JP2020514302A - 抗5t4抗体−薬物複合体およびその使用 - Google Patents
抗5t4抗体−薬物複合体およびその使用 Download PDFInfo
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Abstract
Description
ここで、前記重鎖可変領域は、
CDR1:GFTFSSYE、
CDR2:ISSSGSTI、および
CDR3:AREMQFGWELLGAFDI、
という3つの相補性決定領域を含み、
前記軽鎖可変領域は、
CDR1’: QSVSSSY、
CDR2’: GAS、および
CDR3’: QQYGSS、
という3つの相補性決定領域を含むものを提供する。
もう一つの好適な例において、前記重鎖可変領域のアミノ酸配列は配列番号7で示される。
もう一つの好適な例において、前記軽鎖可変領域のアミノ酸配列は配列番号8で示される。
もう一つの好適な例において、前記抗体は配列番号9で示される重鎖を含む。
もう一つの好適な例において、前記抗体は配列番号10で示される軽鎖を含む。
もう一つの好適な例において、前記薬物は、デュオスタチン(Duostatin)5、MMAF、デュオスタチン(Duostatin)14、デュオマイシン(Duomycin)2、デュオマイシン(Duomycin)4、カリケアミシン(Calicheamicin)、アマニチン(Amanitine)からなる群から選ばれる小分子薬物を含む。
Ab−(L-D)n I
(ここで、Abは前記抗体である。
Lはなしか、前記抗体と前記薬物を連結するリンカーである。
Dは腫瘍細胞を抑制する小分子薬物である。
nは前記抗体に結合した前記薬物の数である。
「−」は結合またはリンカーである。)
Ab、D、nは前記の通りである。
波線は抗体との連結部位を表す。)
ZV0508、ZV0512、ZV0513、ZV0501、ZV0503、ZV0504、ZV0517、ZV0518、ZV0505、ZV0516、ZV0515、ZV0519。
ここで、複合体ZV0508の構造は以下の通りである。
または本発明の第二の側面に記載の組成物を施用する工程を含む方法を提供する。
抗体および遊離のリンカーを含む薬物分子を含む反応系を調製した後、結合反応を行うことによって、前記抗体-薬物複合体を得、
ここで、前記薬物分子はリンカーである工程を含む方法を提供する。
本発明は2種類の結合方法を提供し、毒素小分子を特定のリンカーを介して抗体に結合させ、抗体の親和性を変えずに大幅に腫瘍細胞に対する殺傷力を向上させる。
たとえば、本発明の抗体は以下の方法によって製造することができる。
CDR1:GFTFSSYE (配列番号1)、
CDR2:ISSSGSTI (配列番号2)、および
CDR3:AREMQFGWELLGAFDI(配列番号3)。
本発明のもう一つの好適な実施形態において、前記抗5T4抗体の前記軽鎖可変領域は、3つの相補性決定領域を含む:
CDR1’: QSVSSSY (配列番号4)、
CDR2’: GAS (配列番号5)、および
CDR3’: QQYGSS(配列番号6)。
MDWTWRFLFVVAAATGVQSQVQLVQSGGGLVQPGGSLRLSCAAS GFTFSSYE MNWVRQAPGKGLEWVSY ISSSGSTI YYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AREMQFGWELLGAFDI WGQGTMVTVSS (配列番号7)。
MDMRVPAQLLGLLLLWLSGARCEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSFGQGTKLEIK (配列番号8)。
MDWTWRFLFVVAAATGVQSQVQLVQSGGGLVQPGGSLRLSCAAS GFTFSSYE MNWVRQAPGKGLEWVSY ISSSGSTI YYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYC AREMQFGWELLGAFDI WGQGTMVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (配列番号9)。
MDMRVPAQLLGLLLLWLSGARCEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (配列番号10)。
Ab-(L-D)n II
(ここで、Abは抗体である。
Dは腫瘍細胞を抑制する小分子薬物である。
Lは前記抗体と前記薬物を連結するリンカーである。)
もう一つの好適な例において、nは1〜8で、好ましくは整数である。
もう一つの好適な例において、Dは以下の群から選ばれる。
デュオスタチン(Duostatin)5:
Ab、D、nは前記の通りである。
波線は抗体との連結部位を表す。)
ZV0508、ZV0512、ZV0513、ZV0501、ZV0503、ZV0504、ZV0517、ZV0518、ZV0505、ZV0516、ZV0515、ZV0519。
(1) 本発明の5T4を標的とする抗体薬物複合体は、顕著な抗腫瘍効果を有する。
(2) 本発明の抗体-薬物複合体によれば、5T4抗原および5T4抗原を発現する腫瘍細胞のいずれにおいても高い親和力を表し、かつ5T4抗原を発現する腫瘍細胞において強い取り込み性を有する。
カルボキシ化合物をジクロロメタンまたはN,N-ジメチルホルムアミドに溶解させ、1.5当量のN-ヒドロキシスクシンイミド、1.5当量のEDCIを入れた。カルボキシ化合物が完全に消耗されるまで、反応液を室温で1時間撹拌した。RP-HPLCで反応過程をモニタリングした。ジクロロメタンで反応液を希釈し、そしてクエン酸(10%溶液)と飽和食塩水で有機相を洗浄した。 有機相を分離して乾燥し、HPLCまたは中圧順相クロマトグラフィーによって精製し、相応する活性エステルを得た。
EVQLVESGGGLVQPGGSLRLSCAASGYTFTNFGMNWVRQAPGKGLEWVAWINTNTGEPRYAEEFKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDWDGAYFFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (配列番号11) 。
DIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYFATNRYTGVPSRFSGSGYGTDFTLTISSLQPEDFATYYCQQDYSSPWTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (配列番号12)。
カリケアミシン小分子の合成経路:
化合物8の製造:
化合物2 (100 mg, 0.06 mmol)を4 mLのアセトニトリルと0.3 mLのジメチルホルムアミド(DMF)に溶解させた後、それに化合物3(75 mg, 0.24 mmol)を入れた。 反応は撹拌しながら16時間続けた後、120 μLのピペリジンを入れた。30分間後、HPLCによって精製して化合物4(60 mg)を得た。MS m/z 1654.4 (M+H)。
化合物4(20 mg, 12 μmol,2 mLのジメチルホルムアミド(DMF)に溶解させたもの)に化合物5(11 mg, 14 μmol)、N-ヒドロキシベンゾトリアゾール(HOBt, 2 mg)および5μLジイソプロピルエチルアミン(DIEA)を入れた。反応混合物を1時間撹拌した後、40 μLのピペリジンを入れた。10分間後、当該混合物をHPLCによって精製して化合物6(21 mg)を得た。MS m/z 2059.6 (M+H)。
化合物6(21 mg, 10 μmol,2 mLのジクロロメタン(DCM)に溶解させたもの)に化合物7(13 mg, 13 μmol)および3μLジイソプロピルエチルアミン(DIEA)を入れた。当該反応混合物を20撹拌した後、溶媒を除去してHPLCによって精製して化合物8(11 mg)を得た。MS m/z 2558.6 (M+H).
デュオスタチン5小分子の合成経路:
化合物19のTFA塩(1 mmol)、化合物24(1 eq.)、HOAt (3 eq.)、ジクロロメタン(DCM)(20 mL)、ジイソプロピルエチルアミン(DIEA6 eq.)およびDIC (2 eq.)を丸底フラスコに置いた。16時間撹拌した後、反応液を20mLのジクロロメタンで希釈し、そして20mLの水で洗浄した。有機相を硫酸ナトリウムで乾燥した後、減圧で溶媒を除去し、得られたガラス状固体をそのまま次の工程の反応に使用した。得られた固体を10 mLのジクロロメタン(DCM)、10 mLのトリフルオロ酢酸(TFA)および1mLのトリイソプロピルシランに溶解させて1時間撹拌した。 真空で溶媒を除去した後、HPLCによって精製して化合物6を得た。MS m/z 1351.5 (M+H)。
化合物25(0.5 mmol)、アセトニトリル20 mL、水5 mLおよび飽和炭酸水素ナトリウム10 mL水溶液をを丸底フラスコに置いた後、チオ硫酸ナトリウム(Na2S2O4)(4 eq.)を入れて20 分間撹拌した。 HPLCによって精製して化合物7を得た。MS m/z 1321.7 (M+H)。
化合物26(0.4 mmol)を10 mLのアセトニトリルに溶解させた後、1,4-ジブロモブタン-2,3-ジオン(3 eq.)を入れた。20撹拌した後、HPLCによって精製して化合物27を得た。MS m/z 1527.6 (M+H)。
化学合成によって抗体(抗5T4抗体および対照抗体A1)の重鎖と軽鎖の可変領域の遺伝子配列を得、得られた抗体(抗5T4抗体および対照抗体A1)の重鎖と軽鎖の定常領域の遺伝子配列に対してPCR増幅を行った。酵素切断と連結によって、重鎖の可変領域および定常領域を発現ベクターに組み込み、類似する方法によって軽鎖の可変領域および定常領域をもう一つの発現ベクターに組み込み、さらに酵素切断と連結によって、重鎖の可変領域および定常領域の発現ベクターおよび軽鎖の可変領域および定常領域の発現ベクターを一体化させ、すなわち、抗体の組み換え発現ベクターを得た。抗体の発現ベクターで形質転換されたCHO細胞を発現させた。
5T4-抗体を37℃で15×モル当量のTCEP(水で調製されたもの)でC-Lock緩衝液(50mMリン酸ナトリウム、4mM EDTA,pH7.0)において3時間還元させたか、または室温で一晩還元させた。
PD-10ゲルろ過カラムまたはAmicon回転濃縮器によって緩衝液を置換し、完全に還元された抗体を精製してTCEPを除去した。
分光光度計によって412nm吸光度および280nm吸光度を測定することによって、抗体の遊離チオールを定量した。3つのジスルフィド結合から約6つの遊離チオールができるはずである。TCEPを除去した後、分光光度計によって280nm吸光度を測定することによって、抗体の濃度を定量した。
K-Lock法またはC-Lock法などの結合方法によって、相応する薬物を抗体と結合させ、表1に挙げられたADCを形成した。
室温25℃(範囲は4〜37℃でもよい)で、10mg/mlの抗体(リン酸緩衝液PBSに濃度範囲5〜30mg/mlで溶解させたもの)に抗体の6〜10倍のモル量の薬物分子(DMAに体積がPBSの10%を超えないように溶解させたもの)を入れて3〜16h反応させ、限外ろ過で過剰量の薬物分子を除去した。抗体-薬物複合体を疎水性クロマトグラフィーカラム(HIC)にかけ、0.75〜1 Mの硫酸アンモニウム溶液で平衡化した後、さらに25 mMの硫酸アンモニウム溶液で溶離させ、結合数が2の溶離液を合併してPBSで置換し、結合数が2の抗5T4抗体-薬物複合体を得た。
A.結合
結合される薬物(デュオスタチン5)(実施例1における化合物27)を60%アセトニトリル/水に溶解させて10mMストック溶液を調製した。
4.5×の最終薬物当量まで、5分間おきに0.5×モル当量の薬物を還元された5T4抗体に入れた。反応系を室温で回転器で混合した。
HIC-HPLCで反応させてフィッティング曲線を分析した。未結合の抗体は0%で、DAR 4ピーク≧70%になるはずである。
ADC産物はDAR 2-4を含有する異質混合物を残す場合、Amicon回転濃縮器の緩衝液で置換することによって遊離薬物を除去した。緩衝液は50mMリン酸ナトリウム+30%プロピレングリコールであった。
均一相のDAR 3ピークが必要な場合、産物を疎水作用カラムで精製することによって必要ではないDARを除去した。
抗体-薬物複合体を疎水性クロマトグラフィーカラム(HIC)にかけ、精製して結合数が4の抗5T4抗体-薬物複合体を得た。
TSKゲルブチルNPRカラム(4.6 mmIDx3.5 cm, 2.5 mm, Tosoh Bioscience, Montgomeryville, PA)を使用し、移動相はそれぞれ1.5M 硫酸アンモニウムと0.025Mリン酸ナトリウム緩衝液(pH7)および75% 0.025Mリン酸ナトリウム緩衝液と25%イソプロパノール(pH7.0)で、勾配溶離は10% B〜70% B、10分、70% B〜100% B、5分、100% B〜10% B, 2分であった。
図1は、本発明の抗体-薬物複合体ZV0508よるHIC分析結果を示すが、結果から示された。
親和性検出の実験手順は以下の通りである。
ZV05およびZV0508を3.3μg/mlに希釈した後、3倍の勾配で希釈し、濃度はそれぞれ10、3.3、1.1、0.33μg/mlで、それぞれ3.0×105個のMDA-MB-468細胞を含有するエッペンドルフ管に入れ、4℃の条件において30分間インキュベートした。沈殿細胞を遠心し、PBSを入れて1回洗浄した。さらに、600μlのFITCで標識された二次抗体希釈液を入れ、4℃の条件において光を避けて30 分間インキュベートした。沈殿細胞を遠心し、PBSで2回洗浄し、最後に500μlのPBSを入れて細胞を均一に懸濁させ、フローサイトメーターによって平均蛍光強度値を検出した。
検出結果は以下の通りである。
細胞取り込み性の実験手順は以下の通りである。
ZV05およびZV0508を10μg/mlに希釈し、それぞれ3.0×105個のMDA-MB-468細胞を含有するエッペンドルフ管に入れ、4℃の条件において30分間インキュベートした。沈殿細胞を遠心し、PBSを入れて1回洗浄した。各EP管における細胞を等量の二つにわけ、その一つは4℃で2hインキュベートし、もう一つは37℃で2hインキュベートした。遠心で細胞を沈殿させ、PBSを入れて1回洗浄した。さらに、各EP管に600μlのFITCで標識された二次抗体希釈液を入れ、4℃の条件において光を避けて30 分間インキュベートした。沈殿細胞を遠心し、PBSで2回洗浄し、最後に500μlのPBSを入れて細胞を均一に懸濁させ、フローサイトメーターによって平均蛍光強度値を検出した。取り込み率の計算式:取り込み率(%)=(MFI4℃-MFI37℃)/MFI4℃。検出結果は以下の通りである。
本実施例において、本発明の抗体-薬物複合体の5T4陽性細胞の細胞周期に対する阻害効果を検出した。本実施例における腫瘍細胞株はいずれも米国ATCCから購入された。
実験の手順は以下の通りである。
実験結果から、薬物の作用で抗体薬物複合体ZV0508が細胞周期がG2/M期に留まるようにさせたことが示され、結果は図4に示すように、図4ではZV05は薬物が結合していない抗体対照である。
抗5T4抗体-薬物複合体の体内抗腫瘍活性の検出手順は以下の通りである。
腫瘍細胞をヌードマウスまたはSCIDマウスの腋下に接種し、腫瘍体積が100〜300mm3に生長したら尾静脈に投与し、OE19は3回に分けて、3日に1回で投与し、ほかのモデルはしずれも単回で投与し、投与後一定の時間で腫瘍の大きさ、腫瘍塊の長径(a)、短径(b)を測量し、腫瘍体積(tumor volume,TV)の計算式はTV = 1/2×a×b2である。
図5は、ADCでマウス体内におけるMDA-MB-468乳癌移植腫瘍(+++)を治療する場合の治療効果を示す。
図6は、ADCでマウス体内におけるBxPC-3膵臓癌移植腫瘍(++)を治療する場合の治療効果を示す。
図7は、ADCでマウス体内におけるH1975肺癌移植腫瘍(+++)を治療する場合の治療効果を示す。
図8は、ADCでマウス体内におけるDU-145前立腺癌移植腫瘍(+++)を治療する場合の治療効果を示す。
図9はADCでマウス体内におけるPA-1卵巣癌移植腫瘍(+)を治療する場合の治療効果を示す。
図10は、ADCでマウス体内におけるLovo結腸癌移植腫瘍(+)を治療する場合の治療効果を示す。ここで、対照としての抗体薬物複合体(A1-MMAF)の腫瘍阻害効果は顕著に本発明の抗体薬物複合体よりも低かった。
ZV05-MMAF(0501)、すなわちZV0501;
ZV05-0115(0508)、すなわちZV0508;
ZV05-0154(0505)、すなわちZV0505;
ZV05-0155(0504)、すなわちZV0504;
ZV05-0174(0503)、すなわちZV0503;
ZV05-0472(0516)、すなわちZV0516;
ZV05-0481(0517)、すなわちZV0517;
ZV05-0482(0518)、すなわちZV0518;
ZV05-0441(0512)、すなわちZV0512;
ZV05-0443(0513)、すなわちZV0513;
ZV05-0454(0515)、すなわちZV0515;
ZV05-0428(0519)、すなわちZV0519。
A1-MMAFはUS2012251558に記載の方法によって製造された、従来の抗体のジスルフィド結合を還元させることによってチューブリン阻害剤であるMMAFをヒト化された抗5T4モノクローナル抗体A1に連結した抗体薬物複合体で、ここで、DARは約4である。
Claims (19)
- 抗体-薬物複合体またはその薬学的に許容される塩であって、前記抗体-薬物複合体は抗体と前記抗体に結合した薬物とを含み、前記抗体は1つの重鎖可変領域と1つの軽鎖可変領域を含み、
ここで、前記重鎖可変領域は、
CDR1:GFTFSSYE、
CDR2:ISSSGSTI、および
CDR3:AREMQFGWELLGAFDI、
という3つの相補性決定領域を含み、
前記軽鎖可変領域は、
CDR1’: QSVSSSY、
CDR2’: GAS、および
CDR3’: QQYGSS、
という3つの相補性決定領域を含む、
ことを特徴とする抗体-薬物複合体またはその薬学的に許容される塩。 - 前記重鎖可変領域のアミノ酸配列は配列番号7で示されることを特徴とする請求項1に記載の抗体-薬物複合体またはその薬学的に許容される塩。
- 前記軽鎖可変領域のアミノ酸配列は配列番号8で示されることを特徴とする請求項1に記載の抗体-薬物複合体またはその薬学的に許容される塩。
- 前記抗体は配列番号9で示される重鎖を含むことを特徴とする請求項1に記載の抗体-薬物複合体またはその薬学的に許容される塩。
- 前記抗体は配列番号10で示される軽鎖を含むことを特徴とする請求項1に記載の抗体-薬物複合体またはその薬学的に許容される塩。
- 前記薬物は、デュオスタチン(Duostatin)5、MMAF、デュオスタチン(Duostatin)14、デュオマイシン(Duomycin)2、デュオマイシン(Duomycin)4、カリケアミシン(Calicheamicin)、アマニチン(Amanitine)からなる群から選ばれる小分子薬物を含むことを特徴とする請求項1に記載の抗体-薬物複合体またはその薬学的に許容される塩。
- 前記抗体-薬物複合体の構造が式Iで表されることを特徴とする請求項1に記載の抗体-薬物複合体またはその薬学的に許容される塩。
Ab−(L-D)n I
(ここで、Abは前記抗体である。
Lはなしか、前記抗体と前記薬物を連結するリンカーである。
Dは腫瘍細胞を抑制する小分子薬物である。
nは前記抗体に結合した前記薬物の数である。
「−」は結合またはリンカーである。) - 前記抗体-薬物複合体の軽鎖定常領域に少なくとも1つの薬物分子が結合し、かつ前記薬物分子が前記軽鎖定常領域のリシン部位に連結していることを特徴とする請求項1に記載の抗体-薬物複合体またはその薬学的に許容される塩。
- 前記薬物分子は腫瘍細胞を阻害する小分子薬物であることを特徴とする請求項7に記載の抗体-薬物複合体またはその薬学的に許容される塩。
- nは前記抗体-薬物抱合体における薬物の平均抱合数で、好適に1〜4、好ましくは1.5〜3.5、より好ましくは1.8〜2であることを特徴とする請求項7に記載の抗体-薬物複合体またはその薬学的に許容される塩。
- 前記Dは、デュオスタチン(Duostatin)5、MMAF、デュオスタチン(Duostatin)14、デュオマイシン(Duomycin)2、デュオマイシン(Duomycin)4、カリケアミシン(Calicheamicin)、アマニチン(Amanitine)からなる群から選ばれることを特徴とする請求項7に記載の抗体-薬物複合体またはその薬学的に許容される塩。
- 前記抗体-薬物複合体の構造が式IIIで表されることを特徴とする請求項7に記載の抗体-薬物複合体またはその薬学的に許容される塩。
Ab、D、nは前記の通りである。
波線は抗体との連結部位を表す。) - 前記抗体-薬物複合体は以下の群から選ばれることを特徴とする請求項1に記載の抗体-薬物複合体またはその薬学的に許容される塩:
ZV0508、ZV0512、ZV0513、ZV0501、ZV0503、ZV0504、ZV0517、ZV0518、ZV0505、ZV0516、ZV0515、ZV0519。
(ここで、複合体ZV0508の構造は以下の通りである。
- 前記抗体-薬物複合体はZV0508、ZV0512、ZV0513、ZV0503からなる群から選ばれることを特徴とする請求項1に記載の抗体-薬物複合体またはその薬学的に許容される塩。
(ここで、複合体ZV0508の構造は以下の通りである。
- 請求項1に記載の抗体-薬物複合体と、薬学的に許容される担体とを含むことを特徴とする薬物組成物。
- 抗腫瘍の薬物の製造における、請求項1に記載の抗体-薬物複合体の使用。
- 前記腫瘍は5T4陽性腫瘍で、好ましくは乳癌、胃癌、卵巣癌、肺癌などを含むことを特徴とする請求項16に記載の使用。
- 腫瘍を治療または予防する方法であって、必要な対象に請求項1に記載の抗体-薬物複合体、または請求項15に記載の薬物組成物を施用する工程を含むことを特徴とする方法。
- 請求項1に記載の抗体-薬物複合体を製造する方法であって、
前記抗体および遊離のリンカーを含む薬物分子を含む反応系を調製した後、結合反応を行うことによって、前記抗体-薬物複合体を得、
ここで、前記薬物分子はリンカーである工程を含むことを特徴とする方法。
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