JP5569946B2 - 免疫抑制剤および自己免疫疾患の予防および治療剤 - Google Patents
免疫抑制剤および自己免疫疾患の予防および治療剤 Download PDFInfo
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- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000001488 sodium phosphate Substances 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
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- GGHPAKFFUZUEKL-UHFFFAOYSA-M sodium;hexadecyl sulfate Chemical compound [Na+].CCCCCCCCCCCCCCCCOS([O-])(=O)=O GGHPAKFFUZUEKL-UHFFFAOYSA-M 0.000 description 1
- 229940035044 sorbitan monolaurate Drugs 0.000 description 1
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- 235000011071 sorbitan monopalmitate Nutrition 0.000 description 1
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- YODZTKMDCQEPHD-UHFFFAOYSA-N thiodiglycol Chemical compound OCCSCCO YODZTKMDCQEPHD-UHFFFAOYSA-N 0.000 description 1
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Description
(1)Tim-3のリガンド結合にはガレクチン-9以外の結合、すなわちガレクチン-9 ― Tim-3シグナル伝達系以外の経路が存在し、抗Tim-3抗体はそれらの経路を遮断していること、
および
(2)樹状細胞上のTim-3経路は炎症メカニズムの上流にあり、それを遮断することが自己免疫疾患の治療に重要であること
を明らかにしたものである。
(1)ガレクチン-9―Tim-3シグナル伝達経路を遮断する物質を有効成分とする免疫抑制剤および自己免疫疾患の予防および治療剤。
(1-2)免疫抑制および自己免疫疾患の治療が必要な対象者に、有効量のガレクチン-9―Tim-3シグナル伝達経路を遮断する物質を投与することを含む、免疫抑制及び自己免疫疾患の予防および治療の方法。
(1-3)免疫抑制剤および自己免疫疾患の予防および治療用の医薬品の製造における、ガレクチン-9―Tim-3シグナル伝達経路を遮断する物質の使用。
(1-4)自己免疫疾患の予防および治療に使用される、ガレクチン-9―Tim-3シグナル伝達経路を遮断する物質。
(2)抗Tim-3抗体を有効成分とする(1)に記載の免疫抑制剤および自己免疫疾患の予防および治療剤。
(2-2)免疫抑制および自己免疫疾患の治療が必要な対象者に有効量の抗Tim-3抗体を投与することを含む、(1-2)に記載の方法。
(2-3)免疫抑制剤および自己免疫疾患の予防および治療用の医薬品の製造における、抗Tim-3抗体の使用。
(2-4)自己免疫疾患の予防および治療に使用される、抗Tim-3抗体。
(3)抗ガレクチン-9抗体を有効成分とする(1)に記載の免疫抑制剤および自己免疫疾患の予防および治療剤。
(4)抗Tim-3抗体が、ガレクチン-9によるヘルパーT細胞サブタイプ1(Th1細胞)のアポトーシスを誘導しない低濃度のガレクチン-9存在下で、ガレクチン-9によるTh1細胞アポトーシス誘導を増強することを特徴とする、(2)に記載の免疫抑制剤および自己免疫疾患の予防および治療剤。
(5)ガレクチン-9に特異的に結合し、ガレクチン-9とTim-3との結合を阻害するRNAおよびDNAアプタマーをそれぞれ有効成分とする(1)に記載の免疫抑制剤および自己免疫疾患の予防および治療剤。
(6)Tim-3に特異的に結合し、ガレクチン-9とTim-3との結合を阻害するRNAおよびDNAアプタマーをそれぞれ有効成分とする(1)に記載の免疫抑制剤および自己免疫疾患の予防よび治療剤。
(7)ガレクチン-9に特異的に結合し、ガレクチン-9とTim-3との結合を阻害する低分子化合物を有効成分とする(1)に記載の免疫抑制剤および自己免疫疾患の予防および治療剤。
(8)Tim-3に特異的に結合し、Tim-3とガレクチン-9との結合を阻害する低分子化合物を有効成分とする(1)に記載の免疫抑制剤および自己免疫疾患の予防及び治療剤。
(9)Tim-3に強固に結合し、立体構造を破壊することによりガレクチン-9との結合性を消失させる低分子化合物を有効成分とする(1)に記載の免疫抑制剤および自己免疫疾患の予防および治療剤。
(10)自己免疫疾患が、ヘルパーT細胞サブタイプ1(Th1)が関与する1型糖尿病、関節リウマチ、全身性エリトマトーデス、抗リン脂質抗体症候群、多発性筋炎、皮膚筋炎、全身性硬化症、シェーグレン症候群、混合性結合組織病、成人発症スチル病、血管炎症候群(大動脈炎、結節性動脈周囲炎、ANCA関連血管炎)、ウェゲナー肉芽腫症、サルコイドーシス、キャッスルマン病、ベーチェット病、IgA腎症、膜性腎症、急速進行性糸球体腎炎、バセドウ病(Grave’s disease)、潰瘍性大腸炎、クローン病、およびギランバレー症候群、多発性硬化症、再生不良性貧血、移植後拒絶反応および移植片対宿主病(GVHD) を含む(1)に記載の免疫抑制剤および自己免疫疾患の予防及び治療剤。
(11)下記の工程からなる(7)に記載のガレクチン-9に結合し、Tim-3との結合を阻害する低分子化合物のスクリーニング方法。
(a)低分子化合物サンプルをガレクチン-9と接触させる工程、
(b)低分子化合物のガレクチン-9への結合を検出する工程、
(c)低分子化合物のガレクチン-9への結合がガレクチン-9とTim-3との結合を阻害することを評価する工程。
(12)下記の工程からなる8)に記載のTim-3に結合し、ガレクチン-9の結合を競合的に阻害する低分子化合物のスクリーニング方法。
(a)ガレクシン-9をTim-3に接触させる工程、
(b)低分子化合物をガレクチン-9結合Tim-3に接触させる工程、
(c)Tim-3に結合したガレクチン-9量の減少を評価する工程。
(13)下記の工程からなる(9)に記載のTim-3に強固に結合し、立体構造を破壊することによりガレクチン-9との結合性を消失させる低分子化合物のスクリーニング方法。
(a)低分子化合物サンプルをTim-3と接触させる工程、
(b)低分子化合物のTim-3への結合を検出する工程、
(c)低分子化合物のTim-3への結合によるTim-3とガレクチン-9との結合阻害および抗Tim-3抗体との反応性消失などを評価する工程。
、ベーチェット病、IgA腎症、膜性腎症、急速進行性糸球体腎炎、バセドウ病(Grave’s disease)、潰瘍性大腸炎、クローン病、ギランバレー症候群、多発性硬化症、再生不良性貧血、移植後拒絶反応、及び移植片体宿主病への応用が想定される。
(a)ガレクチン-9をアプタマーの存在、および非存在下で一定時間インキュベーションし、ついで、
(b)反応液を固定化Tim-3(flTim-3-IgあるいはsTim-3-Ig融合タンパク質であってもよい)に加えて一定時間インキュベーションした後、
(c)Tim-3に結合したガレクチン-9量をガレクチン-9 ELISAで測定し、ガレクチン-9のTim-3への結合を阻害するアプタマーを選別すること
により、本発明の上記(1)のRNAおよびDNAアプタマーを得ることができる。
(a)Tim-3(flTim-3-IgあるいはsTim-3-Ig融合タンパク質であってもよい)をアプタマーの存在、および非存在下で一定時間インキュベーションし、ついで、
(b)反応液を固定化ガレクチン-9に加えて一定時間インキュベーションした後、
(c)ガレクチン-9に結合したTim-3量をTim-3 ELISAで測定し、Tim-3のガレクチン-9への結合を阻害するアプタマーを選別すること
により、本発明の上記(2)のRNAおよびDNAアプタマーを得ることができる。
1)NODマウスとICRマウスの膵島におけるガレクチン-9発現の比較
免疫染色法は以下の方法により実施した。
ホルマリン固定した組織を100%キシレンで5分ずつ計3回、脱パラフィン化した。その後、100%エタノールで5分ずつ3回、90%エタノールで5分、80%エタノールで5分、70%エタノールで5分、親水化を行った。洗浄後、0.3%過酸化水素水とメタノールで、内因性ペルオキシダーゼのブロッキングを実施した。2次抗体由来の正常ウサギ血清(10%)でブロッキングした。Vector社(Burlingame, CA, US)のAVIDIN-BIOTIN BLOCKING KIT(SP-2001)を使用し、Avidin block(15min), Biotin block(15min)を施行した。Goat polyclonal Galectin-9 antibody(M-20)(Santa Cruz Biotechnology, Santa Cruz, CA)を1:50に希釈し、4℃で一晩インキュベーションした。さらに2次抗体Biotinylated Anti-Goat IgG(H+L)(Vector社 BA-7000)を50倍に希釈し反応後、Vector社のABC Kit(PK-4100)の3次抗体を反応させた。DAB試薬(Vector社)を1分反応させ、マイヤーヘマトキシリンでカウンター染色5秒、40℃の水に1分間つけ発色させた。さらにエタノール、キシレンで脱水し、M・X(松浪硝子工業株式会社)で包埋した。
投与実験のプロトコール(1)を以下に示す。
(a)NODマウス(n = 20, メス) に遺伝子組み換えマウスガレクチン-9 (1mg/kg BW)、および対照群としてPBS-DTTを7週齢から42週齢まで週に一回、腹腔内投与する。
(遺伝子組み換えマウスガレクチン-9の生産と調製は、後述の実施例4-1)により実施)
(b)週1回血糖測定を行い2回連続して血糖値レベルが250 mg/dl以上に達した時に、糖尿病発症と規定する。
(c)マウスは糖尿病発症後(ケトアシドーシスに陥り死亡するので)、直ちに殺して試験に供する。
遺伝子組み換えマウスガレクチン-9の投与によるNODマウスの1型糖尿病発症に及ぼす効果をKaplan-Meyerの生存曲線で図3に示す。
膵島におけるインスリンの染色は以下のように実施した。
ホルマリン固定した組織を100%キシレンで5分ずつ計3回、脱パラフィン化した。その後、100%エタノールで5分ずつ3回、90%エタノールで5分、80%エタノールで5分、70%エタノールで5分、親水化を行った。洗浄後、0.3%過酸化水素水とメタノールで、内因性ペルオキシダーゼのブロッキングを施行した。正常ヤギ血清(10%)でブロッキングした。Vector社のAVIDIN-BIOTIN BLOCKING KIT(SP-2001)を使用し、Avidin block(15min), Biotin block(15min)を施行した。Polyclonal Guinea Pig Anti-Swine(DAKO社:A 0564)を500倍に希釈し、4℃で一夜、インキュベーションした。
次に、ガレクチン-9がどの細胞に作用するかについてフローサイトメトリ(Flow Cytometry)を用いて検討した。
そのプロトコールを以下に示す。
(a)7週齢のNODマウスとICRマウスに解析24時間前に遺伝子組み換えマウスガレクチン-9 (1mg/kg・BW)、および対照群としてPBSを投与する。
(遺伝子組み換えマウスガレクチン-9の生産と調製は、後述の実施例4-1)により実施)
(b)マウスを殺して後、脾細胞を分離し、Lymphocyte-Mを用いて、リンパ球の分離を行う。
(c)リンパ球を染色後、速やかにBD FACSAria Cell Sorterで解析する。
FACS解析結果を図5に示す。
CD4+, CD8+, CD4+CD25+およびCD4+ Tim3+の各々の細胞分画についてAnnexin Vを用い、アポトーシスについて解析した。その結果を図6に示す。
ガレクチン-9―Tim-3シグナル伝達経路を遮断する抗ガレクチン-9抗体および抗Tim-3抗体をそれぞれ作製した。
(a)マウスガレクチン-9は公知の方法(Wada J., et al.: J. Biol. Chem. 272:6078-6086, 1997; Wada J., et al.: J. Clin. Invest. 99:2452-2461, 1997)に基づいて、pTrcHisベクター(Invitrogen, San Diego, CA, US)を使用して産生させた。なおガレクチン-9は、C末端にc-mycエピトープ及び(His)6を有する融合たんぱく質として産生される。
(b)マウスガレクチン-9をコードするDNAを含むベクター(以下、「pTrcHis2/G9」という)を、TOP10バクテリア宿主(Invitrogen社製)にトランスフォーメーションした。トランスフォーメーションした細菌コロニーを、Luria-Bertani’s培地で培養し、1 mmol/Lのisopropyl-β-D-thiogalactopyranoside (IPTG)を加えることによりタンパク質合成を誘導した。1%TritonX-100、10mmol/L benzamidine、10 mmol/L ε-amino-n-caproic acid及び2 mmol/L phenylmethanesulfonyl fluorideを含むTris-dithiothreitol (Tris-DTT)緩衝液(20 mmol/L Tris (pH 7.4), 5 mmol/L ethylenediaminetetraacetic acid (EDTA), 150 mmol/L sodium chloride, 1 mmol/L)で細菌を溶解した。
マウスTim-3は、マウスTim-3 (BALB-type) (Monney L., et al.: Nature 415: 536-541, 2002)およびTim-3のメジャーなバリアントのマウスTim-3 (B6 type) (McIntire JJ., et al.: Nat. Immunol. 2: 1109-1116, 2001)のそれぞれの細胞外部(1-191アミノ酸残基)とマウスIgG2aのFc部との融合タンパク質(mouse Tim-3-Ig)をそれぞれ安定発現させたCHO細胞の培養上清からProtein Gカラムクロマトグラフィーで精製することにより調製した (Oikawa T., et al.: J. Immunology 177: 4281-4287, 2006)。
遺伝子組み換えマウスガレクチン-9 100μgを初回はcomplete Freund’s adjuvantおよび2, 3回目はincomplete Freund’s adjuvantとともにSDラットのfootpadに2週間ごとに3回免疫し、最終免疫の7日後にpopliteal lymph node cellsをP3U1ミエローマ細胞と融合して、ハイブリドーマの培養上清中の抗体活性を遺伝子組み換えマウスガレクチン-9に対する ELISAでスクリーニングした。クローニングすることにより抗ガレクチン-9抗体(RG9-35)を安定して産生するハイブリドーマを樹立した。
マウスTim-3-Ig融合タンパク質(BALB typeおよびB6 type)それぞれを抗原として、上記と同様にSDラットを免疫後、同様にハイブリドーマを作製した。BALB type Tim-3およびB6 type Tim-3のそれぞれに対する抗体産生ハイブリドーマは、それぞれの全長マウスTim-3を安定して発現させたNRK細胞を用いてFACSでスクリーニングした。
抗体RG9-35 (rat IgG 2a, κ)およびRMT3-23 (rat IgG2a, κ)の生産と精製は、それぞれの抗体産生ハイブリドーマをヌードマウスの腹腔内に移植し、生成される復水からカプリル酸/硫酸アンモニウム(caprylic acid/ammonium sulfate)沈殿法により実施した。
1)抗ガレクチン-9 および抗Tim-3抗体によるガレクチン-9とTim-3結合の阻害作用
抗ガレクチン-9抗体(RG9-35)および抗Tim-3抗体(RMT3-23)のそれぞれによるガレクチン-9とTim-3との結合阻害作用を図7に示す。
ガレクチン-9刺激によるTh1細胞死誘導に及ぼす作用を調べた結果を図8に示す。
ガレクチン-9には、1型糖尿病発症抑制効果があり、その作用機序はガレクチン-9が成熟Th1細胞(CD4+Tim-3+)に作用してTh1細胞のアポトーシスを介していると考えられた。
(a)抗ガレクチン-9抗体、あるいは抗Tim-3抗体をNODマウス1個体あたり0.25 mg, 週に2回、8週齢から51週齢までの計43週間、腹腔内投与する。
(b)実施例2で示したガレクチン-9投与実験の場合と同様に、週に1回の血糖測定を行い、連続して2回250 mg/dl以上を示した時に、糖尿病発症と規定する。
(c)糖尿病発症後、速やかに殺して各種試験に供する。
実施例5-2(図8)の結果から明らかなように、抗Tim-3抗体(RMT3-23)は、ガレクチン-9(0.2μM)存在下で培養されたTh1細胞の細胞死に対してほとんど影響を及ぼさなかった。本実施例では、Th1アポトーシス誘導に対する作用量(0.2μモル)および無作用量のガレクチン-9(0.04μM)の存在下において抗Tim-3抗体の影響を検討した。
1. メスのICRマウスの脾臓から、CD4 microbeads (Miltenyi)を用いてCD4+ T cellを分離した。
2. 抗CD3 mAb (2C11, 10μg/ml) をコーティングした24 well プレートに5×105個ずつまき、抗CD28Ab (PV-1) 10μg/ml, マウス IL-12 10 ng/ml、抗IL-4Ab (11B11) 10μg/ml を添加し、4日間培養した。
3. 回収して96 wellプレートに 5×105/ml の濃度でまき直し、ヒトIL-2 20 U/ml を添加し、3日間培養した。
4. 解析24時間前に遺伝子組み換えマウスガレクチン-9 (rGal-9) (0.2 μM又は0.04 μM)、抗Tim-3抗体(RMT3-23) (10 μg/ml又は100 μg/ml)を添加し、FACS Ariaを用いてアポトーシスについて解析した。
Claims (4)
- 抗Tim-3抗体及び/または抗ガレクチン-9抗体を有効成分とする、ヘルパーT細胞サブタイプ1(Th1)が関与する1型糖尿病の予防および治療剤。
- 抗Tim-3抗体を有効成分とする請求項1記載の予防および治療剤。
- 抗ガレクチン-9抗体を有効成分とする請求項1記載の予防および治療剤。
- 抗Tim-3抗体が、ガレクチン-9によるTh1細胞のアポトーシスを誘導しない低濃度のガレクチン-9存在下で、ガレクチン-9によるTh1細胞アポトーシス誘導を増強することを特徴とする、請求項2に記載の予防および治療剤。
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EP3049442A4 (en) | 2013-09-26 | 2017-06-28 | Costim Pharmaceuticals Inc. | Methods for treating hematologic cancers |
JOP20200094A1 (ar) | 2014-01-24 | 2017-06-16 | Dana Farber Cancer Inst Inc | جزيئات جسم مضاد لـ pd-1 واستخداماتها |
JOP20200096A1 (ar) | 2014-01-31 | 2017-06-16 | Children’S Medical Center Corp | جزيئات جسم مضاد لـ tim-3 واستخداماتها |
FR3021970B1 (fr) | 2014-06-06 | 2018-01-26 | Universite Sciences Technologies Lille | Anticorps dirige contre la galectine 9 et inhibiteur de l'activite suppressive des lymphocytes t regulateurs |
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KR102011205B1 (ko) * | 2014-11-06 | 2019-08-14 | 에프. 호프만-라 로슈 아게 | 항-tim3 항체 및 사용 방법 |
US11014983B2 (en) | 2015-08-20 | 2021-05-25 | Sutro Biopharma, Inc. | Anti-Tim-3 antibodies, compositions comprising anti-Tim-3 antibodies and methods of making and using anti-Tim-3 antibodies |
HUE055407T2 (hu) | 2015-10-02 | 2021-11-29 | Hoffmann La Roche | PD1-re és TIM3-ra specifikus bispecifikus antitestek |
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