JP2023136704A - Preventive and/or therapeutic medicine of cancer - Google Patents
Preventive and/or therapeutic medicine of cancer Download PDFInfo
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- JP2023136704A JP2023136704A JP2022042531A JP2022042531A JP2023136704A JP 2023136704 A JP2023136704 A JP 2023136704A JP 2022042531 A JP2022042531 A JP 2022042531A JP 2022042531 A JP2022042531 A JP 2022042531A JP 2023136704 A JP2023136704 A JP 2023136704A
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Abstract
Description
本発明は、癌の予防及び／又は治療薬に関する。より詳しくは、癌の予防及び／又は治療薬、薬剤、予防及び／又は治療薬、並びにクローディン－１４結合剤に関する。 TECHNICAL FIELD The present invention relates to a preventive and/or therapeutic drug for cancer. More specifically, the present invention relates to cancer preventive and/or therapeutic agents, drugs, preventive and/or therapeutic agents, and claudin-14 binding agents.
医療技術の進歩により癌の奏功率は向上しているが、良好な癌治療法は未開発である。その理由の一つとして、生体内の癌細胞は凝集塊を形成しており、その深部への抗癌剤の透過性が低いことが知られている。更に、凝集塊深部は常に低酸素・低栄養のストレス状態であり、これらが治療抵抗性の獲得、悪性化、再発の一因になっている。そのため、癌原遺伝子に作用する抗癌剤の開発だけでなく、凝集塊の抗癌剤透過性やストレス状態を改善する新しいタイプの薬剤の開発が期待されている。 Advances in medical technology have improved the response rate for cancer, but good cancer treatments have not yet been developed. One of the reasons for this is that cancer cells in vivo form aggregates, and it is known that anticancer drugs have low permeability into the deep part of the aggregates. Furthermore, the deep part of the aggregate is always in a stress state of low oxygen and malnutrition, which contributes to the acquisition of treatment resistance, malignant transformation, and recurrence. Therefore, not only the development of anticancer drugs that act on proto-oncogenes, but also the development of new types of drugs that improve the permeability of anticancer drugs and the stress state of aggregates are expected.
ここで、多くの固形癌組織において、クローディン（CLDN）サブタイプの異常発現が報告されている。CLDNは、上皮細胞や内皮細胞の密着結合部位に存在する膜タンパク質である。CLDNには、27種類のサブタイプが存在することが知られており、固形癌におけるCLDNサブタイプの異常発現は組織によって異なる。 Here, abnormal expression of claudin (CLDN) subtypes has been reported in many solid cancer tissues. CLDN is a membrane protein present at the tight junctions of epithelial and endothelial cells. It is known that there are 27 subtypes of CLDN, and the abnormal expression of CLDN subtypes in solid tumors varies depending on the tissue.
これまでに、本願発明者らの研究グループは、非特許文献１等に示すように、肺腺癌組織に細胞間接着分子のクローディン－２（CLDN2）が高発現し、CLDN2が細胞増殖の亢進や抗癌剤抵抗性の獲得に寄与することを発見した。更に、同研究グループは、特許文献１に示すように、CLDN2の発現低下作用を有する低分子化合物を同定した。 To date, the research group of the present inventors has found that the intercellular adhesion molecule claudin-2 (CLDN2) is highly expressed in lung adenocarcinoma tissues, and that CLDN2 inhibits cell proliferation. We discovered that it contributes to the upregulation and acquisition of anticancer drug resistance. Furthermore, as shown in Patent Document 1, the same research group identified a low-molecular-weight compound that has the effect of lowering the expression of CLDN2.
しかしながら、CLDNサブタイプに関する研究開発は未だ十分でない。また、前述の通り、凝集塊の抗癌剤透過性やストレス状態を改善する、新しいタイプの薬剤の開発が期待されているという実情がある。 However, research and development regarding CLDN subtypes is still insufficient. Furthermore, as mentioned above, there are expectations for the development of new types of drugs that improve the permeability of anticancer drugs and the stress state of aggregates.
このような実情のもと、本発明では、新しい作用機序に基づく癌の予防及び／又は治療薬などを提供することを主目的とする。 Under these circumstances, the main purpose of the present invention is to provide a preventive and/or therapeutic drug for cancer based on a new mechanism of action.
すなわち、本発明では、まず、ベルパタスビルを含有する、癌の予防及び／又は治療薬を提供する。
また、本発明では、ベルパタスビルを含有する、癌細胞増殖能の低下剤、癌細胞遊走能の低下剤、癌細胞低酸素状態の改善剤、細胞間バリア機能の低下剤、及び抗癌剤感受性の亢進剤からなる群のいずれか１種以上の薬剤も提供する。
更に、本発明では、前記癌の予防及び／又は治療薬、又は前記薬剤を含有し、抗癌剤と併用される、癌補助療法薬も提供する。
また、前記癌の予防及び／又は治療薬、又は前記薬剤は、クローディン－１４（CLDN14）の発現を認める癌の予防及び／又は治療に用いられてもよい。
更に、前記癌の予防及び／又は治療薬、又は前記薬剤は、大腸癌、胃癌、又は肝癌の、予防及び／又は治療に用いられてもよい。
また、本発明では、ベルパタスビルを含有する、クローディン－１４の発現がその原因となる又はその病態を形成する疾患に対する予防及び／又は治療薬も提供する。
更に、本発明では、ベルパタスビルを含有する、クローディン－１４結合剤も提供する。
That is, the present invention first provides a cancer preventive and/or therapeutic agent containing velpatasvir.
The present invention also provides an agent for reducing cancer cell proliferation ability, an agent for reducing cancer cell migration ability, an agent for improving cancer cell hypoxia, an agent for reducing intercellular barrier function, and an agent for enhancing anticancer drug sensitivity, which contain velpatasvir. Also provided are any one or more agents of the group consisting of:
Furthermore, the present invention also provides a prophylactic and/or therapeutic agent for cancer, or an auxiliary cancer therapeutic agent containing the aforementioned agent and used in combination with an anticancer agent.
Further, the cancer preventive and/or therapeutic agent or the drug may be used for the prevention and/or treatment of cancer in which claudin-14 (CLDN14) is expressed.
Furthermore, the cancer preventive and/or therapeutic agent or the drug may be used for the prevention and/or treatment of colon cancer, stomach cancer, or liver cancer.
The present invention also provides a prophylactic and/or therapeutic agent containing velpatasvir for diseases caused by or forming the pathological condition of claudin-14 expression.
Additionally, the present invention also provides claudin-14 binding agents containing velpatasvir.
本発明によれば、新しい作用機序に基づく癌の予防及び／又は治療薬などを提供することができる。
なお、ここに記載された効果は、必ずしも限定されるものではなく、本明細書中に記載されたいずれかの効果であってもよい。
According to the present invention, it is possible to provide a cancer preventive and/or therapeutic agent based on a new mechanism of action.
Note that the effects described here are not necessarily limited, and may be any of the effects described in this specification.
以下、本発明を実施するための好適な形態について説明する。
以下に説明する実施形態は、本発明の代表的な実施形態の一例を示したものであり、これにより本発明の範囲が狭く解釈されることはない。
Hereinafter, preferred embodiments for carrying out the present invention will be described.
The embodiment described below shows an example of a typical embodiment of the present invention, and the scope of the present invention should not be interpreted narrowly thereby.
１．癌の予防及び／又は治療薬
本発明に係る癌の予防及び／又は治療薬は、ベルパタスビルを少なくとも有効成分として含有する。
ベルパタスビルは、下記化学式（１）に示す化合物である。従来、Ｃ型肝炎ウイルス感染症の治療に用いられている。
1. Cancer preventive and/or therapeutic drug The cancer preventive and/or therapeutic drug according to the present invention contains velpatasvir as at least an active ingredient.
Velpatasvir is a compound represented by the following chemical formula (1). Conventionally, it has been used to treat hepatitis C virus infection.
ここで、CLDN14は、細胞間のタイトジャンクション（細胞間密着結合）の形成に関わるクローディンファミリータンパク質の一つである。従来、CLDNにはいくつかのサブタイプ（例えば、CLDN1、CLDN2、CLDN3、CLDN4等）が存在することが知られているが、本願発明者らの研究グループは、特に大腸癌組織において、CLDN14の発現量が増加していることを見出し、細胞増殖、移動能の亢進や抗癌剤耐性化に寄与することを見出した。したがって、CLD14が大腸癌の新たな治療標的になると考えられたため、CLDN14の発現低下作用を有する化合物を探索したところ、ベルパタスビルがCLDN14に対して高い選択性乃至特異性を示すことを見出した。したがって、ベルパタスビルは、他のファミリーメンバーよりもCLDN14に対して特異的乃至優先的に結合し、CLDN14選択的な作用を奏する。 Here, CLDN14 is one of the claudin family proteins involved in the formation of tight junctions between cells. Conventionally, it has been known that there are several subtypes of CLDN (e.g., CLDN1, CLDN2, CLDN3, CLDN4, etc.), but the research group of the present inventors has discovered that CLDN14 is particularly effective in colorectal cancer tissues. It was found that the expression level was increased, and it was found that it contributes to enhancement of cell proliferation and migration ability and resistance to anticancer drugs. Therefore, since CLD14 was thought to be a new therapeutic target for colorectal cancer, we searched for compounds that have the effect of reducing CLDN14 expression and found that velpatasvir exhibits high selectivity or specificity for CLDN14. Therefore, velpatasvir binds specifically or preferentially to CLDN14 over other family members and exerts a CLDN14-selective action.
CLDN14には、4つの膜貫通ドメインが存在し、カルボキシ末端とアミノ末端が、細胞質側に存在する。2つの細胞外ループのうち、カルボキシ側の第2細胞外ループ（145～159番目のアミノ酸）がCLDN同士の結合に重要であると考えられている。ここで、本願発明者らの研究グループは、ベルパタスビルがCLDN14の第2細胞外ループに直接結合することを見出した。したがって、この結合特性によって、細胞間のタイトジャンクションに分布するCLDN14の発現（存在量）を低下させ、これにより、癌細胞増殖能の低下、癌細胞遊走能の低下、癌細胞低酸素状態の改善、細胞間バリア機能の低下などの作用効果が生じ、ひいては、癌細胞（典型的には、細胞凝集塊を構成している癌細胞）の悪性化を抑制するという特有の作用効果を発揮する。 CLDN14 has four transmembrane domains, with the carboxy and amino termini located on the cytoplasmic side. Of the two extracellular loops, the second extracellular loop on the carboxy side (amino acids 145 to 159) is thought to be important for binding between CLDNs. Here, the research group of the present inventors discovered that velpatasvir directly binds to the second extracellular loop of CLDN14. Therefore, this binding property reduces the expression (abundance) of CLDN14 distributed in tight junctions between cells, thereby reducing cancer cell proliferation ability, reducing cancer cell migration ability, and improving cancer cell hypoxia. This produces effects such as a reduction in intercellular barrier function, and in turn exerts the unique effect of suppressing malignant transformation of cancer cells (typically, cancer cells forming cell aggregates).
ベルパタスビルは、従来公知の合成法により調製することができる。また、市販のものを用いてもよい。ベルパタスビル自体は、上記化学式（１）に示す通り、低分子化合物であり、且つ、既承認薬であることからも、比較的安価に製造できるという利点を有する。そのため、医療費の削減にも貢献できる。 Velpatasvir can be prepared by conventionally known synthetic methods. Alternatively, commercially available products may be used. Velpatasvir itself is a low-molecular-weight compound as shown in the above chemical formula (1) and is an approved drug, so it has the advantage of being relatively inexpensive to produce. Therefore, it can also contribute to reducing medical costs.
なお、本発明において、「癌」とは、広義に解釈され、「悪性腫瘍」と互換的に使用される。また、病理学的に診断が確定される前の段階、すなわち、腫瘍としての良性、悪性のどちらかが確定される前には、良性腫瘍、良性悪性境界病変、悪性腫瘍を総括的に含む場合もあり得る。一般的に、癌はその発生の母体となった臓器の名、或いは発生母組織の名で呼ばれ、例えば、舌癌、歯肉癌、咽頭癌、上顎癌、喉頭癌、唾液腺癌、食道癌、胃癌、小腸癌、大腸癌、直腸癌、肝臓癌、胆道癌、胆嚢癌、膵臓癌、肺癌、乳癌、甲状腺癌、副腎癌、脳下垂体腫瘍、松果体腫瘍、子宮癌、卵巣癌、膣癌、膀胱癌、腎臓癌、前立腺癌、尿路上皮癌、網膜芽細胞腫、結膜癌、神経芽腫、神経膠腫（グリオーマ）、神経膠芽腫（グリオブラストーマ）、皮膚癌、髄芽種、白血病、悪性リンパ腫、睾丸腫瘍、骨肉腫、横紋筋肉腫、平滑筋肉腫、血管肉腫、脂肪肉腫、軟骨肉腫、ユーイング肉腫等が挙げられる。そして、発生臓器の部位の特徴によって、上・中・下咽頭癌、上部・中部・下部食道癌、胃噴門癌、胃幽門癌、子宮頚癌、子宮体癌等に細分類されているが、これらは限定的ではなく、本発明の「癌」としての記載に含まれ得る。 In the present invention, "cancer" is interpreted in a broad sense and is used interchangeably with "malignant tumor." In addition, at the stage before the pathological diagnosis is confirmed, that is, before it is confirmed whether the tumor is benign or malignant, cases that include benign tumors, benign-malignant borderline lesions, and malignant tumors in general It is also possible. Generally, cancer is called by the name of the organ or tissue in which it occurs, such as tongue cancer, gingival cancer, pharyngeal cancer, maxillary cancer, laryngeal cancer, salivary gland cancer, esophageal cancer, Stomach cancer, small intestine cancer, colon cancer, rectal cancer, liver cancer, biliary tract cancer, gallbladder cancer, pancreatic cancer, lung cancer, breast cancer, thyroid cancer, adrenal gland cancer, pituitary gland tumor, pineal gland tumor, uterine cancer, ovarian cancer, vagina Cancer, bladder cancer, kidney cancer, prostate cancer, urothelial cancer, retinoblastoma, conjunctival cancer, neuroblastoma, glioma, glioblastoma, skin cancer, medulla bud species, leukemia, malignant lymphoma, testicular tumor, osteosarcoma, rhabdomyosarcoma, leiomyosarcoma, angiosarcoma, liposarcoma, chondrosarcoma, Ewing's sarcoma, and the like. Depending on the characteristics of the organ where it occurs, it is subdivided into upper, middle, and hypopharyngeal cancer, upper, middle, and lower esophageal cancer, gastric cardia cancer, gastric pylorus cancer, cervical cancer, and endometrial cancer. These are not limiting and may be included in the description of "cancer" in the present invention.
本発明に係る癌の予防及び／又は治療薬は、これらの中でも特に、CLDN14の発現を認める癌の予防及び／又は治療に用いられる。なお、本発明において、「予防」とは、対象における症状又は疾患の発症（再発も含む。）の防止若しくは遅延、又は対象における症状又は疾患の発症の危険性の低下等の意味も含む。また、「治療」とは、対象における症状又は随伴症状の緩和（軽症化）、症状悪化の防止若しくは遅延等の意味を含む。 The cancer prevention and/or treatment agent according to the present invention is particularly used for the prevention and/or treatment of cancers in which CLDN14 is expressed. In addition, in the present invention, "prevention" includes the meaning of preventing or delaying the onset (including recurrence) of a symptom or disease in a subject, or reducing the risk of onset of a symptom or disease in a subject. Moreover, "treatment" includes the meaning of alleviation (alleviation) of symptoms or accompanying symptoms in a subject, prevention or delay of worsening of symptoms, etc.
本発明に係る癌の予防及び／又は治療薬は、好ましくは、CLDN14の高発現を認める癌の予防及び／又は治療に用いられる。なお、本発明において、「高発現」とは、CLDN14の発現量が対照群と比較して多いことを意味する。CLDN14の高発現を認める癌としては、これまでに、大腸癌、胃癌、又は肝癌が確認されている。したがって、本発明に係る癌の予防及び／又は治療薬は、これらの癌の予防及び／又は治療に用いられることが好ましい。 The cancer prevention and/or treatment agent according to the present invention is preferably used for the prevention and/or treatment of cancers in which CLDN14 is highly expressed. In the present invention, "high expression" means that the expression level of CLDN14 is higher than that of the control group. Cancers that exhibit high expression of CLDN14 have so far been confirmed to include colon cancer, gastric cancer, and liver cancer. Therefore, the cancer preventive and/or therapeutic agent according to the present invention is preferably used for the prevention and/or treatment of these cancers.
本発明に係る癌の予防及び／又は治療薬は、有効成分であるベルパタスビルのみからなるものであってもよく、該有効成分とそれ以外の任意の成分とを配合した組成物であってもよい。 The cancer preventive and/or therapeutic drug according to the present invention may consist only of the active ingredient velpatasvir, or may be a composition containing the active ingredient and any other ingredients. .
本発明に係る癌の予防及び／又は治療薬の製剤化は、従来公知の方法により行うことができる。製剤化する場合には、例えば、製剤上許容され得る他の成分（例えば、担体、賦形剤、崩壊剤、緩衝剤、乳化剤、懸濁剤、無痛化剤、安定剤、保存剤、防腐剤、界面活性剤、滑沢剤、稀釈剤、被覆剤、糖衣剤、矯味矯臭剤、乳化・可溶化・分散剤、pH調製剤、等張剤、可溶化剤、香料、着色剤、溶解補助剤、生理食塩水など）等を含有させることができる。 The cancer preventive and/or therapeutic agent according to the present invention can be formulated by conventionally known methods. When formulating, for example, other pharmaceutically acceptable ingredients (e.g., carriers, excipients, disintegrants, buffers, emulsifiers, suspending agents, soothing agents, stabilizers, preservatives, preservatives) , surfactants, lubricants, diluents, coating agents, sugar coating agents, flavoring agents, emulsifying/solubilizing/dispersing agents, pH adjusters, isotonic agents, solubilizing agents, fragrances, coloring agents, solubilizing agents , physiological saline, etc.).
本発明に係る癌の予防及び／又は治療薬を製剤化する場合の剤形も、特に限定されない。剤形としては、例えば、錠剤、散剤、細粒剤、顆粒剤、カプセル剤、シロップ剤、液剤、懸濁剤、乳剤、ゼリー剤、注射剤、外用剤、吸入剤、点鼻剤、点眼剤、座剤等が挙げられる。 The dosage form for formulating the cancer preventive and/or therapeutic agent according to the present invention is also not particularly limited. Examples of dosage forms include tablets, powders, fine granules, granules, capsules, syrups, solutions, suspensions, emulsions, jellies, injections, external preparations, inhalants, nasal drops, and eye drops. , suppositories, etc.
本発明に係る癌の予防及び／又は治療薬には、本発明の効果が奏されるために必要な量（すなわち、治療上有効量）の有効成分が含有される。本発明に係る癌の予防及び／又は治療薬中の有効量は、一般に剤形によって異なるが、所望の投与量を達成できるような有効量（例えば０．０１重量％～約１００重量％の範囲内など）を適宜設定する。また、対象は、通常ヒトであるが、ヒト以外の哺乳動物、例えばイヌ、ネコ等のペット動物、ウシ、ヒツジ、ブタ、ヤギ等の家畜、マウス、ラット、ウサギ、モルモット、ハムスター、サル等の実験動物も含む。 The prophylactic and/or therapeutic agent for cancer according to the present invention contains the active ingredient in an amount (ie, a therapeutically effective amount) necessary for achieving the effects of the present invention. The effective amount in the cancer preventive and/or therapeutic drug according to the present invention generally varies depending on the dosage form, but is an effective amount that can achieve the desired dosage (for example, in the range of 0.01% by weight to about 100% by weight). ) as appropriate. In addition, although the target is usually a human, it may also include non-human mammals, such as pet animals such as dogs and cats, livestock such as cows, sheep, pigs, and goats, mice, rats, rabbits, guinea pigs, hamsters, and monkeys. Also includes laboratory animals.
本発明に係る癌の予防及び／又は治療薬は、その剤形に応じて、経口投与又は非経口投与（例えば、静脈内、動脈内、皮下、皮内、筋肉内、又は腹腔内注射、経皮、経鼻、経粘膜など）によって対象に適用される。なお、これらの投与経路は互いに排他的なものではなく、任意に選択される二つ以上を併用することもできる。また、全身投与によらず、局所投与することにしてもよく、ドラッグデリバリーシステム（ＤＤＳ）などを利用してもよい。 The cancer preventive and/or therapeutic agent according to the present invention can be administered orally or parenterally (e.g., intravenously, intraarterially, subcutaneously, intradermally, intramuscularly, or intraperitoneally), depending on its dosage form. It is applied to the target by skin, nasal, transmucosal, etc.). Note that these administration routes are not mutually exclusive, and two or more arbitrarily selected routes can also be used in combination. Furthermore, instead of systemic administration, local administration may be used, and a drug delivery system (DDS) or the like may be used.
２．薬剤
本発明に係る薬剤は、ベルパタスビルを少なくとも有効成分として含有し、癌細胞増殖能の低下剤、癌細胞遊走能の低下剤、癌細胞低酸素状態の改善剤、細胞間バリア機能の低下剤、及び抗癌剤感受性の亢進剤からなる群のいずれか１種以上からなる。
2. Drug The drug according to the present invention contains velpatasvir as at least an active ingredient, an agent for reducing cancer cell proliferation ability, an agent for reducing cancer cell migration ability, an agent for improving cancer cell hypoxia, an agent for reducing intercellular barrier function, and an anticancer drug sensitivity enhancer.
前述の通り、ベルパタスビルは、CLDN14に直接結合してその発現（存在量）を低下させる。したがって、癌細胞（典型的には、細胞凝集塊を構成している癌細胞）に対してベルパタスビルを作用させると、細胞間タイトジャンクションでのCLDN14の発現が低下し、癌細胞増殖能の低下、癌細胞遊走能の低下、癌細胞低酸素状態の改善、細胞間バリア機能の低下などの作用効果が生じ、癌細胞の悪性化が抑制されるとともに、癌細胞の抗癌剤感受性が亢進する。 As mentioned above, velpatasvir directly binds to CLDN14 and reduces its expression (abundance). Therefore, when velpatasvir acts on cancer cells (typically cancer cells constituting cell aggregates), the expression of CLDN14 at intercellular tight junctions decreases, leading to a decrease in cancer cell proliferation ability, Effects such as a reduction in cancer cell migration ability, improvement in cancer cell hypoxia, and reduction in intercellular barrier function are produced, suppressing malignant transformation of cancer cells and increasing sensitivity of cancer cells to anticancer drugs.
従来、癌薬物療法において、治療抵抗性の獲得が大きな問題の一つになっていた。その原因としては、未だ不明な点が多いが、近年、細胞凝集塊が治療抵抗性に関与することが明らかになってきた。しかしながら、多くの抗癌剤は、凝集塊の深部に作用することが困難であり、深部に残存する癌細胞が再発にも関係すると考えられる。そのため、凝集塊深部への抗癌剤透過性を亢進させる補助療法剤の開発により、既存の抗癌剤を含め、今後開発される抗癌剤の治療効果の向上が期待できる。 Acquisition of therapeutic resistance has traditionally been one of the major problems in cancer drug therapy. Although many aspects of the cause are still unclear, in recent years it has become clear that cell aggregates are involved in treatment resistance. However, it is difficult for many anticancer drugs to act deep within the aggregate, and cancer cells remaining deep inside are thought to be involved in recurrence. Therefore, the development of adjunctive therapeutic agents that enhance the permeability of anticancer drugs deep into the aggregates can be expected to improve the therapeutic effects of anticancer drugs that will be developed in the future, including existing anticancer drugs.
このような実情のもと、本発明では、前述したベルパタスビルに特有の作用効果を利用した用途として、癌細胞増殖能の低下剤、癌細胞遊走能の低下剤、癌細胞低酸素状態の改善剤、細胞間バリア機能の低下剤、及び抗癌剤感受性の亢進剤からなる群のいずれか１種以上である薬剤も提供する。 Under these circumstances, the present invention provides an agent for reducing the ability of cancer cells to proliferate, an agent for reducing the migration ability of cancer cells, and an agent for improving the hypoxic state of cancer cells, as uses that utilize the above-mentioned effects specific to velpatasvir. , an agent for reducing intercellular barrier function, and an agent for enhancing anticancer drug sensitivity.
本発明に係る薬剤は、抗癌剤（本発明に係る癌の予防及び／又は治療薬を除く。）と併用すれば、抗癌剤の薬効が高められ、予防及び／又は治療効果、乃至治療成績の向上が期待できる。すなわち、本発明に係る薬剤は、癌補助療法薬の有効成分として有用であり、抗癌剤とともに、癌の予防及び／又は治療に適用される。なお、本発明において、「抗癌剤」とは、標的の疾病乃至病態である、癌に対する予防及び／又は治療効果を示す薬剤のことを意味する。 When the drug according to the present invention is used in combination with an anticancer drug (excluding the cancer prophylactic and/or therapeutic drug according to the present invention), the efficacy of the anticancer drug is enhanced, and the preventive and/or therapeutic effects and treatment results are improved. You can expect it. That is, the drug according to the present invention is useful as an active ingredient of a cancer auxiliary therapy drug, and is applied to the prevention and/or treatment of cancer together with an anticancer drug. In the present invention, the term "anticancer drug" refers to a drug that exhibits preventive and/or therapeutic effects on cancer, which is the target disease or pathological condition.
本発明では、癌治療において、抗癌剤と併用される（すなわち、抗癌剤の投与に際し、補助的に用いられる。）という典型的な使用態様を表すために、「癌補助療法薬」と呼称しているが、本発明に係る薬剤の有効成分であるベルパタスビルは、前述の通り、それ自体で癌細胞の悪性化を抑制するという作用効果をも発揮する。 In the present invention, the term "adjuvant cancer therapy drug" is used to represent the typical usage mode of being used in combination with an anticancer drug (i.e., used as an adjunct to the administration of an anticancer drug) in cancer treatment. However, as mentioned above, velpatasvir, which is the active ingredient of the drug according to the present invention, also exhibits the effect of suppressing malignant transformation of cancer cells by itself.
本発明に係る薬剤は、既存の抗癌剤や今後開発される抗癌剤といった様々な抗癌剤の薬効を高めることに利用できる点でその有用性は高い。一方で、本発明に係る薬剤によれば、抗癌剤が効きにくい又は効かない、所謂、治療抵抗性の癌に対する有望な治療戦略が提供されることは、臨床上極めて重要且つ有意義である。また、本発明に係る薬剤と抗癌剤との併用は、癌の根絶をも可能にし得るものであり、その価値及び意義は大きい。 The drug according to the present invention is highly useful in that it can be used to enhance the efficacy of various anticancer drugs, including existing anticancer drugs and anticancer drugs to be developed in the future. On the other hand, it is clinically extremely important and meaningful that the drug according to the present invention provides a promising therapeutic strategy for so-called treatment-resistant cancers that are difficult to respond to or are not effective with anticancer drugs. Furthermore, the combined use of the drug according to the present invention and an anticancer drug can also eradicate cancer, which is of great value and significance.
本発明に係る薬剤は、前述した癌の中でも特に、CLDN14の発現を認める癌の予防及び／又は治療に用いられる。好ましくは、CLDN14の高発現を認める癌の予防及び／又は治療に用いられる。CLDN14の高発現を認める癌としては、前述の通り、大腸癌、胃癌、又は肝癌が確認されている。本発明に係る薬剤は、これらの癌の予防及び／又は治療に用いられることが好ましい。 The drug according to the present invention is used for the prevention and/or treatment of cancers in which CLDN14 is expressed, especially among the aforementioned cancers. Preferably, it is used for the prevention and/or treatment of cancers in which CLDN14 is highly expressed. As mentioned above, colon cancer, gastric cancer, and liver cancer have been confirmed as cancers that exhibit high expression of CLDN14. The drug according to the present invention is preferably used for the prevention and/or treatment of these cancers.
本発明に係る薬剤は、有効成分であるベルパタスビルのみからなるものであってもよく、該有効成分とそれ以外の任意の成分（抗癌剤と併用する場合は、抗癌剤を含む。）とを配合した組成物であってもよい。 The drug according to the present invention may consist only of the active ingredient velpatasvir, or it may be a composition containing the active ingredient and any other ingredients (including the anticancer drug when used in combination with an anticancer drug). It may be a thing.
本発明に係る薬剤の製剤化は、従来公知の方法により行うことができる。製剤化する場合には、例えば、前述した製剤上許容される他の成分などを含有させることができる。本発明に係る薬剤を製剤化する場合の剤形も、本発明に係る癌の予防及び／又は治療薬と同様、特に限定されない。また、抗癌剤と併用する場合は、抗癌剤との合剤としてもよい。 The drug according to the present invention can be formulated by conventionally known methods. When formulating, for example, other pharmaceutically acceptable ingredients as described above may be included. The dosage form for formulating the drug according to the present invention is not particularly limited, as is the case with the cancer preventive and/or therapeutic drug according to the present invention. Furthermore, when used in combination with an anticancer drug, it may be used as a combination drug with the anticancer drug.
本発明に係る薬剤は、抗癌剤と併用すると、前述の通り、治療成績の向上などが期待できる。なお、本発明において、「治療成績の向上」には、治療効果の増大、奏功率乃至有効率の向上、副作用の低減乃至回避等の概念を含む。 When the drug according to the present invention is used in combination with an anticancer drug, improvement in therapeutic results can be expected, as described above. In the present invention, "improving therapeutic results" includes concepts such as increasing therapeutic efficacy, improving response rate or effectiveness rate, and reducing or avoiding side effects.
併用される抗癌剤は、特に限定されない。抗癌剤としては、例えば、シスプラチン、ネダプラチン、オキサリプラチン、カルボプラチン等のプラチナ製剤；シクロホスファミド、イホスファミド、ニトロソウレア、ダカルバジン、テモゾロミド、ニムスチン、ブスルファン、メルファラン、チオテパ、プロカルバジン、ラニムスチン等のアルキル化剤；エノシタビン、カルモフール、カペシタビン、テガフール、テガフール・ウラシル、テガフール・ギメラシル・オテラシルカリウム、ゲムシタビン、シタラビン、シタラビンオクホスファート、ネララビン、フルオロウラシル、フルダラビン、ペメトレキセド、ペントスタチン、メトトレキサート、クラドリビン、ドキシフルリジン、ヒドロキシカルバミド、メルカプトプリン等の代謝拮抗剤；マイトマイシンＣ、ドキソルビシン、エピルビシン、ダウノルビシン、ブレオマイシン、アクチノマイシンＤ、アクラルビシン、イダルビシン、ピラルビシン、ペプロマイシン、ミトキサントロン、アムルビシン、ジノスタチンスチマラマー等の抗腫瘍性抗生物質；ビンブラスチン、ビンクリスチン、ビンデシン等の微小管重合阻害剤；パクリタキセル、ドセタキセル等の微小管脱重合阻害剤；イリノテカン、ノギテカン、エトポシド、ソブゾキサン等のトポイソメラーゼ阻害剤；リツキシマブ（Rituxan（登録商標））、トラスツズマブ（Herceptin（登録商標））、アレムツズマブ（Campath（登録商標））、セツキシマブ（Erbitux（登録商標））、パニツムマブ（Vectibix（登録商標））、オファツムマブ（Arzerra（登録商標））、デノスマブ（Ranmark（登録商標））、イピリムマブ（Yervoy（登録商標））、モガムリズマブ（Poteligeo（登録商標））、ペルツズマブ（Perjeta（登録商標））、オビヌツズマブ（Gazyva（登録商標））、ラムシルマブ（Cyramza（登録商標））、ニボルマブ（Opdivo（登録商標））、ペムブロリズマブ（Keytruda（登録商標））、ブリナツモマブ（Blincyto（登録商標））、ジヌツキシマブ（Unituxin（登録商標））、ダラツムマブ（Darzalex（登録商標））、ネシツムマブ（Portrazza（登録商標））、エロツズマブ（Empliciti（登録商標））等の抗体医薬；ゲムツズマブ オゾガマイシン（Mylotarg（登録商標））、ブレンツキシマブ ベドチン（Adcetris（登録商標））、トラスツズマブ エムタンシン（Kadcyla（登録商標））、イノツズマブ オゾガマイシン（BESPONSA（登録商標））等の抗体薬物複合体（ＡＤＣ）；等が挙げられる。また、抗癌剤を、２種以上併用することも可能である。抗癌剤の投与量は、それを単独で使用する場合の使用量（すなわち、通常の使用量）に準ずるが、本発明に係る薬剤との併用により抗癌剤の薬効の増大が期待できることから、通常の投与量よりも低い投与量に適宜設定してもよい。なお、当業者であれば、対象の病状、年齢、性別、体重等を考慮し、「通常の使用量」を適宜設定することができる。 The anticancer agent used in combination is not particularly limited. Examples of anticancer drugs include platinum preparations such as cisplatin, nedaplatin, oxaliplatin, and carboplatin; alkylating agents such as cyclophosphamide, ifosfamide, nitrosourea, dacarbazine, temozolomide, nimustine, busulfan, melphalan, thiotepa, procarbazine, and ranimustine. ; Enocitabine, carmofur, capecitabine, tegafur, tegafur uracil, tegafur gimeracil oteracil potassium, gemcitabine, cytarabine, cytarabine ocphosphate, nelarabine, fluorouracil, fludarabine, pemetrexed, pentostatin, methotrexate, cladribine, doxifluridine, hydroxycarbamide, Antimetabolites such as mercaptopurine; antitumor antibiotics such as mitomycin C, doxorubicin, epirubicin, daunorubicin, bleomycin, actinomycin D, aclarubicin, idarubicin, pirarubicin, peplomycin, mitoxantrone, amrubicin, dinostatin stimaramer; Microtubule polymerization inhibitors such as vinblastine, vincristine, and vindesine; microtubule depolymerization inhibitors such as paclitaxel and docetaxel; topoisomerase inhibitors such as irinotecan, toptecan, etoposide, and sobuzoxan; rituximab (Rituxan®), trastuzumab (Herceptin) (R)), alemtuzumab (Campath(R)), cetuximab (Erbitux(R)), panitumumab (Vectibix(R)), ofatumumab (Arzerra(R)), denosumab (Ranmark(R)) , ipilimumab (Yervoy®), mogamulizumab (Poteligeo®), pertuzumab (Perjeta®), obinutuzumab (Gazyva®), ramucirumab (Cyramza®), nivolumab (Opdivo®) ), pembrolizumab (Keytruda®), blinatumomab (Blincyto®), dinutuximab (Unituxin®), daratumumab (Darzalex®), necitumumab (Portrazza®), Antibody drugs such as elotuzumab (Empliciti®); gemtuzumab ozogamicin (Mylotarg®), brentuximab vedotin (Adcetris®), trastuzumab emtansine (Kadcyla®), inotuzumab ozogamicin (BESPONSA®); Antibody-drug conjugates (ADCs) such as (registered trademark); and the like. It is also possible to use two or more anticancer drugs in combination. The dose of the anticancer drug is the same as the amount used when it is used alone (i.e., the usual dose), but since the efficacy of the anticancer drug can be expected to increase when used in combination with the drug according to the present invention, The dosage may be appropriately set lower than the actual amount. In addition, those skilled in the art can appropriately set the "usual usage amount" in consideration of the subject's medical condition, age, sex, weight, etc.
本発明に係る薬剤の有効成分であるベルパタスビルは、CLDN14の発現低下を介して、タイトジャンクションのバリア機能を低下させる。したがって、本発明に係る薬剤は、抗癌剤の細胞間透過性を亢進することが期待できる。すなわち、汎用性乃至一般性の高いものであり、様々な抗癌剤と併用され得る。したがって、前述した既存の抗癌剤はもとより、開発中の抗癌剤や、今後開発される抗癌剤との併用も当然に想定される。 Velpatasvir, which is the active ingredient of the drug according to the present invention, reduces the barrier function of tight junctions through decreasing the expression of CLDN14. Therefore, the drug according to the present invention can be expected to enhance the intercellular permeability of anticancer drugs. That is, it is highly versatile and general, and can be used in combination with various anticancer drugs. Therefore, in addition to the existing anticancer drugs mentioned above, it is naturally possible to use them in combination with anticancer drugs currently under development and anticancer drugs to be developed in the future.
本発明に係る薬剤は、抗癌剤と同時又は時間間隔をおいて対象に投与され得る。なお、ここでいう「同時」とは、厳密な同時性を要求するものではない。したがって、本発明に係る薬剤と抗癌剤とを混合した後に対象へ投与する等、両者の投与が時間差のない条件下で実施される場合は勿論のこと、片方の投与後、速やかに他方を投与する等、両者の投与が実質的に時間差のない条件下で実施される場合も、ここでいう「同時」の概念に含まれ得る。 The drug according to the present invention may be administered to a subject at the same time as the anticancer drug or at a time interval. Note that "simultaneously" here does not require strict simultaneity. Therefore, it goes without saying that when the drug according to the present invention and the anticancer drug are mixed and then administered to the subject, the administration of both is carried out under conditions without a time lag, or immediately after the administration of one, the other is administered. The concept of "simultaneously" as used herein also includes cases where both administrations are carried out under conditions with substantially no time difference.
本発明に係る薬剤は、その剤形に応じて、経口投与又は非経口投与（例えば、静脈内、動脈内、皮下、皮内、筋肉内、又は腹腔内注射、経皮、経鼻、経粘膜など）によって対象に適用される。なお、これらの投与経路は互いに排他的なものではなく、任意に選択される二つ以上を併用することもできる。また、全身投与によらず、局所投与することにしてもよく、ドラッグデリバリーシステム（ＤＤＳ）などを利用してもよい。 The drug according to the present invention can be administered orally or parenterally (e.g., intravenously, intraarterially, subcutaneously, intradermally, intramuscularly, or intraperitoneally, transdermally, nasally, transmucosally) depending on its dosage form. etc.) applied to the target. Note that these administration routes are not mutually exclusive, and two or more arbitrarily selected routes can also be used in combination. Furthermore, instead of systemic administration, local administration may be used, and a drug delivery system (DDS) or the like may be used.
３．予防及び／又は治療薬
本発明に係る予防及び／又は治療薬は、ベルパタスビルを少なくとも有効成分として含有し、CLDN14の発現がその原因となる又はその病態を形成する疾患に対する予防及び／又は治療を目的として用いられる。
3. Prophylactic and/or Therapeutic Drug The preventive and/or therapeutic drug according to the present invention contains velpatasvir as at least an active ingredient, and is intended for the prevention and/or treatment of diseases in which the expression of CLDN14 causes or forms the pathological condition. used as.
前述の通り、ベルパタスビルは、CLDN14に直接結合し、細胞間のタイトジャンクションに分布するCLDN14の発現（存在量）を低下させるという作用効果を示す。したがって、CLDN14の発現がその原因となる又はその病態を形成する疾患に対しても、その特有の作用効果を発揮し得る。本発明に係る予防及び／又は治療薬は、好ましくは、CLDN14の高発現がその原因となる又はその病態を形成する疾患に対して用いられる。 As mentioned above, velpatasvir directly binds to CLDN14 and exhibits the effect of reducing the expression (abundance) of CLDN14 distributed in tight junctions between cells. Therefore, it can exert its unique action and effect even on diseases in which the expression of CLDN14 causes or forms the pathological condition thereof. The preventive and/or therapeutic agent according to the present invention is preferably used for diseases in which high expression of CLDN14 is the cause or pathological condition.
４．クローディン－１４結合剤
本発明に係る結合剤は、ベルパタスビルを少なくとも有効成分として含有する。
4. Claudin-14 Binding Agent The binding agent according to the present invention contains velpatasvir as at least an active ingredient.
CLDN14は、各種癌はもとより、その他の疾患の発症や進展等にも関与する可能性があり、基礎研究や、予防及び／又は治療薬、乃至治療法の開発の対象となり得る。したがって、本発明に係る結合剤は、例えば、このような研究・開発における各種ツール（例えば、研究用試薬、診断用試薬など）として有用である。 CLDN14 may be involved in the onset and progression of various cancers as well as other diseases, and can be a target for basic research and the development of preventive and/or therapeutic drugs and treatments. Therefore, the binding agent according to the present invention is useful, for example, as various tools (eg, research reagents, diagnostic reagents, etc.) in such research and development.
以下、実施例に基づいて本発明を更に詳細に説明する。
なお、以下に説明する実施例は、本発明の代表的な実施例の一例を示したものであり、これにより本発明の範囲が狭く解釈されることはない。
Hereinafter, the present invention will be explained in more detail based on Examples.
It should be noted that the embodiment described below shows one example of a typical embodiment of the present invention, and the scope of the present invention should not be interpreted narrowly thereby.
＜実験例１＞
本実験例１では、ウエスタンブロット法を用いて、CLDN14タンパク質の発現低下作用を検討した。
<Experiment example 1>
In this Experimental Example 1, the effect of reducing the expression of CLDN14 protein was examined using Western blotting.
具体的には、6ウェルプレートに1×105個ずつ細胞を播種後、96時間培養した。FCS不含培地に溶媒、1、5、10 μM ベルパタスビルを添加し、24時間インキュベートした。ウエスタンブロット後、化学発光法でCLDN14、CLDN1、β-アクチンのバンドを検出した。ImageJを用いてバンド強度を算出し、溶媒に対する相対値で示した。 Specifically, 1×10 5 cells were seeded in a 6-well plate and cultured for 96 hours. Solvent, 1, 5, and 10 μM velpatasvir were added to the FCS-free medium and incubated for 24 hours. After Western blotting, bands of CLDN14, CLDN1, and β-actin were detected by chemiluminescence. Band intensities were calculated using ImageJ and expressed as relative values to the solvent.
実験例１の結果を図１に示す。ベルパタスビルは、濃度依存的にCLDN14タンパク質の発現量を低下させた一方で、CLDN1タンパク質の発現量はベルパタスビルの処理によって有意に変化しなかったため、CLDN14に選択的に作用することが示唆された。 The results of Experimental Example 1 are shown in FIG. While velpatasvir decreased the expression level of CLDN14 protein in a concentration-dependent manner, the expression level of CLDN1 protein did not change significantly by treatment with velpatasvir, suggesting that it acts selectively on CLDN14.
＜実験例２＞
本実験例２では、CLDN14のmRNA発現量について検討した。
<Experiment example 2>
In this Experimental Example 2, the mRNA expression level of CLDN14 was investigated.
具体的には、6ウェルプレートに1×105個ずつ細胞を播種後、96時間培養した。FCS不含培地に溶媒又は10 μMベルパタスビルを添加し、6時間インキュベートした。TRI Reagentを用いてトータルRNAを抽出後、ReverTraAce（東洋紡社）を用いて逆転写反応を行った。逆転写の条件は、37℃ 15分間、50℃ 5分間、98℃ 5分間とした。THUNDERBIRD SYBR qPCR Mixを用いて、CLDN14、CLDN1、β-アクチンのリアルタイムPCRを行った。Ct値を算出後、溶媒処理細胞に対する相対値で、CLDN mRNA量を示した。 Specifically, 1×10 5 cells were seeded in a 6-well plate and cultured for 96 hours. Solvent or 10 μM velpatasvir was added to the FCS-free medium and incubated for 6 hours. After extracting total RNA using TRI Reagent, reverse transcription reaction was performed using ReverTraAce (Toyobo). The conditions for reverse transcription were 37°C for 15 minutes, 50°C for 5 minutes, and 98°C for 5 minutes. Real-time PCR of CLDN14, CLDN1, and β-actin was performed using THUNDERBIRD SYBR qPCR Mix. After calculating the Ct value, the amount of CLDN mRNA was expressed as a relative value to the solvent-treated cells.
実験例２の結果を図２に示す。図２では、溶媒に対するP>0.05の有意差なしをNSで示している。ベルパタスビルによりCLDN14のmRNA量は変化しなかったため、ベルパタスビルはCLDN14タンパク質に作用し、その発現を低下させることが示唆された。 The results of Experimental Example 2 are shown in FIG. In Figure 2, NS indicates no significant difference with P>0.05 for solvent. Velpatasvir did not change the amount of CLDN14 mRNA, suggesting that velpatasvir acts on CLDN14 protein and reduces its expression.
＜実験例３＞
本実験例３では、蛍光免疫染色法でCLDN14、CLDN1、ZO-1（タイトジャンクションの裏打ちタンパク質）の細胞局在を解析した。
<Experiment example 3>
In Experimental Example 3, the cellular localization of CLDN14, CLDN1, and ZO-1 (tight junction lining proteins) was analyzed using fluorescent immunostaining.
具体的には、具体的には、カバーガラスを載せた6ウェルプレートに1×105個ずつ細胞を播種後、96時間培養した。FCS不含培地に溶媒又は10 μM ベルパタスビルを添加し、24時間インキュベートした。メタノール固定後、0.2 Triton X-100による浸透化、ブロッキング（室温で30分間）、一次抗体（冷蔵庫で一晩）、二次抗体（室温で1時間）の処理を行った。なお、一次抗体反応時にはanti-CLDN1 rabbit antibody、anti-CLDN14 rabbit antibody、anti-ZO-1 mouse antibodyを添加し、二次抗体反応時にはAlexa Fluor 488-conjugated mouse antibody、Alexa Fluor 555-conjugated rabbit antibody、DAPI（核染色用）を添加した。LSM700共焦点レーザー顕微鏡（ツァイス社）を用いて蛍光画像を撮影した。 Specifically, 1×10 5 cells were seeded in a 6-well plate covered with a cover glass, and then cultured for 96 hours. Solvent or 10 μM velpatasvir was added to the FCS-free medium and incubated for 24 hours. After fixation with methanol, permeabilization with 0.2 Triton X-100, blocking (30 minutes at room temperature), treatment with primary antibody (overnight in the refrigerator), and secondary antibody (1 hour at room temperature) were performed. For the primary antibody reaction, add anti-CLDN1 rabbit antibody, anti-CLDN14 rabbit antibody, anti-ZO-1 mouse antibody, and for the secondary antibody reaction, add Alexa Fluor 488-conjugated mouse antibody, Alexa Fluor 555-conjugated rabbit antibody, DAPI (for nuclear staining) was added. Fluorescence images were taken using an LSM700 confocal laser microscope (Zeiss).
実験例３の結果を図３に示す。溶媒のみを処理した細胞では、CLDN14、CLDN1、ZO-1が細胞の隣接部位に分布した。ベルパタスビルの処理により、CLDN14は細胞隣接部位から消失したが、CLDN1とZO-1の分布は変化しなかった。そのため、ベルパタスビルはCLDN14に選択的に作用することが示唆された。 The results of Experimental Example 3 are shown in FIG. In cells treated with vehicle only, CLDN14, CLDN1, and ZO-1 were distributed in adjacent regions of the cells. Upon treatment with velpatasvir, CLDN14 disappeared from adjacent cell sites, but the distribution of CLDN1 and ZO-1 remained unchanged. Therefore, it was suggested that velpatasvir selectively acts on CLDN14.
＜実験例４＞
本実験例４では、CLDN14のエンドサイトーシス機構と分解機構の関与を解明するため、リソソーム阻害剤のクロロキン（CHL）とクラスリン依存性エンドサイトーシス阻害剤のモノダンシルカダベリン（MDC）の効果を検討した。
<Experiment example 4>
In this Experimental Example 4, in order to elucidate the involvement of the endocytosis and degradation mechanisms of CLDN14, we investigated the effects of chloroquine (CHL), a lysosome inhibitor, and monodansylcadaverine (MDC), a clathrin-dependent endocytosis inhibitor. investigated.
具体的には、6ウェルプレートに1×105個ずつ細胞を播種後、96時間培養した。FCS不含培地に溶媒、10 μM ベルパタスビル、10 μMベルパタスビルと10 μM クロロキン（CHL）、10 μM ベルパタスビルと10 μM モノダンシルカダベリン（MDC）を添加し、24時間インキュベートした。ウエスタンブロット後、化学発光法でCLDN14とβ-アクチンのバンドを検出した。ImageJを用いてバンド強度を算出し、溶媒に対する相対値で示した。 Specifically, 1×10 5 cells were seeded in a 6-well plate and cultured for 96 hours. A solvent, 10 μM velpatasvir, 10 μM velpatasvir and 10 μM chloroquine (CHL), and 10 μM velpatasvir and 10 μM monodansylcadaverine (MDC) were added to the FCS-free medium and incubated for 24 hours. After Western blotting, CLDN14 and β-actin bands were detected by chemiluminescence. Band intensities were calculated using ImageJ and expressed as relative values to the solvent.
実験例４の結果を図４に示す。図４では、溶媒に対するP<0.01の有意差を**、ベルパタスビルの処理に対するP<0.01の有意差を##で示している。ベルパタスビルの処理によるCLDN14タンパク質の発現低下は、CHL又はMDCの共処理によって有意に抑制された。そのため、CLDN14はクラスリン依存性エンドサイトーシス機構を介して細胞内に取り込まれ、リソソームで分解されることが示唆された。 The results of Experimental Example 4 are shown in FIG. In FIG. 4, significant differences at P<0.01 for the solvent are indicated by **, and significant differences at P<0.01 for the treatment with velpatasvir are indicated by ##. The decrease in CLDN14 protein expression caused by treatment with velpatasvir was significantly suppressed by co-treatment with CHL or MDC. Therefore, it was suggested that CLDN14 is taken into cells via a clathrin-dependent endocytosis mechanism and degraded in lysosomes.
＜実験例５＞
本実験例５では、CLDN14とベルパタスビルの直接的な結合を証明するため、水晶振動子マイクロバランス解析を行った。
<Experiment example 5>
In this Experimental Example 5, crystal oscillator microbalance analysis was performed to prove the direct binding between CLDN14 and velpatasvir.
具体的には、センサーチップに5 μg/mLのヒトCLDN14リコンビナントタンパク質を固定した。PBSで洗浄後、水晶振動子マイクロバランス（QCM）解析装置にセットした。撹拌しながら、水晶振動子の周波数を経時的に測定した。指定時間に10 μg/mL ベルパタスビルを添加した。ベルパタスビルの濃度と周波数の変化量の関係をグラフに示した。 Specifically, 5 μg/mL of human CLDN14 recombinant protein was immobilized on the sensor chip. After washing with PBS, it was set in a quartz crystal microbalance (QCM) analyzer. While stirring, the frequency of the crystal oscillator was measured over time. 10 μg/mL velpatasvir was added at the indicated times. The relationship between the concentration of velpatasvir and the amount of change in frequency is shown in a graph.
実験例５の結果を図５に示す。ベルパタスビルの添加により、周波数の変化が濃度依存的に増大した。以上の結果から、ベルパタスビルはCLDN14タンパク質に直接結合することが明らかになった。 The results of Experimental Example 5 are shown in FIG. Addition of velpatasvir increased the frequency change in a concentration-dependent manner. The above results revealed that velpatasvir directly binds to the CLDN14 protein.
＜実験例６＞
これまでに、本願発明者らの研究グループは、siRNAを用いたCLDN14ノックダウン実験において、細胞増殖能が低下することを見出した。そこで、本実験例６では、DLD-1細胞にベルパタスビルを処理した。
<Experiment example 6>
To date, the research group of the present inventors has found that cell proliferation ability is reduced in CLDN14 knockdown experiments using siRNA. Therefore, in Experimental Example 6, DLD-1 cells were treated with velpatasvir.
具体的には、図６のＡに示す実験では、6ウェルプレートに5×103個ずつ細胞を播種後、溶媒又は10 μMベルパタスビルを添加した。BZ-X810（キーエンス社）を用いて、24時間毎に明視野像を撮影した。細胞密度計測ソフトウェアを用いて細胞数を計測した。 Specifically, in the experiment shown in FIG. 6A, 5×10 3 cells were seeded in a 6-well plate, and then a solvent or 10 μM velpatasvir was added. Bright field images were taken every 24 hours using BZ-X810 (Keyence Corporation). Cell numbers were counted using cell density measurement software.
また、図６のＢに示す実験では、図６のＡで示した方法で細胞を調製後、72時間後にトリプシンで細胞を剥離した。Muse Cell Cycle Kitで細胞を処理後、Guava Muse セルアナライザー（ルミネックス社）を用いて細胞周期を解析した。 In addition, in the experiment shown in FIG. 6B, cells were prepared by the method shown in FIG. 6A, and 72 hours later, the cells were detached with trypsin. After treating the cells with the Muse Cell Cycle Kit, the cell cycle was analyzed using the Guava Muse Cell Analyzer (Luminex).
実験例６の結果を図６に示す。図６のＡ及びＢでは、溶媒に対するP<0.01の有意差を**、P>0.05の有意差なしをNSで示している。細胞増殖が有意に阻害されたことが確認できた。また、細胞周期の解析において、G0/G1期の細胞数の割合が増加し、S期の細胞数の割合が低下した。したがって、ベルパタスビルはG1期からS期への移行を抑制し、大腸癌細胞の増殖を阻害することが示唆された。 The results of Experimental Example 6 are shown in FIG. In FIGS. 6A and 6B, a significant difference of P<0.01 with respect to the solvent is indicated by **, and a non-significant difference of P>0.05 is indicated by NS. It was confirmed that cell proliferation was significantly inhibited. Furthermore, in cell cycle analysis, the proportion of cells in G0/G1 phase increased and the proportion of cells in S phase decreased. Therefore, it was suggested that velpatasvir suppresses the transition from G1 phase to S phase and inhibits the proliferation of colorectal cancer cells.
＜実験例７＞
CLDN14は細胞間を介した電解質イオンと低分子化合物の輸送に対するバリアを形成すると推察される。そこで、本実験例７では、イオン透過性の指標となる上皮膜間電気抵抗値を測定した。
<Experiment example 7>
It is speculated that CLDN14 forms a barrier to the transport of electrolyte ions and low molecular weight compounds between cells. Therefore, in Experimental Example 7, the epithelial intermembrane electrical resistance value, which is an index of ion permeability, was measured.
具体的には、図７のＡに示す実験では、トランスウェルに5×103個ずつ細胞を播種後、96時間培養した。溶媒又は10 μMベルパタスビルを添加し、24時間インキュベートした。Millicell ERS-2 Volt-Ohm Meter（ミリポア社）を用いて上皮膜間電気抵抗値を測定した。面積とバックグランドを補正後、抵抗値を算出した。 Specifically, in the experiment shown in FIG. 7A, 5×10 3 cells were seeded in transwells and then cultured for 96 hours. Solvent or 10 μM velpatasvir was added and incubated for 24 hours. Epithelial membrane electrical resistance was measured using a Millicell ERS-2 Volt-Ohm Meter (Millipore). After correcting the area and background, the resistance value was calculated.
また、図７のＢ及びＣに示す実験では、トランスウェルの上層チャンバーに50 μg/mL ルシファーイエロー（水溶性蛍光マーカー）又は10 μM ドキソルビシンを添加し、1時間インキュベートした。下層チャンバーの溶液を回収後、Infinite F200を用いてルシファーイエローとドキソルビシンの蛍光強度を測定した。キャリブレーションカーブを作成し、透過量を算出した。 Furthermore, in the experiments shown in FIGS. 7B and 7C, 50 μg/mL Lucifer Yellow (a water-soluble fluorescent marker) or 10 μM doxorubicin was added to the upper chamber of the Transwell and incubated for 1 hour. After collecting the solution in the lower chamber, the fluorescence intensities of Lucifer Yellow and doxorubicin were measured using Infinite F200. A calibration curve was created and the amount of transmission was calculated.
実験例７の結果を図７に示す。図７のＡ～Ｃでは、0 μMに対するP<0.01の有意差を**で示している。ベルパタスビルの処理によって、イオン透過性の指標となる上皮膜間電気抵抗値が低下した。また、トランスウェルの上層から下層へのルシファーイエロー（水溶性蛍光マーカー）とドキソルビシン（DNAポリメラーゼ阻害剤）の透過量が、ベルパタスビルの処理によって増加した。以上の結果から、ベルパタスビルはCLDN14発現の低下を介して、細胞間バリア機能を低下せることが示唆された。 The results of Experimental Example 7 are shown in FIG. In FIGS. 7A to 7C, significant differences of P<0.01 with respect to 0 μM are indicated by **. Treatment with velpatasvir decreased the epithelial membrane electrical resistance value, which is an index of ion permeability. Additionally, the amount of permeation of Lucifer Yellow (a water-soluble fluorescent marker) and doxorubicin (a DNA polymerase inhibitor) from the upper layer of the transwell to the lower layer was increased by treatment with velpatasvir. The above results suggested that velpatasvir decreases intercellular barrier function through decreasing CLDN14 expression.
＜実験例８＞
本実験例８では、CLDN14発現のノックダウンによってスフェロイドの抗癌剤感受性が亢進したため、ベルパタスビルの効果を検討した。
<Experiment example 8>
In Experimental Example 8, the anticancer drug sensitivity of spheroids was increased by knockdown of CLDN14 expression, so the effect of velpatasvir was investigated.
具体的には、図８のＡに示す実験では、96ウェル丸底プレートに1×104個ずつDLD-1細胞を播種後、96時間培養した。溶媒、10 μMベルパタスビル、5、10、20 μM ドキソルビシンを添加し、1時間インキュベートした。BZ-X810を用いて、ドキソルビシンの蛍光画像を撮影した。ImageJを用いてスフェロイド内の蛍光強度を算出し、0 μMに対する相対値で示した。 Specifically, in the experiment shown in FIG. 8A, 1×10 4 DLD-1 cells were seeded in a 96-well round-bottom plate and cultured for 96 hours. Vehicle, 10 μM velpatasvir, 5, 10, and 20 μM doxorubicin were added and incubated for 1 hour. Fluorescence images of doxorubicin were taken using BZ-X810. Fluorescence intensity within the spheroid was calculated using ImageJ and expressed as a value relative to 0 μM.
また、図８のＢに示す実験では、溶媒、10 μMベルパタスビル、5、10、20 μMの各濃度のドキソルビシンを24時間処理後、スフェロイドを回収した。CellTiter-Glo 3D Cell Viability Assay Kit（プロメガ社）を処理後、Infinite F200マイクロプレートリーダー（テカン社）を用いて、生存細胞の化学発光を検出した。細胞生存率を0 μMに対する相対値で示した。 In the experiment shown in FIG. 8B, spheroids were collected after treatment with the solvent, 10 μM velpatasvir, and doxorubicin at concentrations of 5, 10, and 20 μM for 24 hours. After treatment with CellTiter-Glo 3D Cell Viability Assay Kit (Promega), chemiluminescence of viable cells was detected using an Infinite F200 microplate reader (Tecan). Cell viability was expressed as a relative value to 0 μM.
図８のＣに示す実験では、96ウェル丸底プレートに1×104個ずつDLD-1細胞を播種後、96時間培養した。溶媒、10 μMベルパタスビル、50、100、200 μMオキサリプラチン、0.1、1、5 μM SN-38を各濃度で添加し、24時間処理後、スフェロイドを回収した。CellTiter-Glo 3D Cell Viability Assay Kit（プロメガ社）を処理後、Infinite F200マイクロプレートリーダー（テカン社）を用いて、生存細胞の化学発光を検出した。細胞生存率を0 μMに対する相対値で示した。 In the experiment shown in FIG. 8C, 1×10 4 DLD-1 cells were seeded in a 96-well round-bottom plate and cultured for 96 hours. Solvent, 10 μM velpatasvir, 50, 100, 200 μM oxaliplatin, 0.1, 1, 5 μM SN-38 were added at various concentrations, and spheroids were collected after treatment for 24 hours. After treatment with CellTiter-Glo 3D Cell Viability Assay Kit (Promega), chemiluminescence of viable cells was detected using an Infinite F200 microplate reader (Tecan). Cell viability was expressed as a relative value to 0 μM.
実験例８の結果を図８に示す。図８のＡ～Ｄでは、0 μMに対するP<0.01の有意差を**、溶媒に対するP<0.01の有意差を##、P>0.05の有意差なしをNSで示している。ベルパタスビルの処理により、ドキソルビシンの蓄積率が増大し、細胞生存率が低下した。また、作用機序の異なる抗癌剤として、オキサリプラチン（DNA複製阻害剤）やSN-38（トポイソメラーゼ阻害剤であるイリノテカンの活性代謝物）による細胞生存率の低下も、ベルパタスビルによって増強した。 The results of Experimental Example 8 are shown in FIG. In FIGS. 8A to 8D, a significant difference of P<0.01 with respect to 0 μM is indicated by **, a significant difference of P<0.01 with respect to the solvent is indicated by ##, and a non-significant difference of P>0.05 is indicated by NS. Treatment with velpatasvir increased the rate of doxorubicin accumulation and decreased cell viability. Velpatasvir also enhanced the decrease in cell survival caused by anticancer drugs with different mechanisms of action, such as oxaliplatin (a DNA replication inhibitor) and SN-38 (an active metabolite of irinotecan, a topoisomerase inhibitor).
＜実験例９＞
本実験例９では、ヒト大腸癌由来Lovo細胞を用いて検討した。
<Experiment example 9>
In this Experimental Example 9, studies were conducted using human colon cancer-derived Lovo cells.
具体的には、細胞種をヒト大腸癌由来Lovo細胞とした以外は、図８のＢ～Ｃに示した実験と同様の方法で試験を行った。 Specifically, the test was conducted in the same manner as the experiment shown in FIGS. 8B to 8C, except that the cell type was human colon cancer-derived Lovo cells.
実験例９の結果を図９に示す。図９のＡ～Ｃでは、0 μMに対するP<0.01の有意差を**、溶媒に対するP<0.01の有意差を##、P>0.05の有意差なしをNSで示している。上述した実験例８と同様の結果が、ヒト大腸癌由来Lovo細胞でも観察された。以上の結果から、ベルパタスビルは、既存抗癌剤の細胞死誘導効果を増強することが示唆された。 The results of Experimental Example 9 are shown in FIG. In FIGS. 9A to 9C, a significant difference of P<0.01 with respect to 0 μM is indicated by **, a significant difference of P<0.01 with respect to the solvent is indicated by ##, and a non-significant difference of P>0.05 is indicated by NS. Results similar to those in Experimental Example 8 described above were also observed in human colon cancer-derived Lovo cells. The above results suggested that velpatasvir enhances the cell death-inducing effects of existing anticancer drugs.
本発明の有効成分であるベルパタスビルは、癌細胞のCLDN14発現の低下を介して癌細胞の悪性化を抑制するとともに、癌細胞の抗癌剤感受性を亢進する。したがって、ベルパタスビルは、新しい作用機序に基づく癌の予防及び／又は治療薬としての有用性が期待でき、且つ、既存の抗癌剤等とも併用され得る。更に、既承認薬且つ低分子化合物であることから安価に製造でき、抗癌剤の使用量を低下させることも可能となるため、患者の治療機会の向上や、医療費の削減にも繋がる。
Velpatasvir, which is the active ingredient of the present invention, suppresses malignant transformation of cancer cells by reducing the expression of CLDN14 in cancer cells, and also increases the sensitivity of cancer cells to anticancer drugs. Therefore, velpatasvir can be expected to be useful as a cancer preventive and/or therapeutic drug based on a new mechanism of action, and can also be used in combination with existing anticancer drugs. Furthermore, since it is an approved drug and a low-molecular-weight compound, it can be manufactured at low cost, and the amount of anticancer drugs used can be reduced, leading to improved treatment opportunities for patients and a reduction in medical costs.
Claims (7)
A claudin-14 binder containing velpatasvir.
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