JP7407452B2 - Medicines for the treatment and/or prevention of cancer - Google Patents
Medicines for the treatment and/or prevention of cancer Download PDFInfo
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- JP7407452B2 JP7407452B2 JP2020534715A JP2020534715A JP7407452B2 JP 7407452 B2 JP7407452 B2 JP 7407452B2 JP 2020534715 A JP2020534715 A JP 2020534715A JP 2020534715 A JP2020534715 A JP 2020534715A JP 7407452 B2 JP7407452 B2 JP 7407452B2
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- immune checkpoint
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- checkpoint inhibitor
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- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Description
本発明は、免疫チェックポイント阻害剤と組み合わせて用いるための、IL-34の発現を抑制する、IL-34の活性を阻害する及び／若しくはIL-34に結合することでCSF-1RとIL-34との結合を阻害する物質を、又は免疫チェックポイント阻害剤と前記物質との組み合わせを有効成分として含有する、がん、特に治療耐性がんではないがんの治療及び／又は予防のための医薬に関する。 The present invention provides CSF-1R and IL-34 by suppressing IL-34 expression, inhibiting IL-34 activity and/or binding to IL-34 for use in combination with immune checkpoint inhibitors. 34, or a combination of an immune checkpoint inhibitor and said substance as an active ingredient, for the treatment and/or prevention of cancer, especially cancer that is not treatment-resistant. Regarding medicine.
がんにおける免疫応答の抑制に関与する生体分子として、免疫チェックポイントタンパク質と称されるタンパク質が注目を集めている。例えば、免疫チェックポイントタンパク質の一種であるProgrammed-cell Death 1（PD-1）は、活性化T細胞の表面に発現し、抗原提示細胞やがん細胞の表面上に発現するPD-L1/PD-L2と結合することで、T細胞活性化の下方調節に関与している。PD-L1は、これを高発現するがん、例えば肺がん、胃がん、食道がん、大腸がん、腎がん、膀胱がん、子宮頸がん、子宮体がん、頭頸部がん、悪性黒色腫といった様々な固形腫瘍を含む多くのがんにおいて、がん免疫監視機構を回避してがん細胞を増殖させるものと考えられている。 Proteins called immune checkpoint proteins are attracting attention as biomolecules involved in suppressing immune responses in cancer. For example, Programmed-cell Death 1 (PD-1), a type of immune checkpoint protein, is expressed on the surface of activated T cells, and PD-L1/PD expressed on the surface of antigen-presenting cells and cancer cells. -By binding to L2, it is involved in the downregulation of T cell activation. PD-L1 is highly expressed in cancers such as lung cancer, stomach cancer, esophageal cancer, colorectal cancer, kidney cancer, bladder cancer, cervical cancer, endometrial cancer, head and neck cancer, and malignant cancer. In many cancers, including various solid tumors such as melanoma, it is thought that cancer cells proliferate by evading cancer immune surveillance.
がん免疫回避の阻害によるT細胞免疫抑制の解除及びがん免疫応答の増強というコンセプトは、幅広い種類のがんへの適応が可能な新たながん免疫療法を提供するものとして大いに期待されている。免疫チェックポイントタンパク質、例えばPD-1を標的とした抗PD-1抗体等の免疫チェックポイント阻害剤の研究開発が精力的に行われており、その一部は既に臨床で用いられている。 The concept of releasing T-cell immunosuppression and enhancing cancer immune responses by inhibiting cancer immune evasion is highly anticipated as a new cancer immunotherapy that can be applied to a wide variety of cancers. There is. Research and development of immune checkpoint inhibitors such as anti-PD-1 antibodies targeting immune checkpoint proteins such as PD-1 is being actively conducted, and some of these are already in clinical use.
一方、がん組織自身がその周囲に集積した腫瘍随伴マクロファージ（Tumor Associated Macrophage、TAM）によってがん免疫応答を抑制することが明らかにされている。TAMは、細胞増殖因子の産生及び新生血管の誘導に加えて、免疫抑制性サイトカイン産生を介したがん免疫応答の抑制によって、がん細胞の増殖促進に関与すると考えられている。 On the other hand, it has been revealed that tumor associated macrophages (TAMs) that accumulate around cancer tissues themselves suppress cancer immune responses. In addition to producing cell growth factors and inducing new blood vessels, TAMs are thought to be involved in promoting cancer cell growth by suppressing cancer immune responses through the production of immunosuppressive cytokines.
M-CSF（Macrophage Colony Stimulating Factor、CSF-1とも呼ばれる）は、骨代謝関連サイトカインの一種であり、単球等により産生され、マクロファージコロニーの形成を刺激する。M-CSFはまた、多くの種類のがん細胞において産生され、がん組織におけるM-CSFの発現レベルは当該組織におけるTAMの集積レベルと相関することが知られている。M-CSFと特異的に結合する受容体がCSF-1R（Colony Stimulating Factor-1 Receptor）であることから、抗CSF-1R抗体を様々ながん、例えば白血病、乳がん、子宮内膜がん、前立腺がん、卵巣がん、結腸直腸がん、肝細胞がん、腎臓がん、多発性骨髄腫等の治療に用いることが提唱されている（特許文献１）。 M-CSF (Macrophage Colony Stimulating Factor, also called CSF-1) is a type of bone metabolism-related cytokine, is produced by monocytes, etc., and stimulates the formation of macrophage colonies. M-CSF is also produced in many types of cancer cells, and it is known that the expression level of M-CSF in a cancer tissue correlates with the accumulation level of TAM in that tissue. Since the receptor that specifically binds to M-CSF is CSF-1R (Colony Stimulating Factor-1 Receptor), anti-CSF-1R antibodies can be used to treat various cancers, such as leukemia, breast cancer, endometrial cancer, etc. It has been proposed to be used to treat prostate cancer, ovarian cancer, colorectal cancer, hepatocellular carcinoma, kidney cancer, multiple myeloma, etc. (Patent Document 1).
本発明者らの研究により、CSF-1Rの別のリガンドであるInterleukin-34（IL-34）が、CSF-1Rとの結合を介してがんの治療耐性に関与していることが明らかにされた。この知見に基づき、IL-34に対するsiRNAや抗IL-34抗体といったIL-34を阻害する物質を有効成分とする、治療耐性がんに対する治療耐性低減剤が提供されている（特許文献２）。 Our research revealed that Interleukin-34 (IL-34), another CSF-1R ligand, is involved in cancer treatment resistance through binding to CSF-1R. It was done. Based on this knowledge, a treatment resistance reducing agent for treatment-resistant cancers has been provided that contains a substance that inhibits IL-34, such as siRNA against IL-34 or an anti-IL-34 antibody, as an active ingredient (Patent Document 2).
本発明は、免疫チェックポイント阻害剤と組み合わせて用いることでがんを効果的に治療することができる医薬を提供することを目的とする。 An object of the present invention is to provide a medicament that can effectively treat cancer when used in combination with an immune checkpoint inhibitor.
本発明者らは、IL-34の阻害を免疫チェックポイント阻害剤と組み合わせることで、治療耐性がんではないがんを包含するがんに対して、特にIL-34受容体であるCSF-1Rを発現していないがんに対しても、免疫チェックポイント阻害剤を単独で用いた場合の治療効果を上回る優れた治療効果を発揮し得ることを見出し、下記の各発明を完成させた。 By combining IL-34 inhibition with immune checkpoint inhibitors, we have shown that the IL-34 receptor, CSF-1R, is particularly effective against cancers, including non-therapy-resistant cancers. The inventors have discovered that immune checkpoint inhibitors can exhibit superior therapeutic effects that exceed the therapeutic effects of using them alone, even for cancers that do not express the disease, and have completed the following inventions.
（１）免疫チェックポイント阻害剤と組み合わせて用いるための、IL-34に対する特異抗体及びその誘導体並びにIL-34に対する阻害性核酸よりなる群から選択される少なくとも１つを有効成分として含有する、がんの治療及び／又は予防のための医薬。
（２）免疫チェックポイント阻害剤と、IL-34に対する特異抗体及びその誘導体並びにIL-34に対する阻害性核酸よりなる群から選択される少なくとも１つとの組み合わせを有効成分として含有する、がんの治療及び／又は予防のための医薬。
（３）免疫チェックポイント阻害剤がPD-1、PD-L1、PD-L2、CTLA-4、CD80及びCD86よりなる群から選択される少なくとも１つを標的とする、（１）又は（２）に記載の医薬。
（４）免疫チェックポイント阻害剤が抗PD-1抗体及び抗CTLA-4抗体よりなる群から選択される少なくとも１つである、（１）～（３）のいずれか一項に記載の医薬。
（５）がんが治療耐性がんではない、（１）～（４）のいずれか一項に記載の医薬。
（６）がんが免疫チェックポイント阻害療法に対する治療耐性を有するがんではない、（１）～（５）のいずれか一項に記載の医薬。
（７）がんがCSF-1R陰性がんである、（１）～（６）のいずれか一項に記載の医薬。(1) Contains as an active ingredient at least one selected from the group consisting of a specific antibody against IL-34 and its derivative, and an inhibitory nucleic acid against IL-34, for use in combination with an immune checkpoint inhibitor. Medicines for the treatment and/or prevention of cancer.
(2) Cancer treatment containing as an active ingredient a combination of an immune checkpoint inhibitor and at least one selected from the group consisting of a specific antibody against IL-34 and its derivative, and an inhibitory nucleic acid against IL-34. and/or prophylactic medicines.
(3) The immune checkpoint inhibitor targets at least one selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, CD80 and CD86, (1) or (2) Medicines listed in.
(4) The medicament according to any one of (1) to (3), wherein the immune checkpoint inhibitor is at least one selected from the group consisting of anti-PD-1 antibodies and anti-CTLA-4 antibodies.
(5) The medicament according to any one of (1) to (4), wherein the cancer is not a treatment-resistant cancer.
(6) The medicament according to any one of (1) to (5), wherein the cancer is not a cancer that has therapeutic resistance to immune checkpoint inhibition therapy.
(7) The medicament according to any one of (1) to (6), wherein the cancer is CSF-1R negative cancer.
本発明によれば、免疫チェックポイント阻害剤を単独で用いた場合の治療効果を上回る優れた治療効果を得ることができる。また、本発明の一実施形態によると、CSF-1Rを発現していないがんに対しても、効果的な治療が可能となる。 According to the present invention, it is possible to obtain an excellent therapeutic effect that exceeds the therapeutic effect when using an immune checkpoint inhibitor alone. Furthermore, according to one embodiment of the present invention, it is possible to effectively treat cancers that do not express CSF-1R.
本発明の第1の態様は、免疫チェックポイント阻害剤と組み合わせて用いるための、IL-34の発現を抑制する、IL-34の活性を阻害する及び／又はIL-34に結合することでCSF-1RとIL-34との結合を阻害する物質を有効成分として含有する、がんの治療及び／又は予防のための医薬に関する。また、本発明の第2の態様は、免疫チェックポイント阻害剤と、IL-34の発現を抑制する、IL-34の活性を阻害する及び／又はIL-34に結合することでCSF-1RとIL-34との結合を阻害する物質との組み合わせを有効成分として含有する、がんの治療及び／又は予防のための医薬に関する。以下、特に断らない限り、本発明の詳細は、IL-34その他の生体高分子及び分子生物学的機構を含め、ヒトを代表例として説明される。 A first aspect of the present invention is to suppress the expression of IL-34, inhibit the activity of IL-34 and/or bind to IL-34 for use in combination with an immune checkpoint inhibitor. The present invention relates to a medicament for the treatment and/or prevention of cancer, which contains a substance that inhibits the binding between -1R and IL-34 as an active ingredient. In addition, a second aspect of the present invention provides an immune checkpoint inhibitor and an immune checkpoint inhibitor that suppresses the expression of IL-34, inhibits the activity of IL-34, and/or binds to IL-34 to inhibit CSF-1R. The present invention relates to a medicament for the treatment and/or prevention of cancer, which contains as an active ingredient a combination with a substance that inhibits binding to IL-34. Hereinafter, unless otherwise specified, the details of the present invention, including IL-34 and other biopolymers and molecular biological mechanisms, will be explained using humans as a representative example.
免疫チェックポイント阻害剤
免疫チェックポイント阻害剤は、自己に対する免疫応答や過剰な免疫応答を抑制する作用を持つ免疫チェックポイント分子と称される生体分子を標的とし、その分子の発現又は生理活性を阻害又は抑制することができる物質である。免疫チェックポイント分子としては、PD-L1／PD-L2とその受容体であるPD-1、CD80/CD86とその受容体であるCTLA-4、galectin-9とその受容体であるTIM-3、HVEMとその受容体であるBTLA等が知られており、本発明においては、PD-1、PD-L1、PD-L2、CTLA-4、CD80及びCD86よりなる群から選択される少なくとも１つを阻害の標的とすることが好ましい。免疫チェックポイント阻害剤の例としては、免疫チェックポイント分子の生理活性を阻害する低分子化合物、免疫チェックポイント分子に特異的に結合する抗体、免疫チェックポイント分子の発現を抑制する阻害性核酸等を挙げることができる。本発明において好ましい免疫チェックポイント阻害剤は、免疫チェックポイント分子に対する特異抗体、好ましくは抗PD-1抗体、抗PD-L1抗体、抗PD-L2抗体、抗CTLA-4抗体等であり、これらの典型例はニボルマブ（抗PD-1抗体、商品名：オプジーボ）、イピリムマブ（抗CTLA-4抗体、商品名：ヤーボイ）、ペムブロリズマブ（抗PD-1抗体、商品名：キイトルーダ）等の臨床で既に使用されている抗体である。免疫チェックポイント阻害剤は1種類を単独で使用してもよいが、2種以上の併用がより好ましい。 Immune checkpoint inhibitors Immune checkpoint inhibitors target biomolecules called immune checkpoint molecules that have the effect of suppressing self-immune responses and excessive immune responses, and inhibit the expression or physiological activity of these molecules. or a substance that can be suppressed. Immune checkpoint molecules include PD-L1/PD-L2 and its receptor PD-1, CD80/CD86 and its receptor CTLA-4, galectin-9 and its receptor TIM-3, HVEM and its receptors such as BTLA are known, and in the present invention, at least one selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4, CD80 and CD86 is used. Preferably, the inhibition is targeted. Examples of immune checkpoint inhibitors include low molecular weight compounds that inhibit the physiological activity of immune checkpoint molecules, antibodies that specifically bind to immune checkpoint molecules, and inhibitory nucleic acids that suppress the expression of immune checkpoint molecules. can be mentioned. Preferred immune checkpoint inhibitors in the present invention are specific antibodies against immune checkpoint molecules, preferably anti-PD-1 antibodies, anti-PD-L1 antibodies, anti-PD-L2 antibodies, anti-CTLA-4 antibodies, etc. Typical examples are nivolumab (anti-PD-1 antibody, brand name: Opdivo), ipilimumab (anti-CTLA-4 antibody, brand name: Yervoy), and pembrolizumab (anti-PD-1 antibody, brand name: Keytruda), which are already in clinical use. This is an antibody that has been tested. Although one type of immune checkpoint inhibitor may be used alone, a combination of two or more types is more preferable.
IL-34の発現を抑制する、IL-34の活性を阻害する及び／又はIL-34に結合することでCSF-1RとIL-34との結合を阻害する物質
本発明の医薬は、IL-34の発現を抑制する、IL-34の活性を阻害する及び／又はIL-34に結合することでCSF-1RとIL-34との結合を阻害する物質を含有する。これらの物質は、核酸、抗体、抗体誘導体及び化合物よりなる群から選択することができる。 A substance that inhibits the binding between CSF-1R and IL-34 by suppressing the expression of IL-34, inhibiting the activity of IL-34, and/or binding to IL-34. Contains a substance that suppresses the expression of IL-34, inhibits the activity of IL-34, and/or inhibits the binding between CSF-1R and IL-34 by binding to IL-34. These substances can be selected from the group consisting of nucleic acids, antibodies, antibody derivatives and compounds.
IL-34の発現を抑制する物質としては、IL-34をコードする遺伝子からのmRNA転写を抑制することができる物質、当該mRNAを分解することができる物質及び当該mRNAからのタンパク質翻訳を抑制することのできる物質を挙げることができる。これらの物質の典型例は、NCBI GeneにGene ID:146433として登録されているヒトIL-34の遺伝子及びタンパク質に翻訳されるmRNAの塩基配列を基にして、当業者が設計、作製することができるアンチセンスRNA又はsiRNA等の阻害性核酸である。阻害性核酸の例としては、MyBioSourceから市販されているsiRNA（IL34 siRNA (Human), Cat.#: MBS8239554）又はこれが標的とするIL-34 mRNA上の塩基配列にハイブリダイズしてIl-34 mRNAを分解することができる核酸を挙げることができる。 Substances that suppress the expression of IL-34 include substances that can suppress mRNA transcription from the gene encoding IL-34, substances that can degrade the mRNA, and substances that suppress protein translation from the mRNA. List of substances that can. Typical examples of these substances can be designed and produced by those skilled in the art based on the human IL-34 gene registered in NCBI Gene as Gene ID: 146433 and the base sequence of mRNA translated into protein. It is an inhibitory nucleic acid such as antisense RNA or siRNA that can be used. Examples of inhibitory nucleic acids include siRNA commercially available from MyBioSource (IL34 siRNA (Human), Cat.#: MBS8239554), or siRNA that hybridizes to the base sequence on the target IL-34 mRNA to inhibit IL-34 mRNA. Examples include nucleic acids that can degrade .
また、siRNAの塩基配列を含むshRNA、適当な発現プロモーターの支配下に置かれることで上記アンチセンスRNA又はsiRNA等を転写誘導することのできるDNA、及び上記アンチセンスRNA又はsiRNA等の塩基配列の一部が修飾されてヌクレアーゼによる分解に対する安定性が高められたRNAも、上記アンチセンスRNA又はsiRNAと機能的に等価な核酸として、本発明にいう発現を抑制する物質に包含される。ヌクレアーゼによる分解に対する安定性を向上させるための修飾としては、2'O-メチル化、2'-F化、4'-チオ化等を挙げることができる。 In addition, shRNA containing the base sequence of siRNA, DNA that can induce transcription of the above-mentioned antisense RNA or siRNA when placed under the control of an appropriate expression promoter, and the base sequence of the above-mentioned antisense RNA or siRNA, etc. RNA that has been partially modified to have increased stability against degradation by nucleases is also included in the expression-suppressing substances referred to in the present invention as nucleic acids functionally equivalent to the antisense RNA or siRNA. Modifications to improve stability against degradation by nucleases include 2'O-methylation, 2'-F conversion, 4'-thiolation, and the like.
さらに、上記RNAのリボヌクレオチドの一部が、対応するデオキシリボヌクレオチド又はヌクレオチド類似体に置き換えられたキメラRNAもまた、本発明にいう発現を抑制する物質に包含される。ヌクレオチド類似体としては、例えば、5位修飾ウリジン又はシチジン、例えば5-（2-アミノ）プロピルウリジン、5-ブロモウリジン等；8位修飾アデノシン又はグアノシン、例えば8-ブロモグアノシン等；デアザヌクレオチド、例えば7-デアザ-アデノシン等；O-又はN-アルキル化ヌクレオチド、例えばN6-メチルアデノシン等を挙げることができる。 Furthermore, chimeric RNAs in which a portion of the ribonucleotides of the RNA described above are replaced with corresponding deoxyribonucleotides or nucleotide analogs are also included in the expression-suppressing substances referred to in the present invention. Examples of nucleotide analogs include 5-position modified uridine or cytidine, such as 5-(2-amino)propyl uridine, 5-bromouridine, etc.; 8-position modified adenosine or guanosine, such as 8-bromoguanosine; deaza nucleotides, Examples include 7-deaza-adenosine and the like; O- or N-alkylated nucleotides, such as N6-methyladenosine.
上記阻害性核酸において、修飾される又は置換される塩基の種類又は個数は、そのIL-34の発現を抑制する能力を失わない限り、特に制限は無い。 In the above-mentioned inhibitory nucleic acid, the type or number of bases to be modified or substituted is not particularly limited as long as the ability to suppress IL-34 expression is not lost.
上記阻害性核酸は、遺伝子組み換え技術又は化学合成技術を利用して人工的に合成することができる。遺伝子組み換え方法、核酸の化学合成方法、また非天然型の塩基の合成手法又はこれを含む核酸の合成手法としては、当業者に周知である手法を採用することができる。またいわゆるDNAシンセサイザー等の機器を用いることで、核酸を合成してもよい。 The above-mentioned inhibitory nucleic acid can be artificially synthesized using genetic recombination technology or chemical synthesis technology. As a genetic recombination method, a method for chemically synthesizing nucleic acids, a method for synthesizing a non-natural base, or a method for synthesizing a nucleic acid containing the same, methods well known to those skilled in the art can be employed. Nucleic acids may also be synthesized using a device such as a so-called DNA synthesizer.
IL-34の活性を阻害する物質及びIL-34に結合することでCSF-1RとIL-34との結合を阻害する物質としては、IL-34に結合してその活性を阻害する低分子化合物又は特異抗体若しくは抗体誘導体、IL-34に結合することでCSF-1RとIL-34との結合を阻害する低分子化合物又は特異抗体若しくは抗体誘導体を挙げることができる。そのような物質の例は、IL-34上のCSF-1R結合部位をブロックすることでIL-34とCSF-1Rとの結合を阻害する抗IL-34抗体、前記結合部位とは異なる部位でIL-34に結合するが立体障害的にIL-34とCSF-1Rとの結合を阻害する抗IL-34抗体、及びこれらの誘導体等を挙げることができる。 Substances that inhibit IL-34 activity and substances that inhibit the binding between CSF-1R and IL-34 by binding to IL-34 include low molecular weight compounds that bind to IL-34 and inhibit its activity. Alternatively, specific antibodies or antibody derivatives, low-molecular compounds, or specific antibodies or antibody derivatives that inhibit the binding between CSF-1R and IL-34 by binding to IL-34 can be mentioned. An example of such a substance is an anti-IL-34 antibody that inhibits the binding of IL-34 to CSF-1R by blocking the CSF-1R binding site on IL-34, a site different from said binding site. Examples include anti-IL-34 antibodies that bind to IL-34 but inhibit the binding between IL-34 and CSF-1R due to steric hindrance, and derivatives thereof.
上記抗体は、モノクローナル抗体、キメラ抗体、ヒト化抗体若しくはヒト抗体であり得て、また抗体誘導体は、上記抗体に由来するFab、Fab’、F(ab’)2、scFv若しくはF(ab’)2等の抗体断片、ダイアボディ（diabody）、dsFv、CDRを含むペプチド等であり得る。 The antibody may be a monoclonal, chimeric, humanized or human antibody, and the antibody derivative may be a Fab, Fab', F(ab')2, scFv or F(ab') derived from the antibody. They may be antibody fragments such as 2, diabodies, dsFv, CDR-containing peptides, and the like.
抗体は、好ましくは遺伝子組換え手法で作製されたIL-34を抗原として、ウサギ、マウス、ラット等の適当な実験動物を免疫することを含む一般的な抗体作製方法によって調製することができる。あるいは、公知文献、例えば特表2015-510510及びWO2013/119716（これらの文献は参照によりその全体が本明細書に組み込まれる。）に記載されている抗IL-34抗体、R&D systemsから市販されているHuman IL-34 Antibody（Clone:578416, Cat.#:MAB5265）、Thermo Fisher Scientificから市販されているIL-34 Monoclonal Antibody（Clone:578416, Product #:MA5-24259）、ミリポアから市販されているAnti-IL-34, clone 1D12 Antibody（Clone:1D12, Cat.#:MABT493）、BioLegendから市販されているanti-human IL-34 Antibody（Clone:E033B8, Cat. #:361401, 361402）、その他の既存の抗IL-34抗体、又はこれらの抗体のCDR配列と同じアミノ酸配列をCDR配列として含む抗体を使用してもよい。 The antibody can be prepared by a general antibody production method, which involves immunizing a suitable experimental animal such as a rabbit, mouse, or rat, using IL-34 produced by a genetic recombination technique as an antigen. Alternatively, anti-IL-34 antibodies described in known documents, such as Japanese Patent Application Publication No. 2015-510510 and WO2013/119716 (these documents are incorporated herein by reference in their entirety), commercially available from R&D systems. Human IL-34 Antibody (Clone:578416, Cat.#:MAB5265) available from Thermo Fisher Scientific, IL-34 Monoclonal Antibody (Clone:578416, Product #:MA5-24259) available from Millipore Anti-IL-34, clone 1D12 Antibody (Clone:1D12, Cat.#:MABT493), anti-human IL-34 Antibody commercially available from BioLegend (Clone:E033B8, Cat. #:361401, 361402), and others Existing anti-IL-34 antibodies or antibodies containing the same amino acid sequence as the CDR sequence of these antibodies may be used.
本発明の医薬は、上記核酸、抗体又は抗体誘導体以外の、IL-34の発現を抑制する、IL-34の活性を阻害する及び／又はCSF-1RとIL-34との結合を阻害することのできる物質を含んでもよい。そのような物質は、IL-34を発現する適当な細胞を用いたIL-34発現抑制能のスクリーニング、又はCSF-1RとIL-34とを用いたIL-34の活性阻害能若しくは結合阻害能のスクリーニングを通じて探索することができる。 The medicament of the present invention suppresses the expression of IL-34, inhibits the activity of IL-34, and/or inhibits the binding between CSF-1R and IL-34 other than the above-mentioned nucleic acids, antibodies, or antibody derivatives. It may also contain substances that can. Such substances can be screened for their ability to suppress IL-34 expression using appropriate cells that express IL-34, or their ability to inhibit IL-34 activity or binding using CSF-1R and IL-34. can be explored through screening.
本発明の好ましい実施形態において、IL-34の発現を抑制する、IL-34の活性を阻害する及び／又はIL-34に結合することでCSF-1RとIL-34との結合を阻害する物質は、IL-34に対する特異抗体及びその誘導体並びにIL-34に対する阻害性核酸よりなる群から選択される少なくとも１つである。 In a preferred embodiment of the present invention, a substance that suppresses the expression of IL-34, inhibits the activity of IL-34, and/or inhibits the binding between CSF-1R and IL-34 by binding to IL-34. is at least one selected from the group consisting of a specific antibody against IL-34 and its derivative, and an inhibitory nucleic acid against IL-34.
医薬又は医薬組成物
本発明の医薬は、上記のIL-34の発現を抑制する、IL-34の活性を阻害する及び／若しくはIL-34に結合することでCSF-1RとIL-34との結合を阻害する物質を、又は免疫チェックポイント阻害剤と前記物質との組み合わせを有効成分として含有し、がんの治療及び／又は予防のための医薬として使用することができる。ここで「有効成分として含有する」とは、有効量のかかる物質又はこれを含む組み合わせを含有することを意味する。 Pharmaceutical or Pharmaceutical Composition The pharmaceutical of the present invention suppresses the expression of IL-34, inhibits the activity of IL-34, and/or binds to IL-34, thereby inhibiting the interaction between CSF-1R and IL-34. It contains a substance that inhibits binding or a combination of an immune checkpoint inhibitor and the above substance as an active ingredient, and can be used as a medicament for the treatment and/or prevention of cancer. Here, "containing as an active ingredient" means containing an effective amount of such a substance or a combination containing it.
本発明の医薬における前記物質の有効量は、免疫チェックポイント阻害剤と組み合わされたときに、免疫チェックポイント阻害剤が単独で用いられた場合に発揮するがんの治療及び／又は予防の効果を上回る強さの効果を発揮する量を意味し、前記物質及び組み合わされる免疫チェックポイント阻害剤の種類、用法、対象の年齢、性別、体重、がんの種類その他の条件等に応じて適宜決定される。 The effective amount of the substance in the medicament of the present invention, when combined with an immune checkpoint inhibitor, has the effect of treating and/or preventing cancer that is exerted when the immune checkpoint inhibitor is used alone. It refers to the amount that exhibits a stronger effect, and is determined as appropriate depending on the type and usage of the substance and the immune checkpoint inhibitor to be combined, the age, sex, weight, type of cancer, and other conditions of the subject. Ru.
本明細書において用いられる用語「治療」は、疾患の治癒、一時的寛解等を目的とする医学的に許容される全てのタイプの治療的介入を包含する。また用語「予防」は、疾患の罹患又は発症の防止若しくは抑制等を目的とする医学的に許容される全てのタイプの予防的介入を包含する。すなわち、がんの治療及び／又は予防とは、がんの進行の遅延又は停止、病変の退縮又は消失、発症の予防又は再発の防止等を含む、種々の目的の医学的に許容される介入を包含する。 The term "therapy" as used herein encompasses all types of medically acceptable therapeutic interventions aimed at curing, temporary remission, etc. of disease. Furthermore, the term "prevention" includes all types of medically acceptable preventive interventions aimed at preventing or suppressing the onset or onset of disease. In other words, cancer treatment and/or prevention refers to medically acceptable interventions for various purposes, including delaying or stopping cancer progression, regression or disappearance of lesions, prevention of onset or prevention of recurrence, etc. includes.
本発明の医薬は、がんに罹患した又は罹患するおそれのある対象、例えばマウス、ラット、ハムスター、モルモットを含むげっ歯類、ヒト、チンパンジー、アカゲザルを含む霊長類、ブタ、ウシ、ヤギ、ウマ、ヒツジを含む家畜、イヌ、ネコを含む愛玩動物といった哺乳動物に投与される。好ましい対象は、ヒトである。 The medicament of the present invention can be applied to subjects suffering from or at risk of suffering from cancer, such as mice, rats, hamsters, rodents including guinea pigs, humans, primates including chimpanzees and rhesus monkeys, pigs, cows, goats, and horses. , domestic animals including sheep, and pets including dogs and cats. Preferred subjects are humans.
本発明の医薬により治療及び／又は予防することができるがんは、任意の種類のがんであり得て、例としては、肺がん、胃がん、食道がん、大腸がん、腎がん、膀胱がん、卵巣がん、乳がん、子宮頸がん、子宮体がん、頭頸部がん、悪性黒色腫等を挙げることができる。また、本発明の医薬により治療及び／又は予防することができるがんは、任意のステージのがんであり得る。 The cancer that can be treated and/or prevented by the medicament of the present invention can be any type of cancer, and examples include lung cancer, stomach cancer, esophageal cancer, colorectal cancer, kidney cancer, and bladder cancer. Examples include ovarian cancer, breast cancer, cervical cancer, endometrial cancer, head and neck cancer, and malignant melanoma. Furthermore, cancer that can be treated and/or prevented by the medicament of the present invention can be at any stage.
本発明の一実施形態において、治療及び／又は予防することができるがんは、IL34発現陽性かつM-CSF発現陰性の骨髄腫細胞を有する多発性骨髄腫を含まない。したがって、この実施形態は、免疫チェックポイント阻害剤と組み合わせて用いるための、IL-34の発現を抑制する、IL-34の活性を阻害する及び／又はIL-34に結合することでCSF-1RとIL-34との結合を阻害する物質を、又は免疫チェックポイント阻害剤と前記物質との組み合わせを有効成分として含有する、がん（ただしIL34発現陽性及びM-CSF発現陰性の骨髄腫細胞を有する多発性骨髄腫を除く。）の治療及び／又は予防のための医薬と表すこともできる。 In one embodiment of the invention, the cancer that can be treated and/or prevented does not include multiple myeloma having myeloma cells that are positive for IL34 expression and negative for M-CSF expression. Accordingly, this embodiment provides CSF-1R by suppressing expression of IL-34, inhibiting activity of IL-34, and/or binding to IL-34 for use in combination with an immune checkpoint inhibitor. Cancer (however, myeloma cells that are positive for IL34 expression and negative for M-CSF expression) containing as an active ingredient a substance that inhibits the binding of IL-34 to IL-34, or a combination of an immune checkpoint inhibitor and the above substance It can also be referred to as a medicament for the treatment and/or prevention of multiple myeloma (excluding multiple myeloma).
本発明の一実施形態において、治療及び／又は予防することができるがんは、化学療法、放射線療法、免疫療法等に対する治療耐性を有する治療耐性がんではない。したがって、この実施形態は、免疫チェックポイント阻害剤と組み合わせて用いるための、IL-34の発現を抑制する、IL-34の活性を阻害する及び／又はIL-34に結合することでCSF-1RとIL-34との結合を阻害する物質を、又は免疫チェックポイント阻害剤と前記物質との組み合わせを有効成分として含有する、がん（ただし治療耐性がんを除く。）の治療及び／又は予防のための医薬と表すこともできる。また、さらなる特定の実施形態において、前記物質又は組み合わせを有効成分として含有する、治療耐性を有さないがんの治療及び／又は予防のための医薬も提供される。これらの実施形態において、治療耐性は、好ましくは、免疫チェックポイント阻害療法に対する治療耐性であり、また獲得性の治療耐性である。 In one embodiment of the invention, the cancer that can be treated and/or prevented is not a treatment-resistant cancer that is resistant to chemotherapy, radiotherapy, immunotherapy, etc. Accordingly, this embodiment provides CSF-1R by suppressing expression of IL-34, inhibiting activity of IL-34, and/or binding to IL-34 for use in combination with an immune checkpoint inhibitor. Treatment and/or prevention of cancer (excluding treatment-resistant cancer) containing as an active ingredient a substance that inhibits the binding of IL-34 to IL-34, or a combination of an immune checkpoint inhibitor and the above substance. It can also be expressed as a medicine for. In a further specific embodiment, there is also provided a medicament for the treatment and/or prevention of cancer that is not resistant to treatment, which contains the substance or combination as an active ingredient. In these embodiments, the therapeutic resistance is preferably therapeutic resistance to immune checkpoint inhibition therapy and is acquired therapeutic resistance.
がんの治療耐性は、当業者に公知の方法によって確認することができ、一例として、患者から採取したがん細胞に、適切な処理、例えば治療耐性がんに対しては奏功しないが治療耐性がんでないがんに対しては効果が期待できる用量の抗がん剤若しくは免疫療法剤又は放射線照射を施し、そのがん細胞の生存又は増殖の程度を観察することによって確認することができる。 Treatment resistance of cancer can be confirmed by methods known to those skilled in the art, for example, cancer cells collected from a patient are subjected to appropriate treatments, such as treatment-resistant cancers that do not respond to treatment-resistant cancers. Confirmation can be made by administering a dose of an anticancer drug or immunotherapeutic agent or radiation that is expected to be effective to non-cancerous cancers, and observing the degree of survival or proliferation of the cancer cells.
別の実施形態において、本発明の医薬により治療及び／又は予防することができるがんは、CSF-1R陰性がんである。ここでCSF-1R陰性がんとは、CSF-1Rが実質的に発現していないがんであり、例えばRT-PCRや免疫学的検出法等の分子生物学的手法によってCSF-1Rの発現を検出することができないか、又はその発現量が僅かであるがんである。 In another embodiment, the cancer that can be treated and/or prevented by the medicament of the present invention is a CSF-1R negative cancer. Here, CSF-1R-negative cancer refers to cancer in which CSF-1R is not substantially expressed, and CSF-1R expression can be detected using molecular biological methods such as RT-PCR or immunological detection. It is a cancer that cannot be detected or its expression level is small.
さらに別の実施形態において、本発明の医薬により治療及び／又は予防することができるがんは、M-CSF陽性がんである。ここでM-CSF陽性がんとは、M-CSFが実質的に発現しているがんであり、例えばRT-PCRや免疫学的検出法等の分子生物学的手法によってM-CSFの発現を検出することができるがんである。 In yet another embodiment, the cancer that can be treated and/or prevented by the medicament of the present invention is M-CSF positive cancer. Here, M-CSF-positive cancer is cancer that substantially expresses M-CSF, and for example, M-CSF expression can be detected using molecular biological methods such as RT-PCR or immunological detection. It is a cancer that can be detected.
本発明の医薬は、上記の有効成分に加えて、有効成分以外の薬物又は緩衝剤、抗酸化剤、保存剤、タンパク質、親水性ポリマー、アミノ酸、キレート化剤、非イオン性界面活性剤、賦形剤、安定化剤、担体等の薬学的に許容される成分と医薬組成物を形成し又は製剤化して、使用することができる。薬学的に許容される成分は当業者において周知であり、当業者が通常の実施能力の範囲内で、例えば第十七改正日本薬局方その他の規格書に記載された成分から製剤の形態に応じて適宜選択して使用することができる。 In addition to the above-mentioned active ingredients, the medicament of the present invention includes drugs other than the active ingredients, buffers, antioxidants, preservatives, proteins, hydrophilic polymers, amino acids, chelating agents, nonionic surfactants, excipients. A pharmaceutical composition can be formed or formulated with pharmaceutically acceptable ingredients such as excipients, stabilizers, carriers, etc., and then used. Pharmaceutically acceptable ingredients are well known to those skilled in the art, and can be determined according to the form of the preparation from ingredients listed in the 17th edition of the Japanese Pharmacopoeia and other specifications within the scope of ordinary skill. can be selected and used as appropriate.
本発明の医薬又はこれを含む医薬組成物の剤形は任意であり、標的部位やがんの種類等に応じて適宜選択することができる。剤形は、一般に非経口製剤であることが好ましく、例えば注射剤、経皮剤、経腸剤、点滴剤等であることができる。また本発明の医薬の投与経路は、特に制限されないが、非経口製剤である場合は、例えば血管内投与（好ましくは静脈内投与）、腹腔内投与、腸管内投与、皮下投与、標的部位への局所投与等を挙げることができる。好ましい実施形態の一つにおいて、本発明の医薬は、静脈内投与又は局所投与により生体に投与される。また、本発明の医薬又はこれを含む医薬組成物の投与量は、用法、対象の年齢、性別、体重、がんの種類その他の条件等に応じて適宜選択される。 The dosage form of the medicament of the present invention or a pharmaceutical composition containing the same is arbitrary and can be appropriately selected depending on the target site, type of cancer, etc. The dosage form is generally preferably a parenteral preparation, and can be, for example, an injection, a transdermal preparation, an enteral preparation, an infusion, or the like. The route of administration of the medicament of the present invention is not particularly limited, but in the case of a parenteral preparation, for example, intravascular administration (preferably intravenous administration), intraperitoneal administration, intraintestinal administration, subcutaneous administration, or administration to the target site. Topical administration and the like can be mentioned. In one of the preferred embodiments, the medicament of the present invention is administered to a living body by intravenous or local administration. Further, the dosage of the medicament of the present invention or a pharmaceutical composition containing the same is appropriately selected depending on the usage, the age, sex, body weight of the subject, the type of cancer, and other conditions.
本発明の第一の態様の医薬又はこれを含む医薬組成物は、免疫チェックポイント阻害剤と組み合わせて用いるためのものである。「免疫チェックポイント阻害剤と組み合わせて用いるための」医薬とは、免疫チェックポイント阻害剤と組み合わせて用いることが意図される限り、実際に組み合わせられる前の状態の医薬であってよく、すなわち組み合わせ医薬の製造に用いられる医薬、組み合わせて用いるために製造又は販売されている医薬等も、本発明の範囲内にある。また、ここで「免疫チェックポイント阻害剤と組み合わせて用いる」とは、その必要がある、すなわちがんの治療及び／又は予防が望まれる患者に対して、免疫チェックポイント阻害剤と一緒に又は別々に、同時に又は逐次的に投与することを意味する。 The medicament of the first aspect of the present invention or a pharmaceutical composition containing the same is for use in combination with an immune checkpoint inhibitor. A medicament "for use in combination with an immune checkpoint inhibitor" may be a medicament in its pre-combined state, as long as it is intended to be used in combination with an immune checkpoint inhibitor, i.e., a combination medicament. Also within the scope of the present invention are medicaments used in the manufacture of , medicaments manufactured or sold for use in combination, and the like. In addition, "to be used in combination with an immune checkpoint inhibitor" here refers to the use of the drug together with or separately from an immune checkpoint inhibitor for patients who need it, that is, for whom treatment and/or prevention of cancer is desired. , simultaneously or sequentially.
本発明の第二の態様の医薬又はこれを含む医薬組成物は、免疫チェックポイント阻害剤と前記物質との組み合わせを有効成分として含有する。「組み合わせを有効成分として含有する」医薬は、免疫チェックポイント阻害剤と前記物質とを一緒に又は別々に、同時に又は逐次的に、その必要がある対象に投与することを目的として調製される医薬であればよく、それぞれ独立に製剤化された免疫チェックポイント阻害剤と前記物質とを含む併用剤、又は製剤化可能である限り免疫チェックポイント阻害剤と前記物質とを含む合剤であってもよい。 The medicament of the second aspect of the present invention or a pharmaceutical composition containing the same contains a combination of an immune checkpoint inhibitor and the above-mentioned substance as an active ingredient. A drug "containing a combination as an active ingredient" is a drug prepared for the purpose of administering an immune checkpoint inhibitor and the above-mentioned substance together or separately, simultaneously or sequentially to a subject in need thereof. It may be a combination drug containing an immune checkpoint inhibitor and the above-mentioned substance formulated independently, or a combination drug containing an immune checkpoint inhibitor and the above-mentioned substance as long as it can be formulated. good.
本発明において、免疫チェックポイント阻害剤の量は、前記物質と組み合わされたときにがんを治療及び／又は予防することができる量であればよく、一般に、単独で用いられる場合の量と同等であるか、又はこれより少ない。単独で用いられる場合の量と同等の量の免疫チェックポイント阻害剤を用いることで、がんに対するより強力な効果が発揮され、より短期間に、又は単独で用いても効果が確認できなかった対象において、がんを治療及び／又は予防することができる。また、単独で用いられる場合の量よりも少ない量の免疫チェックポイント阻害剤を用いることは、がんに対する効果を維持しながら、免疫チェックポイント阻害剤の量を減らすことができるという利点を有する。 In the present invention, the amount of immune checkpoint inhibitor may be any amount that can treat and/or prevent cancer when combined with the substance, and is generally equivalent to the amount when used alone. or less. Using an immune checkpoint inhibitor at a dose similar to that used alone had a stronger effect against cancer, and no effect was observed when used for a shorter period of time or alone. Cancer can be treated and/or prevented in a subject. Also, using a smaller amount of the immune checkpoint inhibitor than when used alone has the advantage that the amount of the immune checkpoint inhibitor can be reduced while maintaining its effectiveness against cancer.
本発明の医薬において、免疫チェックポイント阻害剤は１種類を単独で使用してもよく、2種以上を組み合わせて使用してもよい。「組み合わせて用いる」とは、その必要がある、すなわちがんの治療及び／又は予防が望まれる患者に対して、2種以上の免疫チェックポイント阻害剤を一緒に又は別々に、同時に又は逐次的に投与することを意味する。 In the medicament of the present invention, one type of immune checkpoint inhibitor may be used alone, or two or more types may be used in combination. “Used in combination” refers to the use of two or more immune checkpoint inhibitors together or separately, simultaneously or sequentially, for patients who need it, that is, for whom treatment and/or prevention of cancer is desired. It means to be administered to.
がんの治療及び／又は予防のための方法
本発明はまた、免疫チェックポイント阻害剤、並びにIL-34の発現を抑制する、IL-34の活性を阻害する及び／又はIL-34に結合することでCSF-1RとIL-34との結合を阻害する物質のそれぞれの有効量を、一緒に又は別々に、同時に又は逐次的に、その必要がある対象に投与することを含む、がんの治療及び／又は予防のための方法を別の態様として提供する。 Methods for the treatment and/or prevention of cancer The present invention also provides immune checkpoint inhibitors and agents that suppress the expression of IL-34, inhibit the activity of IL-34, and/or bind to IL-34. treatment of cancer, comprising administering to a subject in need thereof, together or separately, simultaneously or sequentially, an effective amount of each of the substances that inhibit the binding of CSF-1R and IL-34. In another aspect, methods for treatment and/or prevention are provided.
本発明はさらに、免疫チェックポイント阻害剤と、IL-34の発現を抑制する、IL-34の活性を阻害する及び／又はIL-34に結合することでCSF-1RとIL-34との結合を阻害する物質との組み合わせの有効量を、その必要がある対象に投与することを含む、がんの治療及び／又は予防のための方法をさらなる別の態様として提供する。 The present invention further provides an immune checkpoint inhibitor that suppresses the expression of IL-34, inhibits the activity of IL-34, and/or binds to IL-34 to bind CSF-1R and IL-34. In yet another embodiment, there is provided a method for treating and/or preventing cancer, which comprises administering to a subject in need thereof an effective amount of a combination with a substance that inhibits cancer.
免疫チェックポイント阻害剤の効果の増強
本発明の一実施形態において、IL-34の発現を抑制する、IL-34の活性を阻害する及び／又はIL-34に結合することでCSF-1RとIL-34との結合を阻害する物質は、組み合わされる免疫チェックポイント阻害剤の効果を増強する作用を有するものと考えられる。したがって、本発明は、IL-34の発現を抑制する、IL-34の活性を阻害する及び／又はIL-34に結合することでCSF-1RとIL-34との結合を阻害する物質を有効成分として含有する、免疫チェックポイント阻害剤の増強剤；並びにIL-34の発現を抑制する、IL-34の活性を阻害する及び／又はIL-34に結合することでCSF-1RとIL-34との結合を阻害する物質の有効量を、免疫チェックポイント阻害剤が投与された又は投与が予定される対象に投与することを含む、免疫チェックポイント阻害剤のがんの治療及び／又は予防の効果を増強する方法を、それぞれ別の態様として提供する。ここで、「免疫チェックポイント阻害剤の効果を増強する」及び「免疫チェックポイント阻害剤の増強剤」とは、免疫チェックポイント阻害剤が単独で用いられた場合に発揮するがんの治療及び／又は予防の効果を上回る強さの効果を発揮させること、並びにそのための剤をいい、その有効量は前記物質及び組み合わされる免疫チェックポイント阻害剤の種類、用法、対象の年齢、性別、体重、がんの種類その他の条件等に応じて適宜決定される。本態様におけるその他の各用語の意義は先行する別の態様において説明したとおりである。 Enhancement of the effects of immune checkpoint inhibitors In one embodiment of the present invention, CSF-1R and IL-34 can be inhibited by suppressing IL-34 expression, inhibiting IL-34 activity, and/or binding to IL-34. Substances that inhibit binding to -34 are thought to have the effect of enhancing the effects of the combined immune checkpoint inhibitor. Therefore, the present invention provides effective substances that suppress the expression of IL-34, inhibit the activity of IL-34, and/or inhibit the binding between CSF-1R and IL-34 by binding to IL-34. Contains as a component an enhancer of immune checkpoint inhibitors; and inhibits IL-34 expression, inhibits IL-34 activity, and/or binds to IL-34 to enhance CSF-1R and IL-34. Treatment and/or prevention of cancer with an immune checkpoint inhibitor, comprising administering an effective amount of a substance that inhibits the binding of an immune checkpoint inhibitor to a subject to whom the immune checkpoint inhibitor has been administered or is scheduled to be administered. Methods of enhancing efficacy are provided in separate embodiments. Here, "enhancing the effects of immune checkpoint inhibitors" and "enhancers of immune checkpoint inhibitors" refer to the effects of cancer treatment and/or effects when immune checkpoint inhibitors are used alone. or to exert a stronger effect than the preventive effect, and an agent for that purpose, and the effective amount thereof depends on the type and dosage of the substance and the immune checkpoint inhibitor to be combined, and the age, sex, and weight of the subject. The amount will be determined as appropriate depending on the type of material and other conditions. The meanings of the other terms in this embodiment are as explained in the previous embodiment.
以下の実施例によって本発明をさらに詳細に説明するが、本発明はこれらの例に限定されるものではない。 The present invention will be explained in more detail with reference to the following examples, but the present invention is not limited to these examples.
実施例１
１）マウスIL-34遺伝子をノックアウトするためのガイドRNAをpCas-ガイドベクター中に組み込んだIL34-gene knockout kit via CRISPR, Mouse (-) (SantaCruz, SC-429354) を、卵巣がん細胞株HM-1（RIKEN RBCより入手）に、FuGENE (登録商標) 6 Transfection Reagent (Promega) を用いてトランスフェクションし、IL-34遺伝子がノックアウトされた卵巣がん細胞株（HM1/IL34KO）を作製した。また、マウスIL-34遺伝子（Gene ID: 76527）をプラスミドベクターpLenti-EF1a-C-Myc-DDK-IRES-PURO（Origene, PS100085）に組み込むことにより作製したIL-34発現ベクターをHM1/IL34KOに導入し、IL-34を過剰発現する卵巣がん細胞株（HM1/IL34OE）を作製した。 Example 1
1) The IL34-gene knockout kit via CRISPR, Mouse (-) (SantaCruz, SC-429354), in which guide RNA for knocking out the mouse IL-34 gene was incorporated into a pCas-guide vector, was used in the ovarian cancer cell line HM. -1 (obtained from RIKEN RBC) using FuGENE (registered trademark) 6 Transfection Reagent (Promega) to create an ovarian cancer cell line (HM1/IL34KO) in which the IL-34 gene was knocked out. In addition, an IL-34 expression vector created by integrating the mouse IL-34 gene (Gene ID: 76527) into the plasmid vector pLenti-EF1a-C-Myc-DDK-IRES-PURO (Origene, PS100085) was used in HM1/IL34KO. We created an ovarian cancer cell line (HM1/IL34OE) that overexpresses IL-34.
HM-1（以下、WT HM-1とも表す）、HM1/IL34KO及びHM1/IL34OEを、10% FBS supplemented Mem-alpha（Wako, 135-15175）を用いて、37℃、5% CO2下で培養した。培養後の上清を回収し、ELISA kit（Legend MAX mouse IL-34 ELISA kit, catalog no. 439107）及びMouse HSC Panel (13-plex)（Legendplex 740677）を用いて上清中のIL-34及びM-CSFの濃度を定量した。WT HM-1培養上清で観察されたIL-34産生はHM1/IL34KO培養上清では認めなかった一方、HM1/IL34OE培養上清ではIL-34発現量の大幅な増加が観察されたことから、HM1/IL34KOにおけるIL-34のノックアウト及びHM1/IL34OEにおけるIL-34過剰発現が確認された。また、いずれの細胞株ともM-CSFを検出上限以上に産生していた（図１）。HM-1 (hereinafter also referred to as WT HM-1), HM1/IL34KO and HM1/IL34OE were grown at 37°C under 5 % CO2 using 10% FBS supplemented Mem-alpha (Wako, 135-15175). Cultured. The supernatant after culture was collected, and IL-34 and The concentration of M-CSF was quantified. The IL-34 production observed in the WT HM-1 culture supernatant was not observed in the HM1/IL34KO culture supernatant, whereas a significant increase in IL-34 expression was observed in the HM1/IL34OE culture supernatant. , IL-34 knockout in HM1/IL34KO and IL-34 overexpression in HM1/IL34OE were confirmed. Furthermore, all cell lines produced M-CSF above the detection limit (Figure 1).
さらに、培養後の細胞をAPC標識した抗CSF-1R抗体（Biolegend、135510）及びアイソタイプコントロール抗体（Rat IgG2a、400512）で染色し、フローサイトメトリー（FACS Aria II, Beckman Coulter）により解析した。いずれの細胞株もCSF-1Rの発現は陰性であった（図２）。 Furthermore, the cultured cells were stained with APC-labeled anti-CSF-1R antibody (Biolegend, 135510) and isotype control antibody (Rat IgG2a, 400512), and analyzed by flow cytometry (FACS Aria II, Beckman Coulter). All cell lines showed negative expression of CSF-1R (Fig. 2).
２）B6C3F1マウス（雌、6-8週齢）を4群（WT IgG (n=7)、KO IgG (n=6)、WT αPD-1 (n=7)、KO αPD-1 (n=8)）に分けて、２つの群（WT IgG、WT αPD-1）にWT HM-1を、残り２つの群（KO IgG、KO αPD-1）にHM-1/IL34KOを、それぞれ1 × 105個／匹ずつ腹腔内に移植した。移植後２日目から、２つの群（WT IgG、KO IgG）にコントロールIgG（ChromePure Rat IgG, whole molecule, Jackson ImmunoResearch）を、残り２つの群（WT αPD-1、KO αPD-1）に抗PD-1抗体（RMP1-14、順天堂大学医学部免疫講座・八木田秀雄先生より分与）を、それぞれ100μg/200μl/mouseずつ週2回腹腔内投与し、通常の飼育環境下で飼育した。がん細胞移植後55日目まで飼育したときの各群のマウスの生存率を図３に示す。2) Four groups of B6C3F1 mice (female, 6-8 weeks old) (WT IgG (n=7), KO IgG (n=6), WT αPD-1 (n=7), KO αPD-1 (n= 8)), WT HM-1 was given to two groups (WT IgG, WT αPD-1), and HM-1/IL34KO was given to the remaining two groups (KO IgG, KO αPD-1), each 1 × 10 5 pieces/mouse were implanted intraperitoneally. From the second day after transplantation, control IgG (ChromePure Rat IgG, whole molecule, Jackson ImmunoResearch) was administered to two groups (WT IgG, KO IgG), and anti-antibody was administered to the remaining two groups (WT αPD-1, KO αPD-1). PD-1 antibody (RMP1-14, provided by Dr. Hideo Yagita, Department of Immunology, Juntendo University School of Medicine) was intraperitoneally administered at 100 μg/200 μl/mouse each twice a week, and the animals were kept in a normal breeding environment. Figure 3 shows the survival rate of mice in each group when they were kept until 55 days after cancer cell transplantation.
HM-1/IL34KOを移植し抗PD-1抗体を投与した群（KO αPD-1 mAb）では、HM-1を移植しコントロールIgGを投与した群（WT Control IgG）、HM-1/IL34KOを移植しコントロールIgGを投与した群（KO Control IgG）及びHM-1を移植し抗PD-1抗体を投与した群（WT αPD-1 mAb）のいずれと比較しても有意な生存期間の延長が観察され、IL-34の阻害と抗PD-1抗体との組み合わせによる優れた抗腫瘍効果が確認された。 In the group in which HM-1/IL34KO was transplanted and anti-PD-1 antibody was administered (KO αPD-1 mAb), the group in which HM-1 was transplanted and control IgG was administered (WT Control IgG), and in the group in which HM-1/IL34KO was transplanted and control IgG was administered (WT Control IgG). There was a significant prolongation of survival compared to both the group transplanted with control IgG (KO Control IgG) and the group transplanted with HM-1 and administered anti-PD-1 antibody (WT αPD-1 mAb). This confirmed the excellent antitumor effect of the combination of IL-34 inhibition and anti-PD-1 antibody.
実施例２
１）実施例１の１）と同様にして、大腸がん細胞株CT26（遺伝子病制御研究所 北村秀光先生より分与）から、IL-34遺伝子がノックアウトされた大腸がん細胞株（CT26/IL34KO）及びCT26/IL34KOにIL-34遺伝子を組み込んだIL-34遺伝子過剰発現株（CT26/IL34OE）を作製した。 Example 2
1) In the same manner as in 1) of Example 1, a colorectal cancer cell line (CT26/ IL-34 gene overexpression lines (CT26/IL34OE) were created by integrating the IL-34 gene into CT26/IL34KO) and CT26/IL34KO.
CT26、CT26/IL34KO及びCT26/IL34OEを、10% FBS supplemented RPMI-1640（Wako, 189-02025）を用いて、37℃、5% CO2下で培養した。培養後の細胞を回収し、Tripure Isolation Reagent（Roche Life Science）を用いてRNAを抽出し、ReverTra Ace qPCR RT Master Mix（TOYOBO）を用いてcDNAを合成し、KAPA SYBR Fast qPCR Kitを用いて以下のプライマーでRT-PCRを行った。
マウス Il-34
フォワードプライマー 5’- CTTTGGGAAACCAGAATTTGGAG -3’（配列番号１）
リバースプライマー 5’- GCAATCCTGTAGTTGATGGGGAA -3’（配列番号２）CT26, CT26/IL34KO, and CT26/IL34OE were cultured at 37° C. under 5% CO 2 using 10% FBS supplemented RPMI-1640 (Wako, 189-02025). Collect cells after culture, extract RNA using Triple Isolation Reagent (Roche Life Science), synthesize cDNA using ReverTra Ace qPCR RT Master Mix (TOYOBO), and perform the following using KAPA SYBR Fast qPCR Kit. RT-PCR was performed using the primers.
Mouse Il-34
Forward primer 5'- CTTTGGGAAACCAGAATTTGGAG -3' (SEQ ID NO: 1)
Reverse primer 5'- GCAATCCTGTAGTTGATGGGGAA -3' (SEQ ID NO: 2)
野生型のCT26では弱いIL-34発現が観察された一方、CT26/IL34KOではIL-34発現は消失し、またCT26/IL34OEではIL-34発現量の大幅な増加が観察され、CT26/IL34KO におけるIL-34のノックアウト及びCT26/IL34OEにおけるIL-34過剰発現が確認された（図４）。 While weak IL-34 expression was observed in wild-type CT26, IL-34 expression disappeared in CT26/IL34KO, and a significant increase in IL-34 expression was observed in CT26/IL34OE. Knockout of IL-34 and overexpression of IL-34 in CT26/IL34OE were confirmed (Figure 4).
また、培養上清中のM-CSF濃度を実施例１の１）と同様にして定量した。いずれの細胞株ともM-CSFを検出上限以上に産生していた（図５）。さらに、培養後の細胞におけるCSF-1Rの発現を実施例１の１）と同様にしてフローサイトメトリーにより解析した。いずれの細胞株ともCSF-1Rの発現は陰性であった（図６）。 In addition, the M-CSF concentration in the culture supernatant was determined in the same manner as in Example 1, 1). All cell lines produced M-CSF above the detection limit (Figure 5). Furthermore, the expression of CSF-1R in the cultured cells was analyzed by flow cytometry in the same manner as in Example 1, 1). CSF-1R expression was negative in all cell lines (Figure 6).
２）BALB/cマウス（雌、７週齢）を4群（KO IgG、OE IgG、KO αPD-1、OE αPD-1；いずれもn=5）に分けて、２つの群（KO IgG、KO αPD-1）にCT26/IL34KOを、残り２つの群（OE IgG、OE αPD-1）にCT26/IL34OEを、それぞれ2×105個／匹ずつ皮下移植した。移植後7日目から、２つの群（KO IgG、OE IgG）にコントロールIgG（ChromePure Rat IgG, whole molecule, Jackson ImmunoResearch）を、残り２つの群（KO αPD-1、OE αPD-1）に抗PD-1抗体（RMP1-14、順天堂大学医学部免疫講座・八木田秀雄先生より分与）を、それぞれ250μg/mouseずつ、一週間毎に腹腔内に投与し、通常の飼育環境下で飼育した。抗体投与開始後28日目までの各群のマウスの腫瘍体積（平均値）の変化を図７に、抗体投与開始後28日目の各群の腫瘍体積を図８に示す。2) BALB/c mice (female, 7 weeks old) were divided into 4 groups (KO IgG, OE IgG, KO αPD-1, OE αPD-1; n = 5 for each), and 2 groups (KO IgG, CT26/IL34KO was subcutaneously transplanted into the KO αPD-1) group, and CT26/IL34OE was subcutaneously transplanted into the remaining two groups (OE IgG, OE αPD-1) at 2×10 5 cells/mouse each. From
CT26/IL34KOを移植し抗PD-1抗体を投与した群（KO αPD-1 mAb）では、CT26/IL34OEを移植しコントロールIgGを投与した群（OE Control IgG）、CT26/IL34KOを移植しコントロールIgGを投与した群（KO Control IgG）及びCT26/IL34OEを移植し抗PD-1抗体を投与した群（OE αPD-1 mAb）のいずれと比較しても腫瘍体積が有意に小さく、IL-34の阻害と抗PD-1抗体との組み合わせによる優れた抗腫瘍効果が確認された。 In the group transplanted with CT26/IL34KO and administered anti-PD-1 antibody (KO αPD-1 mAb), in the group transplanted with CT26/IL34OE and administered with control IgG (OE Control IgG), in the group transplanted with CT26/IL34KO and administered with control IgG The tumor volume was significantly smaller compared to both the group administered with CT26/IL34OE (KO Control IgG) and the group treated with CT26/IL34OE and administered anti-PD-1 antibody (OE αPD-1 mAb). Excellent antitumor effects were confirmed by the combination of inhibition and anti-PD-1 antibody.
試験例
B6C3F1マウスに、HM1、HM1/IL34KO及びHM1/IL34OEをそれぞれ1 × 106個／匹ずつ腹腔内に投与した。投与後7日目からPBS (ヘパリン含)でマウスの腹腔内洗浄液を回収し、単細胞懸濁液とした。これをanti-CD11b（Biolegend）、anti-F4/80（Biolegend）及びanti-CD206（Biolegend）で染色し、フローサイトメトリー解析によりM2マクロファージの含有率（CD11b陽性かつF4/80陽性細胞に対するCD206陽性細胞の割合）を測定した。 Test example
HM1, HM1/IL34KO, and HM1/IL34OE were each intraperitoneally administered to B6C3F1 mice at 1×10 6 mice/mouse. From
結果を図９に示す。HM1/IL34KOを投与したマウスのM2マクロファージ含有率は、野生型のHM1を投与したマウスのそれの半分強であり、一方でIL-34を過剰発現させたHM1/IL34OEを投与したマウスではM2マクロファージ含有率はHM1投与マウスのそれと同等であった。 The results are shown in FIG. M2 macrophage content in mice treated with HM1/IL34KO was slightly more than half that of mice treated with wild-type HM1, whereas M2 macrophage content in mice treated with HM1/IL34OE overexpressing IL-34 was The content was comparable to that of HM1-treated mice.
HM-1細胞株、CT26細胞株がいずれもM-CSF陽性及びCSF-1R陰性であること、IL-34のノックアウトはM2マクロファージを劇的には低減させなかったことから、IL-34阻害による抗PD-1抗体の抗腫瘍効果の増強は、がん細胞が発現するCSF-1RとIL-34との相互作用の阻害やIL-34誘導性TAM集積の阻害以外の、未知の機構が存在するものと推察された。 Both HM-1 and CT26 cell lines were M-CSF positive and CSF-1R negative, and IL-34 knockout did not dramatically reduce M2 macrophages, indicating that IL-34 inhibition The anti-tumor effect of anti-PD-1 antibodies is enhanced by an unknown mechanism other than inhibition of the interaction between CSF-1R expressed by cancer cells and IL-34 and inhibition of IL-34-induced TAM accumulation. It was presumed that it would.
実施例３
BALB/cマウス（雌、７週齢、三協ラボサービス）を10群（KO-NT、OE-NT、KO IgG、OE IgG、KO αPD-1、OE αPD-1、KO αCTLA-4、OE αCTLA-4、KO αPD-1 & αCTLA-4、OE αPD-1 & αCTLA-4；いずれもn=5）に分けた。KO-NT、KO IgG、KO αPD-1、KO αCTLA-4及びKO αPD-1 & αCTLA-4に、マトリゲルに懸濁したCT26/IL34KOを2×105個／匹ずつ皮下移植し、OE-NT、OE IgG、OE αPD-1、OE αCTLA-4及びOE αPD-1 & αCTLA-4に、マトリゲルに懸濁したCT26/IL34OEを2×105個／匹ずつ皮下移植した。 Example 3
10 groups of BALB/c mice (female, 7 weeks old, Sankyo Labo Service) (KO-NT, OE-NT, KO IgG, OE IgG, KO αPD-1, OE αPD-1, KO αCTLA-4, OE αCTLA-4, KO αPD-1 & αCTLA-4, OE αPD-1 &αCTLA-4; n = 5 for each). KO-NT, KO IgG, KO αPD-1, KO αCTLA-4, and KO αPD-1 & αCTLA-4 were subcutaneously implanted with 2 × 10 5 CT26/IL34KO suspended in Matrigel, and OE- CT26/IL34OE suspended in Matrigel was subcutaneously implanted into NT, OE IgG, OE αPD-1, OE αCTLA-4, and OE αPD-1 & αCTLA-4 at 2×10 5 cells/mouse each.
腫瘍の平均長径が5mm弱となった日（移植後5～7日目）を初回投与日として、一週間に一度、KO IgG及びOE IgGにコントロールIgG（ChromePure Rat IgG, whole molecule, Jackson ImmunoResearch）を、KO αPD-1及びOE αPD-1に抗PD-1抗体（RMP1-14）を、KO αCTLA-4及びOE αCTLA-4に抗CTLA-4抗体（UC10-4F10、順天堂大学医学部免疫講座・八木田秀雄先生より分与）を、KO αPD-1 & αCTLA-4及びOE αPD-1 & αCTLA-4に抗PD-1抗体及び抗CTLA-4抗体を、いずれも抗体合計量として250 μg/mouseずつ腹腔内に投与し、通常の飼育環境下で飼育した。抗体投与開始後8日目までの各群のマウスの腫瘍体積（平均値）の変化を図１０に、抗体投与開始後8日目の各群の腫瘍体積を図１１に示す。図１０のグラフ右の表記は、上から下に向けて、8日目の時点で腫瘍体積が大きい順にマウス群を列記したものである。
Control IgG (ChromePure Rat IgG, whole molecule, Jackson ImmunoResearch) was administered to KO IgG and OE IgG once a week, with the first administration date being the day when the average length of the tumor was less than 5 mm (5th to 7th day after transplantation). , anti-PD-1 antibody (RMP1-14) to KO αPD-1 and OE αPD-1, and anti-CTLA-4 antibody (UC10-4F10, Department of Immunology, Juntendo University School of Medicine) to KO αCTLA-4 and OE αCTLA-4. (distributed by Dr. Hideo Yagita), anti-PD-1 antibody and anti-CTLA-4 antibody to KO αPD-1 & αCTLA-4 and OE αPD-1 & αCTLA-4, each with a total antibody amount of 250 μg/mouse. The mice were intraperitoneally administered and reared in a normal breeding environment. Figure 10 shows the changes in tumor volume (average value) of mice in each group up to 8 days after the start of antibody administration, and Figure 11 shows the tumor volume of each
CT26/IL34OEを移植した群では、抗PD-1抗体又は抗CTLA-4抗体を単独で投与しても腫瘍増殖はほとんど抑制されず、抗PD-1抗体及び抗CTLA-4抗体の併用投与で腫瘍増殖は抑制された。一方、CT26/IL34KOを移植した群では、抗PD-1抗体又は抗CTLA-4抗体の単独投与で腫瘍増殖は抑制され、特に抗PD-1抗体及び抗CTLA-4抗体の併用投与で腫瘍増殖は顕著に抑制された。以上から、IL-34の阻害と抗PD-1抗体又は抗CTLA-4抗体との組み合わせによる優れた抗腫瘍効果、及びIL-34の阻害と抗PD-1抗体と抗CTLA-4抗体との組み合わせによるさらに優れた抗腫瘍効果が確認された。 In the group transplanted with CT26/IL34OE, tumor growth was hardly suppressed even when anti-PD-1 antibody or anti-CTLA-4 antibody was administered alone, and tumor growth was hardly suppressed when anti-PD-1 antibody and anti-CTLA-4 antibody were administered together. Tumor growth was suppressed. On the other hand, in the group transplanted with CT26/IL34KO, tumor growth was suppressed by single administration of anti-PD-1 antibody or anti-CTLA-4 antibody, and tumor growth was especially suppressed by combined administration of anti-PD-1 antibody and anti-CTLA-4 antibody. was significantly suppressed. From the above, the combination of IL-34 inhibition and anti-PD-1 antibody or anti-CTLA-4 antibody has an excellent antitumor effect, and the combination of IL-34 inhibition and anti-PD-1 antibody and anti-CTLA-4 antibody Even better antitumor effects were confirmed by the combination.
実施例４
BALB/cマウス（雌、７週齢、三協ラボサービス）を8群に分け、マトリゲルに懸濁したCT26/IL34OEを2×105個／匹ずつ皮下移植した。腫瘍の平均長径が5mm弱となった日（移植後5～7日目）を初回投与日として、図１２に示す投与計画でコントロールIgG（ChromePure Rat IgG, whole molecule, Jackson ImmunoResearch）、抗IL-34抗体（ミリポア、MABT493）、抗PD-1抗体（RMP1-14）、抗CTLA-4抗体（UC10-4F10、順天堂大学医学部免疫講座・八木田秀雄先生より分与）を腹腔内に投与し、通常の飼育環境下で飼育した。抗体投与開始後13日目までの各群のマウスの腫瘍体積（平均値）の変化を図１３に、抗体投与開始後13日目の各群の腫瘍体積を図１４に示す。図１３のグラフ右の表記は、上から下に向けて、13日目の時点で腫瘍体積が大きい順にマウス群を列記したものである。 Example 4
BALB/c mice (female, 7 weeks old, Sankyo Labo Service) were divided into 8 groups, and CT26/IL34OE suspended in Matrigel was subcutaneously implanted at 2×10 5 mice/mouse. Control IgG (ChromePure Rat IgG, whole molecule, Jackson ImmunoResearch), anti-IL- 34 antibody (Millipore, MABT493), anti-PD-1 antibody (RMP1-14), and anti-CTLA-4 antibody (UC10-4F10, provided by Dr. Hideo Yagita, Department of Immunology, Juntendo University School of Medicine) were administered intraperitoneally. The animals were reared in a breeding environment. Figure 13 shows the changes in tumor volume (average value) of mice in each group up to 13 days after the start of antibody administration, and Figure 14 shows the tumor volumes of each
本実施例においても、抗IL-34抗体を抗PD-1抗体又は抗CTLA-4抗体と併用投与することで腫瘍増殖の抑制が観察された。特に、抗IL-34抗体、抗PD-1抗体及び抗CTLA-4抗体の3種類の抗体を併用することで、腫瘍増殖は顕著に抑制された。以上から、IL-34の阻害と抗PD-1抗体又は抗CTLA-4抗体との組み合わせによる優れた抗腫瘍効果、及びIL-34の阻害と抗PD-1抗体と抗CTLA-4抗体との組み合わせによるさらに優れた抗腫瘍効果が確認された。 In this example as well, suppression of tumor growth was observed when anti-IL-34 antibody was administered in combination with anti-PD-1 antibody or anti-CTLA-4 antibody. In particular, tumor growth was significantly suppressed by the combined use of three types of antibodies: anti-IL-34 antibody, anti-PD-1 antibody, and anti-CTLA-4 antibody. From the above, the combination of IL-34 inhibition and anti-PD-1 antibody or anti-CTLA-4 antibody has an excellent antitumor effect, and the combination of IL-34 inhibition and anti-PD-1 antibody and anti-CTLA-4 antibody Even better antitumor effects were confirmed by the combination.
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