JP2022533430A - 切断可能なリンカーを有する抗体薬物複合体 - Google Patents
切断可能なリンカーを有する抗体薬物複合体 Download PDFInfo
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- JP2022533430A JP2022533430A JP2021569277A JP2021569277A JP2022533430A JP 2022533430 A JP2022533430 A JP 2022533430A JP 2021569277 A JP2021569277 A JP 2021569277A JP 2021569277 A JP2021569277 A JP 2021569277A JP 2022533430 A JP2022533430 A JP 2022533430A
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Abstract
Description
本発明を詳細に説明する前に、デバイスおよび方法は変化し得るので、本発明は、説明されたデバイスの特定の構成要素部分、または説明された方法のプロセス工程に限定されないことを理解されたい。また、本明細書で使用される用語は特定の実施形態を説明することのみを目的としており、限定することを意図していないことを理解されたい。本明細書および添付の特許請求の範囲において使用されるように、単数形「a」、「an」、および「the」は文脈が明白に別段の規定をしない限り、単数形および/または複数の対象を含むことに留意しなければならない。さらに、数値で区切られたパラメータ範囲が与えられた場合、その範囲はこれらの制限値を含むものとみなされることも理解されるべきである。
Dは、前記化合物からの切断で1,2-または1,3-ジオールとなる部分を少なくとも1つ含む細胞毒性薬部分であり;
ZはCH2、CH2-CH2、またはCHR3-CHR3であり、R3は独立してHまたは任意にヘテロ原子で置換されていてもよいアルキル基であり;
R1はHまたはC1-C6アルキル基であり;
Aは電子供与基であり;
Eは切断部位であり;
R2は独立してHまたは電子求引もしくは供与基である。
アスパラギン酸プロテアーゼは、それらのペプチド基質の触媒作用のために1つ以上のアスパラギン酸残基に結合した活性化水分子を使用する触媒型のプロテアーゼ酵素である。一般に、それらは、活性部位に2つの高度に保存されたアスパラギン酸塩を有し、酸性pHで最適に活性である。ほとんど全ての既知のアスパルチルプロテアーゼは、ペプスタチンによって阻害される。
Lはリンカーであり、
Tは標的結合部分である。
(i)抗体またはその抗原結合断片;
(ii)抗体様タンパク質、および
(iii)核酸アプタマー。
XはS、SO、またはSO2であり;
R1はHまたはC1-C6アルキル基であり;
R2は独立してHまたは電子求引もしくは供与基であり;
R4はH、OH、O-C1-C8-アルキル、NO2、NH2、F、Cl、Br、またはSHであり;
R5はOH、NH2、またはNHOHであり;
R6、R7は天然または非天然アミノ酸の側鎖であり;
Lはリンカーであり、そして
Tは標的結合部分である。
XはS、SO、またはSO2であり;
YはCH2またはCOであり;
R1はHまたはC1-C6アルキル基であり;
R2は独立してHまたは電子求引もしくは供与基であり; 少なくとも1つのR2基は前記T-L部分に置換されており
R4はH、OH、O-C1-C8-アルキル、NO2、NH2、F、Cl、Br、またはSHであり;
R5はOH、NH2、またはNHOHであり;
Lはリンカーであり、そして
Tは標的結合部分である。
XはS、SO、またはSO2であり;
R1はHまたはC1-C6アルキル基であり;
R2は独立してHまたは電子求引もしくは供与基であり、ただし、R8がT-L部分でない場合、1つのR2は前記T-L部分に置換されており;
R4はH、OH、O-C1-C8-アルキル、NO2、NH2、F、Cl、Br、またはSHであり;
R5はOH、NH2、またはNHOHであり;
R8は直鎖または分岐鎖のアルキル基であり、または、いずれのR2もT-L部分でない場合、T-L部分であり;
Lはリンカーであり、そして
Tは標的結合部分である。
XはS、SO、またはSO2であり;
R1はHまたはC1-C6アルキル基であり;
R2は独立してHまたは電子求引もしくは供与基であり、ただし、R9がT-L部分でない場合、1つのR2は前記T-L部分に置換されており;
R4はH、OH、O-C1-C8-アルキル、NO2、NH2、F、Cl、Br、またはSHであり;
R5はOH、NH2、またはNHOHであり;
R9はHまたは直鎖もしくは分岐鎖のアルキル基であり、または、いずれのR2もT-L部分でない場合、T-L部分であり;
Lはリンカーであり、そして
Tは標的結合部分である。.
13C NMR (126 MHz, CDCl3) d 158.85, 130.53, 127.88, 114.21, 102.99, 71.19, 70.84, 70.70, 70.64, 70.53, 69.73, 67.42, 52.59, 30.33.
MS (ESI+) 実測値:429.17; 計算値 [M+Na]+:429.09 (C17H27BrNaO6)
1H NMR (500 MHz, CDCl3) d 7.30-7.23 (m, 1H), 7.06-7.00 (m, 2H), 6.88 (ddd, J = 8.3, 2.5, 1.1 Hz, 1H), 5.35 (s, 1H), 4.17-4.12 (m, 2H), 3.88-3.84 (m, 2H), 3.81 (t, J = 6.3 Hz, 2H), 3.77-3.71 (m, 2H), 3.71-3.66 (m, 6H), 3.46 (t, J = 6.3 Hz, 2H), 3.32 (s, 6H).
13C NMR (126 MHz, CDCl3) d 158.92, 139.76, 129.32, 119.38, 115.01, 112.74, 103.06, 71.31, 70.95, 70.82, 70.76, 70.65, 69.87, 67.54, 52.84, 30.44.
MS (ESI+) 実測値:375.17/377.17;計算値 [MH-OMe]+:375.08/377.08 (C16H24BrO5)
MS (ESI+) 実測値:393.17/395.17; 計算値 [MH-OMe]+:393.07/395.07 (C16H23BrFO5)
1H NMR (500 MHz, CDCl3) d 7.18 (dd, J = 12.0, 2.1 Hz, 1H), 7.13 (ddt, J = 8.4, 1.9, 0.8 Hz, 1H), 6.97 (t, J = 8.4 Hz, 1H), 5.33 (s, 1H), 4.23-4.17 (m, 2H), 3.90-3.86 (m, 2H), 3.81 (t, J = 6.3 Hz, 2H), 3.76-3.72 (m, 2H), 3.68 (d, J = 9.6 Hz, 6H), 3.46 (t, J = 6.3 Hz, 2H), 3.30 (s, 6H).
13C NMR (126 MHz, , CDCl3) d 152.60 (d, J = 246.1 Hz), 146.92 (d, J = 10.9 Hz), 131.90 (d, J = 5.7 Hz), 122.61 (d, J = 3.6 Hz), 114.93 (d, J = 4.0 Hz), 114.79, 102.20 (d, J = 1.6 Hz), 71.31, 71.06, 70.80, 70.74, 70.65, 69.71, 69.21, 52.67, 30.44.
1H NMR (500 MHz, CDCl3) d 7.42 (d, J = 8.7 Hz, 1H), 7.18 (d, J = 3.2 Hz, 1H), 6.79 (dd, J = 8.7, 3.1 Hz, 1H), 5.50 (s, 1H), 4.16-4.09 (m, 2H), 3.87-3.83 (m, 2H), 3.81 (t, J = 6.3 Hz, 2H), 3.74-3.71 (m, 2H), 3.70-3.66 (m, 6H), 3.47 (t, J = 6.3 Hz, 2H), 3.38 (s, 6H).
13C NMR (126 MHz, CDCL3) d 158.22, 137.89, 133.57, 117.11, 114.31, 113.52, 102.99, 71.34, 70.99, 70.83, 70.77, 70.67, 69.77, 67.89, 54.08, 30.44.
MS (ESI+)
実測値:502.00/504.00/506.00;
計算値[M+NH4]+:502.04/504.04/506.04 (C17H30Br2NO6)
実測値:453.08/455.08/457.08;
計算値 [MH-OMe]+: 452.99/454.99/456.99 (C16H23Br2O5)
MS (ESI+)
実測値:392.25;計算値[M+Na]+: 392.18(C17H27N3NaO6)
実測値:338.25;計算値 [MH-OMe]+:338.17(C16H24N3O5)
13C NMR (126 MHz, CDCl3) d 158.77, 156.47, 143.97, 141.26, 127.84, 127.69, 127.60, 126.98, 125.02, 119.90, 114.14, 102.95, 70.79, 70.55, 70.30, 69.99, 69.85, 69.67, 67.32, 66.44, 52.55, 47.24, 40.90.
MS (ESI+)
実測値:588.33;計算値 [M+Na]+:588.26 (C32H39NNaO8)
実測値:534.33;計算値 [MH-OMe]+:534.25 (C31H36NO7)
MS (ESI+) 実測値:588.33;計算値[M+Na]+:588.26 (C32H39NNaO8)
MS (ESI+)
実測値: 606.33;計算値[M+Na]+:606.25 (C32H38FNNaO8)
実測値:552.33;計算値[MH-OMe]+:552.24 (C31H35FNO7)
MS (ESI+)実測値:666.17/668.17
計算値[M+Na]+:666.17/668.17 (C32H38BrNNaO8)
温度を-70°C未満に維持しながらDMSO(739μl,10.4mmol)をゴム隔膜を介してシリンジで滴下した。15分撹拌後、20mlのジクロロメタンに溶解したFmoc-Val-Ala-PAB-OH(HDP 30.1419,2.062g,4.0mmol)を、滴下漏斗により30分かけて滴下し、混合物をさらに30分撹拌した。
13C NMR (126 MHz, D6-DMSO) d 191.35, 171.75, 171.03, 156.05, 144.40, 143.79, 143.69, 140.61, 131.30, 130.68, 127.52, 127.50, 126.93, 125.22, 119.96, 119.95, 118.76, 65.63, 59.86, 49.20, 46.64, 30.32, 19.06, 18.12, 17.70.
MS (ESI+)実測値: 536.25 計算値 [M+Na]+:536.22 (C30H31N3NaO5)
1H NMR (500 MHz, D6-DMSO) d 9.40 (s, 1H), 8.20 (d, J = 7.0 Hz, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.74 (t, J = 7.6 Hz, 2H), 7.53 (d, J = 8.0 Hz, 1H), 7.46-7.36 (m, 4H), 7.32 (tt, J = 7.5, 1.3 Hz, 2H), 7.23 (td, J = 7.6, 1.7 Hz, 1H), 7.15 (td, J = 7.4, 1.3 Hz, 1H), 5.24 (t, J = 5.6 Hz, 1H), 4.56-4.42 (m, 3H), 4.36-4.28 (m, 1H), 4.28-4.20 (m, 2H), 3.96 (dd, J = 9.1, 6.8 Hz, 1H), 2.04 (h, J = 6.8 Hz, 1H), 1.35 (d, J = 7.1 Hz, 3H), 0.90 (d, J = 6.7 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H).
13C NMR (126 MHz, D6-DMSO) d 171.09, 170.90, 156.09, 143.83, 143.72, 140.65, 140.63, 135.08, 134.74, 127.55, 127.54, 127.23, 126.97, 126.87, 125.27, 124.64, 123.66, 120.00, 119.98, 65.65, 60.03, 59.86, 48.90, 46.65, 40.01, 39.84, 39.67, 39.50, 39.34, 39.17, 39.00, 31.23, 30.33, 19.15, 18.04, 17.89.
MS (ESI+) 実測値:538.25 計算値 [M+Na]+:538.23 (C30H33N3NaO5)
MS (ESI+) 実測値:536.25 計算値[M+Na]+:536.22 (C30H31N3NaO5)
ゼラチン状物質を溶解するために100mlのクロロホルムを加え、相分離した。水相を2x50mlのクロロホルムで逆抽出し、合わせた有機層を50mlの半飽和食塩水で洗浄し、乾燥させ(MgSO4)、蒸発させた。粗生成物をシリカゲル上でジクロロメタン中0~20%酢酸エチルの勾配で精製して、アモルファス固体として3.279g(72%)の標題生成物HDP 30.2769を得た。
13C NMR (126 MHz, D6-DMSO) d 176.52, 176.05, 161.32, 149.06, 148.95, 145.89, 145.87, 140.68, 134.89, 133.97, 132.82, 132.80, 132.38, 132.23, 130.56, 130.55, 129.58, 129.11, 125.27, 106.40, 70.84, 65.01, 58.68, 58.37, 54.27, 51.85, 35.65, 24.41, 23.26, 22.69.
MS (ESI+) 実測値:582.33 計算値 [M+Na]+:582.26 (C32H37N3NaO6)
MS (ESI+) 実測値: 360.25 計算値[M+Na]+:360.19 (C17H27N3NaO4)
13C NMR (126 MHz, D6-DMSO) d 171.03, 170.78, 170.63, 169.50, 135.51, 134.47, 129.50, 128.70, 127.15, 124.23, 123.70, 101.33, 57.27, 53.46, 53.18, 49.08, 33.99, 33.64, 30.32, 19.10, 17.91, 17.28.1
MS (ESI+) 実測値:511.25 計算値 [M+Na]+:511.22 (C24H32N4NaO7)
1H NMR (500 MHz, D6-DMSO) d 9.95 (s, 1H), 8.17 (d, J = 7.0 Hz, 1H), 7.88 (d, J = 7.5 Hz, 2H), 7.75 (t, J = 7.8 Hz, 2H), 7.59 (d, J = 1.9 Hz, 1H), 7.50-7.37 (m, 4H), 7.32 (tt, J = 7.5, 1.6 Hz, 2H), 7.24 (t, J = 7.8 Hz, 1H), 6.99 (d, J = 7.8 Hz, 1H), 5.19 (t, J = 5.7 Hz, 1H), 4.45 (dd, J = 14.7, 6.5 Hz, 3H), 4.36-4.28 (m, 1H), 4.28-4.19 (m, 2H), 3.93 (dd, J = 9.0, 7.1 Hz, 1H), 2.01 (h, J = 6.8 Hz, 1H), 1.32 (d, J = 7.0 Hz, 3H), 0.91 (d, J = 6.7 Hz, 3H), 0.87 (d, J = 6.7 Hz, 3H).
13C NMR (126 MHz, D6-DMSO) d 170.93, 156.08, 143.80, 143.72, 143.16, 140.63, 140.62, 138.78, 128.29, 127.57, 127.54, 126.98, 125.29, 121.21, 120.02, 120.00, 117.41, 117.11, 65.63, 62.77, 59.92, 48.95, 46.61, 30.32, 19.13, 18.19, 18.07, 3.26.
MS (ESI+) 実測値:538.33 計算値[M+Na]+:538.23(C30H33N3NaO5)
13C NMR (126 MHz, D6-DMSO) d 171.09, 170.77, 170.71, 169.76, 138.90, 138.79, 134.52, 128.46, 121.42, 118.99, 117.25, 102.42, 57.71, 52.44, 52.42, 49.08, 34.02, 33.70, 30.26, 19.11, 18.17, 17.83.
MS (ESI+) 実測値:511.25 計算値[M+Na]+:511.22 (C24H32N4NaO7)
乾燥DMF(100μl/mg)中のジオール化合物の溶液に、ジメチルアセタール化合物(10当量)を加えた。混合物をトリフルオロ酢酸(10μl/mg)で酸性化し、透明な溶液が形成されるまでアルゴン雰囲気下で周囲温度で撹拌した。続いて、高真空で溶媒を留去し残りは新しいDMFに再溶解した。サンプルをメタノール中の1%トリエチルアミンでクエンチし、HPLCで分析して、出発物質の完全な変換を示した。
ジオール化合物(1当量)とジメチルアセタール化合物(8当量)を遠心チューブに入れ、DMF/TFA4:1(v/v、20μl/μmolジオール化合物)に溶解した。HPLC制御がジオール化合物の完全な変換を示すまで(1~18時間)、チューブを室温で振とうした。次に、20倍量の氷冷MTBEを添加し、遠心分離によって沈殿物を単離した。最初のペレットを2vol-%トリエチルアミンを含む同量のMTBEに再懸濁し、再度遠心分離した。乾燥したペレットをさらに精製することなく次の反応に使用した。
MS (ESI+) 実測値:1414.67; 計算値[MH]+:1414.58 (C69H84N13O18S)
(MS-ESI+) 実測値:1192.67; 計算値[MH]+:1192.51 (C54H74N13O16S)
500μlの乾燥DMFに溶解した3-(マレイミド)プロピオン酸N-ヒドロキシスクシンイミドエステル(BMPS、14mg、52.42μmol=2当量)を加え、続いて8.92μl(52.42μmol=2当量)のN、N-ジイソプロピルエチルアミンを添加した。室温で2時間撹拌した後、反応混合物を10mlの氷冷されたMTBEに滴下し、そして沈殿物を遠心分離によって単離した。粗ペレットを、15分で水中の5~50%アセトニトリルの勾配を用いたLuna-C18(2)での分取HPLCによって精製した。11.9-12.8分の生成物画分を凍結乾燥して、20.85mg(59%)の無色の凍結乾燥物を得た。
MS (ESI+) 実測値:1343.58; 計算値[MH]+:1343.54 (C61H79N14O19S)
MS (ESI+) 実測値:1371.58; 計算値 [MH]+:1371.52 (C61H80N12NaO21S))
MS (ESI+) 実測値:1371.50; 計算値[MH]+:1371.52 (C61H80N12NaO21S))
MS (ESI+) 実測値:1389.50; 計算値[MH]+:1389.51 (C61H79FN12NaO21S)
MS (ESI+)
実測値:1449.42/1451.42;
計算値 [MH]+:1449.43/1451.43 (C61H79BrN12NaO21S)
D265C突然変異(「チオマブ」、Ig重鎖のアミノ酸位置265におけるアスパラギン酸からシステインへの突然変異)を有する抗Her2neu特異的抗体であるトラスツズマブの誘導体を、アマトキシンリンカー誘導体HDP 30.2669、HDP 30.2670、HDP 30.2671、HDP 30.2672およびHDP 30.2684に結合させた。
トラスツズマブ (抗HER2neu特異的抗体)-アマトキシン複合体の細胞毒性活性を、HER2陽性腫瘍細胞株SKBR-3(乳癌)、NCI-N87(胃癌)およびJIMT-1(乳癌)について、化学発光BrdUーELISA取込みアッセイ(Roche)を用いてインビトロで評価した。試験した複合体は、アマトキシンのaa3(T-D265C-30.2684)に連結された本発明によるジペプチジン切断部位を有する芳香族環状アセタールとの1つの複合体、アマトキシンのaa4に連結されたジペプチジン切断部位を有するパラアミノベンジルエーテルリンカーとの1つの複合体(T-D265C-30.1699)、およびアマトキシンのaa3に連結されたポリエチレングリコール(PEG)リンカーを有する芳香族環状アセタールとの4つの複合体(p-PEG3リンカーを有するT-D265C-30.2669、m-PEG3 リンカーを有する-30.2670、p-PEG3 リンカーおよびフッ化アリール部分を有する-30.2671、o-PEG3 リンカーおよび臭化アリール部分を有する-30.2672)を含んでいた。
種々のHer2陽性細胞株上の種々のトラスツズマブ-アマトキシン複合体のEC50値を表1に示す:
本研究は、皮下Her2陽性SKOV‐3(ヒト卵巣)腫瘍をそれぞれ有する10匹の雌NOD Scidマウスによる7つの実験群から構成された。アマトキシンa3結合を有する2つの芳香族環状アセタール複合体(T‐D265C‐30.2684、T‐D265C‐30.2669)の漸増用量における有効性を、アマトキシンのaa4に結合したジペプチジン切断部位を有するパラ‐アミノ‐ベンジルリンカーを有するT‐D265C‐30.1699および未処理対照と比較した。マウスに単回静脈内投与した。
アマトキシンADC T‐D265C‐30.2669およびT‐D265C‐30.2684の許容性を、それぞれ、1回の静注適用後のNOD/SCIDマウスで評価した。全21匹の動物を使用した。T‐D265C‐30.2669およびT‐D265C‐30.2684は6mg/kgまでの有効量で良好な忍容性を示した。結果を図6に示す。
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Claims (23)
- Dが、アマトキシン、アフィジコリン、アポトリジン、カリケアマイシン、ジギトキシン、ジゴキシン、エトポシド、グルコピリシジンA、ヒポテマイシン、イサトロポロン(isatropolone)A、ラクタシスチン、ムスコトキシン(muscotoxin)A、パンクラチスタチン、ファロイジン、フェンパンスタチン、フィトスフィンゴシン、プロスシラリジン(poscillaridin)A、プセウロチンA、レベッカマイシン、シネフンギン、G-ストロファンチン、スワインソニン、およびツルボスタチン1-4からなる群より選択される、請求項1に記載の化合物。
- 前記アマトキシンが、α-アマニチン、β-アマニチン、アマニン、アマニンアミドおよびそれらの類似体、誘導体および塩からなる群より選択される、請求項2に記載の化合物。
- 前記電子供与基Aが、O、NHおよびSから選択される、請求項1~3のいずれかに記載の化合物。
- 切断部位Eが、2つ以上のアミノ酸、好ましくはバリン-アラニン(Val-Ala)、バリン-シトルリン(Val-Cit)、バリン-リジン(Val-Lys)、バリン-アルギニン(Val-Arg)ジペプチド、フェニルアラニン-リジン-グリシン-プロリン-ロイシン-グリシン(Phe Lys Gly Pro Leu Gly)またはアラニン-アラニン-プロリン-バリン(Ala Ala Pro Val)ペプチド、またはβ-グルクロニドまたはβ-ガラクトシドを含む酵素的に切断可能な部分である、請求項1~4のいずれかに記載の化合物。
- 請求項1~5のいずれかに記載の化合物およびT-L部分を含む複合体であって、前記T-L部分が式IまたはIIの残基R2の少なくとも1つを置換しており、
Lはリンカーであり、
Tは標的結合部分である、複合体。 - リンカーLがアルキレン、ヘテロアルケニレン、ヘテロアルケニレン、アルキニレン、ヘテロアルキニレン、ヘテロアルキレン、シクロアルキレン、ヘテロシクロアルキレン、アリーレン、ヘテロアリーレン、アラルキレン、またはヘテロアラルキレン基であり、N、O、およびSから選択される1~4個のヘテロ原子を含み、任意に前記リンカーが置換されている、請求項6に記載の複合体。
- リンカーLが、以下の部分:ジスルフィド、エーテル、チオエーテル、アミン、エステル、カルボキサミド、ウレタン、および尿素部分のうちの少なくとも1つから選択される部分を含む、請求項6または7のいずれかに記載の複合体。
- 標的結合部分Tが、以下からなる群より選択される、請求項6~8のいずれかに記載の複合体;
(i)抗体またはその抗原結合断片、
(ii)抗体様タンパク質、および
(iii)核酸アプタマー。 - 抗体またはその抗原結合断片が、ダイアボディ、テトラボディ、ナノボディ、キメラ抗体、脱免疫抗体、ヒト化抗体またはヒト抗体から選択される、請求項9に記載の複合体。
- 前記抗原結合断片が、Fab、F(ab')2、Fd、Fv、一本鎖Fv、およびジスルフィド結合Fv(dsFv)からなる群より選択される、請求項9に記載の複合体。
- 酸性条件下で非プロトン性溶媒中で1,2-または1,3-ジオールをジメチルベンジリデンアセタールと反応させることによる、請求項6~16のいずれかに記載の複合体の合成方法。
- 酸性条件下で非プロトン性溶媒中でアマトキシンをジメチルベンジリデンアセタールと反応させることによる、請求項6~16のいずれかに記載の複合体の合成方法。
- 前記アマトキシンが、アルファ-アマニチン、ベータ-アマニチン、アマニン、アマニンアミドおよびそれらのそれぞれのチオエーテルから選択される、請求項18に記載の方法。
- 前記非プロトン性溶媒がDMFであり、および/または前記酸がトリフルオロ酢酸である、請求項18または19のいずれかに記載の方法。
- 医薬として使用するための、請求項6~16のいずれかに記載の複合体。
- 患者における癌の治療における使用のための請求項6~16、21のいずれかに記載の複合体であって、特に前記癌が乳癌、膵臓癌、胆管癌、大腸癌、肺癌、前立腺癌、卵巣癌、胃癌、腎臓癌、悪性黒色腫、白血病、および悪性リンパ腫からなる群より選択される複合体。
- 1つ以上の薬学的に許容される希釈剤、担体、賦形剤、充填剤、結合剤、潤滑剤、崩壊剤、吸着剤、および/または防腐剤を任意にさらに含む、請求項6~16のいずれか1項に記載の複合体を含む医薬組成物。
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