (B) is not particularly limited, but preferred examples include an inhibitor for at least one selected from PD-1, PD-L1, and PD-L2.

Hereinafter, the present invention will be described based on examples. However, the examples are provided for better understanding of the present invention, and the scope of the present invention is intended to be limited to these examples. It is not a thing.

In this example, first, experimental examples in which the protective action of blood vessels by a natriuretic peptide receptor GC-A agonist was examined are shown as Test Example 1 series. In all experiments, one-way analysis of variance and Tukey-Kramer's multiple comparison test were used for comparison of measured values between groups, and the significance level was set to less than 5%.

Test Example 1-1-1 ANP Tumor Vascular Protective Effect on Breast Cancer Mouse Orthotopic Transplant Model Seven-week-old female Balb / c mice (Japan SLC) were used as mice. The Osmotic pump used was ALZET (Cupertino, CA) MODEL 2001 (for 7 days administration). hANP (SEQ ID NO: 1) was prepared according to a known method.

4T1 breast cancer cells (Wako Pure Chemical Industries) were prepared to 1 × 10 ⁶ cells / 100 μL using RPMI-1640 of FBS free. This suspension was injected into the right mammary gland at 100 μL per mouse. One week later, the tumor was excised, and a 3 × 3 mm tumor piece was prepared from this tumor.
Next, 3 x 3 mm tumor pieces were orthotopically transplanted into the right mammary gland, one for each newly prepared mouse. On the 5th day after transplantation, the mice were randomly divided into 2 groups (control group, ANP group) (5-7 mice in each group), and the control group was treated with an osmotic pump filled with physiological saline in the ANP group. Then, an osmotic pump filled with hANP was implanted subcutaneously in the back of each mouse, and administration of hANP was started at a dose of 1.5 μg / kg / min, and the tumor was excised 7 days after transplantation.

The excised tumor sample was immersed in 4% formalin for 1 to 2 days, and then a paraffin section was prepared. After deparaffinization, immunostaining was performed. The primary antibody used for immunostaining (for vascular endothelial cell staining) was Rabbit anti-mouse CD31 (abcam, ab28364), and the secondary antibody was Alexa Fluor 488 goat anti-rabbit (abcam, A11034). Anti-actin, α-smooth muscle-Cy3 antibody (Sigma-Aldrich, C6198) was used as the primary antibody for αSMA (for wall cell staining). For nuclear staining, Vectashield hard set with DAPI (Vector Laboratories, H1500) was used. The fluorescent microscope was IX-81 (Olympus) and photographed (FIG. 1). In the photograph shown in FIG. 1, the “CD31” portion shows a state where vascular endothelial cells are stained, and the “αSMA” portion shows a state where wall cells are stained. In the “Merged” section, an image showing all the stained nuclei of blue cells in addition to vascular endothelial cells and mural cells is shown.

In general, normal (mature) blood vessels have a structure in which mural cells are properly lined around vascular endothelial cells (almost 100%), but from FIG. 1, mural cells are not observed in the control group. This shows that tumor blood vessels have an immature structure in which mural cells have fallen off. On the other hand, since the ANP group shows mural cells, it can be seen that ANP administration has a structure in which vascular endothelial cells in the tumor site are lined with mural cells, and ANP has a maturation action (protective action) of tumor blood vessels. It is suggested.

Here, the ratio (pericyte-coating index, index of blood vessel maturation) of anti-αSMA positive blood vessels in CD31 positive blood vessels is expressed by the following formula:
pericyte-coating index = (number of CD31 and αSMA double positive blood vessels) / CD31 positive blood vessels × 100
Measured and calculated according to Specifically, 10 blood vessels in the tumor area were randomly extracted per animal, and the measured and calculated values were averaged according to the above formula, and the results of calculating the average of each group are shown in FIG. FIG. 2 shows that the pericyte-coated index was significantly higher in the ANP group than in the control group, suggesting that the ANP administration exerted a tumor blood vessel maturation effect.

Test Example 1-1-2 Tumor Vascular Protective Action of ANP on Breast Cancer Mouse Orthotopic Transplant Model A breast cancer mouse orthotopic transplant model was prepared in the same manner as in Test Example 1-1-1, and the mouse was Randomly divided into 2 groups (control group, ANP group) (5-7 mice in each group), control group was filled with physiological pump Osmotic pump, and ANP group was filled with hANP filled Osmotic pump Each of the mice was implanted subcutaneously in the back of the mouse, and hANP was started to be administered at a dose of 1.5 μg / kg / min. Next, on the 7th day after transplantation, 10 mg / kg (about 300 μL) of cisplatin (CDDP) per mouse was administered to each group using cisplatin injection “Marco” manufactured by Nippon Kayaku Co., Ltd. The tumor was removed after a minute.

The excised tumor was measured for intracisternal cisplatin concentration using ICP-MS (inductively coupled plasma mass spectrometer) method, and the average value of each group was calculated. The results are shown in FIG. From FIG. 3, in the ANP group, the cisplatin concentration in the tumor was significantly higher than in the control group, and the blood vessels in the tumor were protected by the administration of ANP, and the drug arrival (cisplatin amount) was efficiently performed. I understand that.

Test Example 1-2-1 Tumor Vascular Protection Effect of ANP on Vascular Mice Orthotopic Transplantation Model In this test example, in order to show that ANP acts specifically on blood vessels, blood vessel-specific GC- A gene-modified mouse was used. For genetically modified mice, mice prepared as previously reported were used (Nojiri et al., PNAS 2015).

LLC lung cancer cells (Wako Pure Chemical Industries) were prepared to 5 × 10 ⁴ cells / 20 μL using PBS. The same amount (20 μL) of Matrigel (Corning) added to this suspension was injected into the right lower lung, 40 μL per mouse. One week later, the tumor was excised, and a 3 × 3 mm tumor piece was prepared from this tumor.
Next, 3 x 3 mm tumor pieces were transplanted into the right lung one by one in newly prepared mice, and tumors were excised 7 days after transplantation.

In the same manner as in Test Example 1-1-1, the vascular state in the tumor was examined by immunostaining. The results are shown in FIG. The wall cell lining ratio was also examined in the same manner. The results are shown in FIG. As a result, pericyte-coated index was significantly higher in vascular endothelium-specific EC-GCA-Tg (overexpression) mice than in the WT (wild type) group. From the above, it was shown that ANP acted specifically on blood vessels and exerted a maturation effect on tumor blood vessels. In vascular endothelium-specific EC-GCA-KO (knockout) mice, no significant difference was observed in pericyte-coated index compared to control mice (Flox / flox).

Test Example 1-2-2 Avascular blood vessel maturation effect of ANP on pulmonary cancer mouse orthotopic transplantation model In this test example, a blood vessel-specific GC-A gene-modified mouse was used as in Test Example 2-1. It was. As for other mice, male C57BL / 6 mice (Japan SLC) aged 8 to 10 weeks were used. The Osmotic pump used was ALZET (Cupertino, CA) MODEL 2002 (for 14 days administration). hANP (SEQ ID NO: 1) was prepared according to a known method.

A orthotopic transplantation model of lung cancer mice was prepared in the same manner as in Test Example 1-2-1, and one mouse was used for genetically modified mice on the 7th day after transplantation using Nippon Kayaku's cisplatin injection “Marco”. Ten mg / kg (about 300 μL) of cisplatin (CDDP) was administered via the tail vein, and the tumor was removed 5 minutes later. For C57BL / 6 mice, the mice were randomly divided into 2 groups (control group, ANP group) on the 5th day after transplantation (5-7 mice in each group), and physiological saline was given to the control group. Osmotic pump filled with Osmotic pump filled with hANP in the ANP group was implanted subcutaneously in the back of the mouse, and hANP was administered at a dose of 1.5 μg / kg / min. 7 days after transplantation In each group, 10 mg / kg (approximately 300 μL) of cisplatin (CDDP) was administered to each group using Nippon Kayaku's cisplatin injection “Marco”, and the tumor was removed 5 minutes later. .

For the excised tumor, the cisplatin concentration in the tumor was measured in the same manner as in Test Example 1-1-2, and the average value of each group was calculated. The results are shown in FIG. FIG. 6 shows that in the ANP group, the cisplatin concentration in the tumor was significantly higher than that in the control group, and the drug arrival (cisplatin amount) was efficiently performed by ANP administration. In addition, in the vascular endothelium-specific EC-GCA-Tg (overexpression) mouse, the intratumoral cisplatin concentration was significantly higher than that in the WT (wild type) group. From the above, it can be seen that ANP protects the blood vessels in the tumor and suppresses the collapse by acting specifically on the blood vessels.

Test Example 1-3 Effect of ANP on Cisplatin-Induced Bone Marrow Suppression Model 8-week-old male C57BL / 6 mice (Japan SLC) were used. The Osmotic pump used was ALZET (Cupertino, CA) MODEL 2002 (for 14 days administration). hANP (SEQ ID NO: 1) was prepared according to a known method, and cisplatin (CDDP) used was Nippon Kayaku's cisplatin injection “Marco”.

First, mice were randomly divided into 2 groups (control group, ANP group) (5-7 mice in each group), the control group was filled with osmotic pump filled with physiological saline, and the ANP group was filled with hANP. Each osmotic pump was previously implanted under the back of the mouse.
Next, one day before CDDP administration (Day-1), administration was started at a dose of 1.5 μg / kg / min for the ANP group. The next day, each group received CDDP at 16 mg / kg (approximately 480 μL) per mouse intraperitoneally, and weighed 6 mice on Day 0 (before CDDP administration), 2, 4, 8 and 14, respectively. After slaughtering and collecting blood from the femoral vein, bone marrow was also collected.

From the obtained blood, the white blood cell count, platelet count, and hemoglobin value were measured using a fully automatic blood cell counter “SELTAC α” MEK-6450 (Nihon Kohden). From the bone marrow, the total number of cells in the bone marrow, the number of living cells, and granulocyte macrophage colony forming units (GM-CFU) were measured using an assay kit from StemCell Technologies. The blood results are shown in FIG. 7, and the bone marrow results are shown in FIG.

In addition, in order to clarify the early mechanism after CDDP administration, blood was collected from the femoral vein of mice on Day 0 (before CDDP administration), 0.5, 1, and 2, and after serum preservation, serum G- The CSF concentration was measured using Mouse G-CSF Quantikine ELISA Kit (Cat. MCS00; R & D systems). The results are shown in FIG.

FIG. 7 shows that the white blood cell count in Day 2 and Day 4 was significantly higher in the ANP group than in the control group. FIG. 8 shows that the number of viable cells in the bone marrow and the GM-CFU value were significantly higher in Day 2, 4, and 8 in the ANP group than in the control group. Moreover, from FIG. 9, compared with the control group, the ANP group showed a higher tendency at Day 0.5, and the Day 1 was significantly higher.
From the above, it is considered that ANP exerts a reducing effect on bone marrow suppression, which is a side effect induced by an anticancer agent such as cisplatin, by increasing plasma G-CSF level.

Test Example 2 Combined Effect of ANP and Taxane Anticancer Agent on Breast Cancer Mouse Orthotopic Transplant Model A 7-week-old female Balb / c mouse (Japan SLC) was used as the mouse. The Osmotic pump used was ALZET (Cupertino, CA) MODEL 2004 (for 28-day administration). hANP (SEQ ID NO: 1) produced according to a known method was used as a representative taxane anticancer agent, docetaxel intravenous infusion 20 mg / 1 mL “NK” of Nippon Kayaku Co., Ltd.

4T1 breast cancer cells (Wako Pure Chemical Industries) were prepared to 1 × 10 ⁶ cells / 100 μL using RPMI-1640 of FBS free. This suspension was injected into the right mammary gland at 100 μL per mouse. One week later, the tumor was excised, and a 3 × 3 mm tumor piece was prepared from this tumor.
Next, 3 x 3 mm tumor pieces were orthotopically transplanted into the right mammary gland, one for each newly prepared mouse. On the 5th day after transplantation, the mice were randomly divided into 4 groups (control group, ANP group, docetaxel (DTX) group, combined use group) (6 mice for each group) and filled with the contents described in Table 1 The Osmotic pump was implanted subcutaneously in the back of the mouse, and hANP-filled one was set to a dose of 1.5 μg / kg / min and administration was started. Thereafter, on the seventh day after transplantation, physiological saline or DTX described in Table 1 was administered at about 100 μL tail vein per mouse.

Observation was continued for 4 weeks after the transplantation including the administration period, and the size of the transplanted tumor was measured every week, the tumor volume was determined by the following estimation formula, and the average value of each group was calculated. The results are shown in FIG.
Tumor volume (mm ³ ) = (π / 6) × d ³
d = average vertical and horizontal diameter (mm)

From FIG. 10, there was no particular difference between the control group and the ANP group. On the other hand, in the DTX group, tumor growth was significantly suppressed as compared with the control group and ANP group, but in the combination group, tumor growth was significantly suppressed as compared with the DTX group. From the above results, it was shown that the antitumor action (tumor growth inhibitory action) of DTX is enhanced by ANP administration.

Test Example 3 Examination of ANP Administration Period for Combined Effects of ANP and Platinum Anticancer Agent on Breast Cancer Mouse Orthotopic Transplant Model In this test example, a 7-week-old female Balb / c mouse was used. Moreover, Osmotic pump used ALZET MODEL1002 (for 14 days administration).
A control group was obtained by implanting an osmotic pump containing physiological saline under the back of a Balb / c mouse. Similarly, an ANP administration group was prepared in which an osmotic pump prepared to administer hANP at a dose of 0.5 μg / kg / min (ANP group) was implanted subcutaneously in mice.
For cisplatin (CDDP) administration, 10 mg / kg (about 300 μL) of CDDP per mouse was administered via the tail vein, and in the control group, the same amount of physiological saline was administered via the tail vein.

4T1 breast cancer cells were prepared using FBS-free RPMI-1640 so that 4T1 cells were 1 × 10 ⁶ cells / 100 μL. This suspension was injected into the right mammary gland at 100 μL per mouse. One week later, the tumor was removed and 5 × 5 mm strips were made from this tumor. For each newly prepared mouse, one 5 x 5 mm tumor piece was orthotopically transplanted into the right mammary gland. The mice were randomly divided into 6 groups (6 groups shown below), and an osmotic pump adjusted to the timing of ANP administration according to each group was implanted subcutaneously into the mice and administration was started. On the seventh day after transplantation, physiological saline or cisplatin 10 mg / kg was administered via the tail vein.
(Each group)
Control group: Osmotic pump filled with physiological saline was implanted on Day 0, and physiological saline was administered to the tail vein on Day 7.
vehicle + CDDP group: Osmotic pump filled with physiological saline is implanted on Day 0, and 10 mg / kg of CDDP is administered on the tail vein on Day 7
ANP daily administration + CDDP group: An osmotic pump filled with hANP at a dose of 0.5 μg / kg / min was implanted on Day 6, and 10 mg / kg CDDP was administered on Day 7 on the tail vein.
ANP 3 days + CDDP group: An osmotic pump filled with hANP at a dose of 0.5 μg / kg / min was implanted on Day 4, and 10 mg / kg CDDP was administered on Day 7 via the tail vein.
ANP 5 days + CDDP group: Osmotic pump filled with hANP at a dose of 0.5 μg / kg / min was implanted on Day 2 and 10 mg / kg CDDP was administered on Day 7 on the tail vein
ANP 7 days + CDDP group: Osmotic pump filled with hANP at a dose of 0.5 μg / kg / min was implanted on Day 0, and 10 mg / kg CDDP was administered on Day 7 on the tail vein

Continue to observe for 4 weeks after transplantation, including the administration period, measure the tumor size at the cell injection site every week, calculate the tumor volume in the same manner as in Test Example 2, and calculate the average value for each group did. The results are shown in FIG.

As shown in FIG. 11, tumor growth was significantly suppressed in the vehicle + CDDP group as compared with the control group. On the other hand, compared with the vehicle + CDDP group, the ANP 1 day administration + CDDP group and the ANP 3 day administration + CDDP group showed no significant difference in tumor growth suppression effect, but the ANP 5 day administration + CDDP group and ANP 7 day administration + CDDP group control + CDDP group The tumor growth inhibitory effect was significantly large. From the above results, it was shown that in order to enhance the antitumor action (tumor growth inhibitory action) of CDDP by ANP administration, the ANP administration period requires at least 5 days or more.

Test Example 4 Combined Effect of ANP and Anti-PD-1 Antibody on Breast Cancer Mouse Orthotopic Transplant Model In this test example, a 7-week-old female Balb / c mouse was used. The Osmotic pump used was ALZET MODEL 2004 (for 28-day administration).
Balb / c mice were implanted with an osmotic pump containing physiological saline in the dorsal skin, and were used as the vehicle group. Similarly, an ANP group was prepared in which an osmotic pump prepared to administer hANP at a dose of 0.5 μg / kg / min (ANP group) was implanted subcutaneously in mice.
As for administration of anti-PD-1 antibody, which is a typical immune checkpoint inhibitor, 20 or 10 mg / kg (total of 100 μL / injection was made using BioXCell anti-mouse PD-1 antibody. (Prepared using irrigation water) was intraperitoneally administered, and in the control group, anti-mouse IgG (BE0260, BioXCell) was intraperitoneally administered in the same amount (100 μL).

4T1 breast cancer cells (Wako Pure Chemical Industries) were prepared using RPMI-1640 of FBS free so that 4T1 cells became 1 × 10 ⁶ cells / 100 μl. This suspension was injected into the right mammary gland at 100 μl per mouse. One week later, the tumor was removed and 3 × 3 mm strips were made from this tumor. For each newly prepared mouse, one 3 x 3 mm tumor piece was orthotopic transplanted into the right mammary gland. On the same day as the transplantation, the mice were randomly divided into 4 groups (4 groups shown below), and an osmotic pump adjusted for administration according to each group was implanted subcutaneously into the mice as shown below. did. In addition, on days 7, 13, and 19 after transplantation, anti-mouse IgG or anti-PD-1 antibody adjusted to administration according to each group was intraperitoneally administered as follows.
(Each group)
Control group: Osmotic pump filled with physiological saline was implanted on Day 0, and anti-mouse IgG was administered intraperitoneally at 20 mg / kg on Day 7 and 10 mg / kg on Day 13 and 19 respectively.
ANP group: An Osmotic pump filled with hANP at a dose of 0.5 μg / kg / min was embedded in Day 0
vehicle + anti-PD-1 antibody group: Osmotic pump filled with physiological saline is implanted on Day 0, and anti-mouse PD-1 antibody is administered intraperitoneally at 20 mg / kg on Day 7 and 10 mg / kg on Day 13 and 19 respectively.
ANP + DTX group: An osmotic pump filled with hANP at a dose of 0.5 μg / kg / min was implanted on Day 0, and anti-mouse PD-1 antibody was 20 mg / kg on Day 7 and 10 mg / kg on Day 13 and 19 respectively. Intraperitoneal administration

The observation was continued for 4 weeks after the start of administration, and the tumor size at the cell injection site was measured every week, the tumor volume was calculated in the same manner as in Test Example 2, and the average value of each group was calculated. The results are shown in FIG.

As shown in FIG. 12, there was no particular difference between the control group and the ANP group. On the other hand, in the vehicle + anti-PD-1 antibody group, tumor growth was significantly suppressed as compared with the control group and ANP group. Furthermore, tumor growth was significantly suppressed in the ANP + anti-PD-1 antibody group as compared with the vehicle + anti-PD-1 antibody group. From the above results, it was shown that the antitumor action (tumor growth inhibitory action) of the anti-PD-1 antibody is enhanced by ANP administration.

Test Example 5-1 Effect of ANP on Pulmonary Fibrosis Mouse Model In this test example, 7-week-old male C57BL / 6N mice (Japan SLC) were used. The Osmotic pump used was ALZET (Cupertino, CA) MODEL1002 (for 14 days administration).
A control group was obtained by implanting an osmotic pump containing physiological saline under the back of C57BL / 6N mice. Similarly, an ANP group was prepared in which an osmotic pump prepared so that hANP was administered at a dose of 0.5 μg / kg / min (ANP group) was implanted subcutaneously in mice.

Regarding the administration of bleomycin, a typical pulmonary fibrosis inducer, 1 mg / kg (prepared with water for injection to give a total of 80 μL / animal) using 5 mg for bleo injection from Nippon Kayaku Co., Ltd. Was administered intratracheally, and in the control group, the same amount (80 μL) of physiological saline was administered intratracheally. After administration of bleomycin and physiological saline, the mice were sacrificed on the 21st day, mouse lungs were stretched and fixed with 4% paraformaldehyde (Wako Pure Chemical Industries), paraffin-embedded blocks were prepared, and Masson trichrome staining was performed. The stained specimen was photographed with a box type fluorescence imaging apparatus FSX100 (Olympus). The lung fibrosis area ratio was defined as fibrosis area / total lung area, and was automatically calculated with CellSens Dimension software version 1.6 (Olympus). The results are shown in FIG.
(Each group)
Control group: group in which physiological saline was administered intratracheally
Vehicle + bleomycin administration group: Osmotic pump filled with physiological saline was implanted, and bleomycin (1 mg / kg) was administered intratracheally 3 days later
ANP + bleomycin administration group: A group in which an osmotic pump filled with ANP at a dose of 0.5 μg / kg / min was implanted, and bleomycin (1 mg / kg) was administered intratracheally 3 days later

As shown in FIG. 13, the pulmonary fibrosis area that was not observed in the control group was significantly increased in the vehicle + bleomycin group, but was significantly suppressed by ANP administration.

Test Example 5-2 Lung Fibrosis Inhibitory Effect Using Tissue-Specific Transgenic (Tg) Mice In this test example, 12-week-old wild type mice, vascular endothelium-specific GC-A-Tg (Tie2-Cre-GC) -A-Tg) mice and fibroblast-specific GC-A-Tg (Periostin-Cre-GC-A-Tg) mice were used, and bleomycin was administered in the same manner as described above.

As before, bleomycin (1 mg / kg) was administered intratracheally to mice in each group, sacrificed on day 21, and mouse lungs were stretched and fixed with 4% paraformaldehyde to produce paraffin-embedded blocks Later, Masson trichrome staining was performed. The stained specimen was photographed with a box type fluorescence imaging apparatus FSX100 (Olympus). The pulmonary fibrosis area ratio was calculated in the same manner as in Test Example 5-1, and the pulmonary fibrosis area was expressed as the ratio of each group when the wild-type mouse was 1. The results are shown in FIG.
(Each group)
Wild-type mouse group: Bleomycin (1 mg / kg) administered intratracheally to wild-type mice Vascular endothelium-specific GC-A-Tg group: Bleomycin (1 mg / kg) to vascular endothelium-specific GC-A-Tg mice Intratracheally administered group Fibroblast-specific GC-A-Tg group: Fibroblast-specific GC-A-Tg mice administered bleomycin (1 mg / kg) intratracheally

As shown in FIG. 14, pulmonary fibrosis area was significantly suppressed in the vascular endothelium-specific GC-A-Tg mice compared to the wild-type mouse group, and fibroblast-specific GC-A-Tg mice. There was no significant suppression. From the above, it is suggested that ANP exerts an effect of suppressing pulmonary fibrosis via blood vessels.

The medicament of the present invention is useful as a medicament for treating malignant tumors having a powerful effect because it can effectively reach the tumor cells through the bloodstream.

Sequence number 1 of a sequence table is a polypeptide of human origin ANP.
Sequence number 2 of a sequence table is a polypeptide of rat origin ANP / mouse origin ANP.
Sequence number 3 of a sequence table is a polypeptide of human origin BNP.
Sequence number 4 of a sequence table is a polypeptide of porcine origin BNP.
Sequence number 5 of a sequence table is a polypeptide of rat origin BNP.
Sequence number 6 of a sequence table is a polypeptide of mouse-derived BNP.
Sequence number 7 of a sequence table is a polypeptide of the ring structure in ANP or BNP.

Claims (29)

1. (A) A therapeutic effect of (B) antineoplastic agent comprising natriuretic peptide receptor GC-A agonist and (B) administered at least 5 days before administration of the antineoplastic agent Enhancer.
2. (B) Three days before administration of the antineoplastic agent, (A) the natriuretic peptide receptor GC-A agonist is administered so that the maximum blood concentration is 0.01 ng / mL to 1.6 ng / mL. The enhancer according to claim 1, wherein
3. (B) The enhancement according to claim 1 or 2, wherein the antineoplastic agent is one or more selected from the group consisting of a platinum preparation, a compound having a microtubule inhibitory action, and a PD-1 pathway inhibitor. Agent.
4. 4. The enhancer according to claim 3, wherein the platinum preparation is cisplatin.
5. The enhancer according to any one of claims 1 to 4, wherein the (A) natriuretic peptide receptor GC-A agonist is an atrial natriuretic peptide or a brain natriuretic peptide.
6. Atrial natriuretic peptide
   (1) a peptide comprising the amino acid sequence set forth in SEQ ID NO: 1 or 2 in the sequence listing, and (2) 1 to several amino acids in the amino acid sequence set forth in SEQ ID NO: 1 or 2 in the sequence listing are substituted, deleted, 6. The enhancer according to claim 5, which is a peptide comprising an inserted and / or added sequence and having agonist activity for the natriuretic peptide receptor GC-A.
7. (A) A pharmaceutical comprising a combination of a natriuretic peptide receptor GC-A agonist and (B ′) a compound having a microtubule inhibitory action or a PD-1 pathway inhibitor.
8. The medicine according to claim 7, which is a combination drug.
9. The medicament according to claim 7, wherein (A) a natriuretic peptide receptor GC-A agonist and (B ') a compound having a microtubule inhibitory action or a PD-1 pathway inhibitor are used in combination.
10. 10. (A) A natriuretic peptide receptor GC-A agonist and (B ′) a compound having a microtubule inhibitory action or a PD-1 pathway inhibitor are administered simultaneously or sequentially. The pharmaceutical described.
11. 10. The (A) natriuretic peptide receptor GC-A agonist and (B ′) a compound having a microtubule inhibitory action or a PD-1 pathway inhibitor are administered separately. Medicine.
12. The medicament according to any one of claims 7 to 11, wherein (A) the natriuretic peptide receptor GC-A agonist is atrial natriuretic peptide or brain natriuretic peptide.
13. Atrial natriuretic peptide
    (1) a peptide comprising the amino acid sequence set forth in SEQ ID NO: 1 or 2 in the sequence listing, and (2) 1 to several amino acids in the amino acid sequence set forth in SEQ ID NO: 1 or 2 in the sequence listing are substituted, deleted, The medicament according to claim 12, which is selected from peptides having an inserted and / or added sequence and having agonist activity against the natriuretic peptide receptor GC-A.
14. The medicament according to any one of claims 7 to 13, wherein the compound having a microtubule inhibitory action is a taxane antineoplastic agent.
15. The medicament according to claim 14, wherein the taxane antineoplastic agent is docetaxel.
16. The medicament according to any one of claims 7 to 13, wherein the PD-1 pathway inhibitor is selected from inhibitors against at least one selected from PD-1, PD-L1, and PD-L2.
17. The medicament according to any one of claims 7 to 13, wherein the PD-1 pathway inhibitor is an antibody against PD-1 or PD-1 ligand or a nucleic acid encoding an antibody against PD-1 or PD-1 ligand.
18. The medicament according to any one of claims 7 to 17, which is used for treatment of malignant tumors or suppression of malignant transformation.
19. (A) An agent for enhancing the therapeutic effect of a malignant tumor of a compound having a microtubule inhibitory action or a PD-1 pathway inhibitor, which contains a natriuretic peptide receptor GC-A agonist.
20. (A) A pharmaceutical composition for use in combination with a compound having a microtubule inhibitory action or a PD-1 pathway inhibitor, which comprises a natriuretic peptide receptor GC-A agonist as an active ingredient.
21. (B ′) A pharmaceutical composition for use in combination with a natriuretic peptide receptor GC-A agonist, comprising a compound having a microtubule inhibitory action or a PD-1 pathway inhibitor as an active ingredient.
22. The pharmaceutical composition according to claim 20 or 21, which is used for treatment of malignant tumor or suppression of malignant transformation.
23. (A) A pharmaceutical composition for a patient who is treated with a compound having a microtubule inhibitory action or a PD-1 pathway inhibitor, comprising a natriuretic peptide receptor GC-A agonist as an active ingredient.
24. (B ′) A pharmaceutical composition for a patient undergoing treatment with a natriuretic peptide receptor GC-A agonist, comprising a compound having a microtubule inhibitory action or a PD-1 pathway inhibitor as an active ingredient.
25. A pharmaceutical composition containing a natriuretic peptide receptor GC-A agonist and used for the prevention or treatment of pulmonary fibrosis or interstitial pneumonia.
26. 26. The pharmaceutical composition according to claim 25, wherein the natriuretic peptide receptor GC-A agonist is atrial natriuretic peptide or brain natriuretic peptide.
27. Atrial natriuretic peptide
    (1) a peptide comprising the amino acid sequence set forth in SEQ ID NO: 1 or 2 in the sequence listing, and (2) 1 to several amino acids in the amino acid sequence set forth in SEQ ID NO: 1 or 2 in the sequence listing are substituted, deleted, 27. The pharmaceutical composition according to claim 26, which is a peptide comprising an inserted and / or added sequence and having agonistic activity against the natriuretic peptide receptor GC-A.
28. A method for preventing or treating pulmonary fibrosis or interstitial pneumonia, comprising administering a natriuretic peptide receptor GC-A agonist.
29. Natriuretic peptide receptor GC-A agonist for the prevention or treatment of pulmonary fibrosis or interstitial pneumonia.

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