JP2021073245A - Il−6阻害剤を有効成分とする精神疾患治療剤 - Google Patents
Il−6阻害剤を有効成分とする精神疾患治療剤 Download PDFInfo
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Abstract
Description
[1]インターロイキン6(IL-6)阻害剤を有効成分とする精神疾患治療剤。
[2]IL-6阻害剤がIL-6受容体阻害剤である[1]に記載の精神疾患治療剤。
[3]IL-6阻害剤が抗IL-6受容体抗体である[1]に記載の精神疾患治療剤。
[4]抗IL-6受容体抗体がキメラ抗体、ヒト化抗体またはヒト抗体である[3]に記載の精神疾患治療剤。
[5]プレパルス抑制効果減弱を抑制することを特徴とする、[1]から[4]のいずれかに記載の精神疾患治療剤。
[6]精神疾患が統合失調症、トゥレット症候群、および/または強迫神経症である、[1]から[5]のいずれかに記載の精神疾患治療剤。
[7]抗IL-6受容体抗体がPM-1抗体である、[3]に記載の精神疾患治療剤。
[8]対象において精神疾患を治療または予防する方法であって、有効量のインターロイキン6(IL-6)阻害剤を、精神疾患を発症した対象または発症する可能性がある対象に投与する工程を含む、前記方法。
[9]IL-6阻害剤がIL-6受容体阻害剤である[8]に記載の方法。
[10]IL-6阻害剤が抗IL-6受容体抗体である[8]に記載の方法。
[11]抗IL-6受容体抗体がキメラ抗体、ヒト化抗体またはヒト抗体である[10]に記載の方法。
[12]プレパルス抑制効果減弱を抑制することを特徴とする、[8]から[11]のいずれかに記載の方法。
[13]精神疾患が統合失調症、トゥレット症候群、および/または強迫神経症である、[8]から[12]のいずれかに記載の方法。
[14]抗IL-6受容体抗体がPM-1抗体である、[3]に記載の方法。
[15]精神疾患の治療のためのインターロイキン6(IL-6)阻害剤。
[16]IL-6受容体阻害剤である[15]に記載のIL-6阻害剤。
[17]抗IL-6受容体抗体である[15]に記載のIL-6阻害剤。
[18]抗IL-6受容体抗体がキメラ抗体、ヒト化抗体またはヒト抗体である[17]に記載のIL-6阻害剤。
[19]プレパルス抑制効果減弱を抑制することを特徴とする、[15]から[18]のいずれかに記載のIL-6阻害剤。
[20]精神疾患が統合失調症、トゥレット症候群、および/または強迫神経症である、[15]から[19]のいずれかに記載のIL-6阻害剤。
[21]抗IL-6受容体抗体がPM-1抗体である、[17]に記載のIL-6阻害剤。
[22]精神疾患治療剤の製造のためのインターロイキン6(IL-6)阻害剤の使用。
[23]IL-6阻害剤がIL-6受容体阻害剤である[22]に記載の使用。
[24]IL-6阻害剤が抗IL-6受容体抗体である[22]に記載の使用。
[25]抗IL-6受容体抗体がキメラ抗体、ヒト化抗体またはヒト抗体である[24]に記載の使用。
[26]プレパルス抑制効果減弱を抑制することを特徴とする、[22]から[25]のいずれかに記載の使用。
[27]精神疾患が統合失調症、トゥレット症候群、および/または強迫神経症である、[22]から[26]のいずれかに記載の使用。
[28]抗IL-6受容体抗体がPM-1抗体である、[24]に記載の使用。
%プレパルス抑制率 = 100 x (120-dBにおける驚愕度合 - 各プレパルスありの驚愕度合)/120-dBにおける驚愕度合
驚愕反応の強度の測定
測定はGeyerらの方法(Braff DL and Geyer MA, Arch Gen Psychiatry 1990, 47:181-188)に修正を加えた方法で行った。驚愕反応試験にはマウス用音驚愕反応測定装置(小原医科産業株式会社)を用いた。マウスを測定用の透明アクリル筒に入れて装置内に固定し、65-dBのバックグラウンドノイズを発生させ、3分間馴れさせたのち、120-dB/40 msのパルス音に対する、78-dB〜90-dB/20 msのプレパルス音有無の条件下における音驚愕反応を測定した。具体的には、各個体について以下のセッション1〜35の条件で音驚愕反応を測定した。
セッション1〜5:120-dB x 5回連続、
セッション6〜30:(1)プレパルスなし+パルス120-dB、(2)プレパルス78-dB+パルス120-dB、(3)プレパルス84-dB+パルス120-dB、(4)プレパルス90-dB+パルス120-dB、(5)パルスなし(バックグラウンド)の5種類のセッションが各5回ずつ、15〜20秒のいずれかの間隔でランダムに発生するように設定した、および
セッション31〜35:120-dB x 5回連続。
%プレパルス抑制率 = 100 x (120-dBにおける驚愕度合 - 各プレパルスありの驚愕度合)/ 120-dBにおける驚愕度合
IL-6の測定試薬にはBDTM CBAマウス高感度Flex set (cat#558301)を用いた。また、試薬の調製にはMouse/Rat Soluble protein Master Buffer Kit (cat#558266)を用いた。測定および検出にはFACSCantoII(BD)を用い、FCAP ArrayTM Softwareにて濃度を算出した。測定は、以下に示す通り、BDから出されているInstruction Manualを参考にしながら修正を加えた方法により行った。
5週齢のC57B6/J雄マウスは、行動試験の誤差を小さくするため、以下の方法により用意した:日本チャールズリバーより交配用の雄雌マウスを購入し、国立精神・神経医療研究センター小型動物飼育施設で繁殖させた。出産後、雄仔マウスのみを出産ケージに残した。3週齢に達したマウスを離乳し、1ケージ3〜4匹になるように分けて5週齢まで飼育した。
5週齢から10週間の高脂肪餌摂餌の実験系で後述の抗体投与を行う場合、抗体投与回数が1匹あたり全10回(1回/週)となり、抗体の使用量が多くなる。そこで、少ない投与回数でMR16-1の効果を判定できる系を確立するために、より短い期間でプレパルス抑制の悪化が誘導される条件を検討した。
8週齢のC57B6/J雄マウスに、普通餌CE-2または高脂肪餌High Fat Diet 32を、3週間(8週齢から11週齢まで)自由摂取させた。高脂肪餌群については抗IL-6受容体抗体MR16-1(中外製薬)またはビヒクルを、普通餌群についてはビヒクルを、3回(8、9、および10週齢において各1回)投与した。MR16-1は、8週齢では1 mg/マウス、9週齢では0.5 mg/マウス、そして10週齢では0.5 mg/マウスの用量で腹腔内注射により投与した。11週齢において、各マウスについて、参考例1と同様に音驚愕反応におけるプレパルス抑制を調べた。
統合失調症患者の死後脳においてGSK3α/βのリン酸化や発現量に変化が認められることが知られている。そこで、上記の高脂肪餌摂餌マウスにおいて誘導されるプレパルス抑制悪化に対する抗IL-6受容体抗体の作用機序を明らかにするため、線条体および前頭前野におけるGSK3a/aのリン酸化ならびにタンパク質発現量に及ぼす影響を解析した。
8週齢のC57B6/J雄マウスに、普通餌CE-2または高脂肪餌High Fat Diet 32を、3週間(8週齢から11週齢まで)自由摂取させた。高脂肪餌群については抗IL-6受容体抗体MR16-1(中外製薬)またはビヒクルを、普通餌群についてはビヒクルを、3回(8、9、および10週齢において各1回)投与した。MR16-1は、8週齢では1 mg/マウス、9週齢では0.5 mg/マウス、そして10週齢では0.5 mg/マウスの用量で腹腔内注射により投与した。11週齢において、各マウスについて、頚椎脱臼ののち速やかに脳を摘出し、冷却したPBSに入れて10秒おいたのち、マウス用ブレインスライサー(EM Japan)にセットし、カミソリを用いて厚さ1mmに切り出したものを冷却したPBSを入れたバット内に即座に移した。さらにVan De Werd らが作成した脳アトラス(Van De Werd HJ and Uylings HB, Brain Struct Funct, 2014, 219: 433-459)に従ってブレグマ+0.74の切片から線条体部位を、ブレグマ+1.70の切片から前頭前野部位を直径1.5mmの生検トレパン(貝印株式会社)を用いて1.5mLチューブに回収し、液体窒素内に入れ速やかに冷凍保存した。ウエスタンブロットの解析方法に関しては沼川らの報告(Numakawa T et al., Proc Natl Acad Sci U S A, 2009, 106: 647-652)を参照してサンプル処理を行い、ウエスタンブロットを行った。1次抗体には抗リン酸化GSK3α/β抗体 (1:2000; rabbit polyclonal, #9331, Cell Signaling Technology, Japan)、抗-GSK3α/β抗体 (1:2000; mouse monoclonal (0011-A), sc-7291, Santa Cruz Biotechnology Inc., CA, USA) および抗-β-actin抗体 (1:5000; mouse monoclonal, A-5441, Sigma Aldrich, MO, USA)を用い、2次抗体にはperoxidase-conjugated抗マウスIgG抗体 (1:1000; goat polyclonal, Jackson Immunology Research Laboratories Inc., PA, USA) および抗ウサギIgG抗体 (1:1000; goat polyclonal, Rockland Immunochemicals, Inc., PA, USA) を用いた。Immunoblotting bandの検出には ImmunoStar(登録商標)(Wako Pure Chemical Industries, Ltd., Tokyo, Japan) を用い、免疫反応性はCS Analyzer software 3 (ATTO & Rise Corp., Tokyo, Japan)を用いて解析を行った。β-actinを標準化に用いた。
高脂肪餌摂餌マウスにおいて、線条体におけるGSK3βのリン酸化が亢進しており、MR16-1投与によってGSK3βのリン酸化亢進が阻害されることを示す結果が得られた(図8aおよびc)。線条体におけるGSK3αのリン酸化およびGSK3α/βのタンパク質発現量には高脂肪餌摂餌の有無およびMR16-1投与の有無による差は見られなかった(図8a、b、d、およびe)。また、前頭前野におけるGSK3α/βリン酸化ならびにタンパク質発現量にも高脂肪餌摂餌の有無およびMR16-1投与の有無による有意な差は認められなかった(図9)。以上の結果より、MR16-1が線条体のGSK3βのリン酸化亢進を特異的に阻害することによりプレパルス抑制悪化誘導を阻止している可能性が示唆された。
Claims (7)
- インターロイキン6(IL-6)阻害剤を有効成分とする精神疾患治療剤。
- IL-6阻害剤がIL-6受容体阻害剤である請求項1に記載の精神疾患治療剤。
- IL-6阻害剤が抗IL-6受容体抗体である請求項1に記載の精神疾患治療剤
- 抗IL-6受容体抗体がキメラ抗体、ヒト化抗体またはヒト抗体である請求項3に記載の精神疾患治療剤。
- プレパルス抑制効果減弱を抑制することを特徴とする、請求項1から4のいずれか一項に記載の精神疾患治療剤。
- 精神疾患が統合失調症、トゥレット症候群、および/または強迫神経症である、請求項1から5のいずれか一項に記載の精神疾患治療剤。
- 抗IL-6受容体抗体がPM-1抗体である、請求項3に記載の精神疾患治療剤。
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