JP2016514103A - 細胞結合剤及び細胞毒性剤を含む複合体 - Google Patents
細胞結合剤及び細胞毒性剤を含む複合体 Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/62—Oxygen or sulfur atoms
- C07D213/70—Sulfur atoms
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- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
- C07D498/18—Bridged systems
Abstract
Description
本出願は、米国特許法第119条(e)の下、2013年2月28日に提出した米国仮特許出願第61/770,794号の提出日に基づく優先権を主張する。該仮出願の全内容は、参照により本明細書に取り込まれる。
本明細書において使用する場合、「アルキル」は、1〜20個の炭素原子の、1価の直鎖または分岐飽和炭化水素ラジカルを指す。「1価」とは、アルキルが、分子の残りの部分と1点で結合することを意味する。アルキル基の例としては、メチル、エチル、1‐プロピル、2‐プロピル、1‐ブチル、2‐メチル‐1‐プロピル、‐CH2CH(CH3)2、2‐ブチル、2‐メチル‐2‐プロピル、1‐ペンチル、2‐ペンチル、3‐ペンチル、2‐メチル‐2‐ブチル、3‐メチル‐2‐ブチル、3‐メチル‐1‐ブチル、2‐メチル‐1‐ブチル、1‐ヘキシル、2‐ヘキシル、3‐ヘキシル、2‐メチル‐2‐ペンチル、3‐メチル‐2‐ペンチル、4‐メチル‐2‐ペンチル、3‐メチル‐3‐ペンチル、2‐メチル‐3‐ペンチル、2,3‐ジメチル‐2‐ブチル、3,3‐ジメチル‐2‐ブチル、1‐ヘプチル及び1‐オクチル等が挙げられるがこれらに限定されるものではない。好ましくは、アルキル基は1〜10個の炭素原子を有する。より好ましくは、アルキル基は1〜4個の炭素原子を有する。
細胞結合剤−薬物部複合体
細胞毒性化合物
リンカー化合物
修飾細胞結合剤
細胞結合剤−薬物複合体の作製
細胞毒性の試験管内評価
様々ながん細胞株の増殖を抑制する能力について、本発明の細胞毒性化合物及び細胞結合剤−薬物複合体を試験管内で評価することができる。当業者に公知の方法を使用して、試験管内細胞毒性分析を実施することができる(例えば、Widdison,W.C.ら、“Semisynthetic maytansine analogues for the targeted treatment of cancer,” J.Med.Chem.(2006)49(14):4392−408)。例えば、評価する細胞を化合物または複合体に1〜5日間曝露し、公知方法による直接分析において、細胞の生存割合を測定することができる。次にIC50値を分析結果から計算することができる。
組成物及び使用方法
類似体及び誘導体
Pys−DM1の合成
Pys−DM4の合成
実施例2
実施例3
実施例5
実施例7
実施例8
実施例9
実施例10
実施例11
実施例12
実施例13
Claims (56)
- 以下の式:
式中、
CBAは細胞結合剤であり;
DMは以下の式:
R、R’及びR’’はそれぞれ独立してHまたは任意に置換されたアルキルであり;
Yは‐(CR3R4)nCR1R2‐であり;
R1〜R4はそれぞれ独立してH、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたシクロアルキル、任意に置換されたヘテロシクリル、任意に置換されたアリールまたは任意に置換されたヘテロアリールであり;
nは0〜15の整数であり;ならびに
wは1〜20の整数であり、
上記はCBAは、遊離チオール(‐SH)基を有する修飾リジン残基を含まない場合の
複合体またはその薬学的に許容できる塩。 - R1及びR2がそれぞれメチルであり、ならびにnが2である請求項2記載の複合体。
- 以下の式:
式中、
CBAは細胞結合剤であり;
DMは以下の式:
R、R’及びR’’はそれぞれ独立してHまたは任意に置換されたアルキルであり;
Yは‐(CR3R4)nCR1R2‐であり;
R1〜R4はそれぞれ独立してH、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたシクロアルキル、任意に置換されたヘテロシクリル、任意に置換されたアリールまたは任意に置換されたヘテロアリールであり;
nは0〜15の整数であり;
JCB’は、
Ra、Rb、Rc及びReはそれぞれ独立してHまたは任意に置換されたアルキルであり;
Zは存在しないか、または‐SO2NR9‐、‐NR9SO2‐、‐C(=O)‐NR9‐、‐NR9‐C(=O)‐、‐C(=O)‐O‐、‐O‐C(=O)‐、‐C(=O)‐NR9‐(CH2CH2O)p‐、‐NR9‐C(=O)‐(CH2CH2O)p‐、‐(OCH2CH2)p‐C(=O)NR9‐もしくは‐(OCH2CH2)p‐NR9‐C(=O)‐であり;
pは1〜1000の整数であり;
Z1は存在しないか、または‐SO2NR9‐、‐NR9SO2‐、‐C(=O)‐NR9‐、‐NR9‐C(=O)‐、‐(CH2CH2)p’NR9‐C(=O)‐、‐C(=O)‐NR9(CH2CH2)p’、‐(CH2CH2)p’‐C(=O)NR9‐、‐NR9C(=O)(CH2CH2)p’‐、‐C(=O)‐O‐もしくは‐O‐C(=O)‐であり;
p’は1〜10の整数であり;
QはH、電荷をもつ置換基、またはイオン化できる基であり;
R9、R10、R11、R12及びR13はそれぞれ独立してHまたは任意に置換されたアルキルであり;
q及びrはそれぞれ独立して0〜10の整数であり;ならびに
wは1〜20の整数である
複合体、またはその薬学的に許容できる塩。 - Qが、i)H;ii)‐SO3H、‐Z’‐SO3H、‐OPO3H2、‐Z’‐OPO3H2、‐PO3H2、‐Z’‐PO3H2、‐CO2H、‐Z’‐CO2H、‐NR11R12もしくは‐Z’‐NR11R12、もしくはそれらの薬学的に許容できる塩;またはiii)‐N+R14R15R16Xーもしくは‐Z’‐N+R14R15R16Xーであり;Z’は任意に置換されたアルキレン、任意に置換されたシクロアルキレンまたは任意に置換されたフェニレンであり;R14〜R16は、それぞれ独立して任意に置換されたアルキルであり;ならびにX−は薬学的に許容できる陰イオンである請求項5または6に記載の複合体。
- Zが‐C(=O)‐NR9‐または‐NR9‐C(=O)‐である請求項5〜9のいずれか1項に記載の複合体。
- Ra、Rb、Rc及びReがそれぞれHであり;Z’が任意に置換されたアルキレンであり;ならびにR9がHである請求項5〜10のいずれか1項に記載の複合体。
- Qが、Hまたは‐SO3Hもしくはその薬学的に許容できる塩である請求項5〜11のいずれか1項に記載の複合体。
- 前記細胞結合剤が抗体、単鎖抗体、標的細胞に特異的に結合する抗体断片、モノクローナル抗体、単鎖モノクローナル抗体、標的細胞に特異的に結合するモノクローナル抗体断片、キメラ抗体、標的細胞に特異的に結合するキメラ抗体断片、ドメイン抗体、標的細胞に特異的に結合するドメイン抗体断片、リンホカイン、ホルモン、ビタミン、増殖因子、コロニー刺激因子または栄養輸送分子である請求項1〜13のいずれか1項に記載の複合体。
- 前記細胞結合剤がモノクローナル抗体、単鎖モノクローナル抗体または標的細胞に特異的に結合するモノクローナル抗体断片である請求項14記載の複合体。
- 前記抗体が表面再形成抗体、表面再形成単鎖抗体または表面再形成抗体断片である請求項14または15に記載の複合体。
- 前記抗体がヒト化抗体、ヒト化単鎖抗体またはヒト化抗体断片である請求項14〜16のいずれか1項に記載の複合体。
- 前記細胞結合剤がミニボディ、二重特異性抗体(diabody)、三重特異性抗体、四重特異性抗体、ナノボディ、プロボディ、ドメインボディ、ユニボディ、二重特異性抗体(bispecific antibody)、アンキリン反復タンパク質(例えば、DARPin)、センチリンまたはAvibodyである請求項1〜13のいずれか1項に記載の複合体。
- 以下の式:
式中、
DMは以下の式:
R、R’及びR’’はそれぞれ独立してHまたは任意に置換されたアルキルであり;
Yは‐(CR3R4)nCR1R2‐であり;
R1〜R4はそれぞれ独立してH、任意に置換されたアルキル、任意に置換されたアルケニル、任意に置換されたシクロアルキル、任意に置換されたヘテロシクリル、任意に置換されたアリールまたは任意に置換されたヘテロアリールであり;
nは0〜15の整数であり;
JCBは、マレイミド、X’‐CRbRc‐C(=O)‐、X’‐CRbRc‐C(=O)‐NRe‐、Ra‐C(=O)‐、Ra‐C(=O)‐Ar‐、NH2‐NRe‐、NH2‐NRe‐C(=O)‐、NH2‐NRe‐Ar‐、NH2‐O‐、
X’はハロゲンであり;
Ra、Rb、Rc及びReはそれぞれ独立してHまたは任意に置換されたアルキルであり;
Zは存在しないか、または‐SO2NR9‐、‐NR9SO2‐、‐C(=O)‐NR9‐、‐NR9‐C(=O)‐、‐C(=O)‐O‐、‐O‐C(=O)‐、‐C(=O)‐NR9‐(CH2CH2O)p‐、‐NR9‐C(=O)‐(CH2CH2O)p‐、‐(OCH2CH2)p‐C(=O)NR9‐もしくは‐(OCH2CH2)p‐NR9‐C(=O)‐であり;
pは1〜1000の整数であり;
Z1は存在しないか、または‐SO2NR9‐、‐NR9SO2‐、‐C(=O)‐NR9‐、‐NR9‐C(=O)‐、‐(CH2CH2)p’NR9‐C(=O)‐、‐C(=O)‐NR9(CH2CH2)p’、‐(CH2CH2)p’‐C(=O)NR9‐、‐NR9C(=O)(CH2CH2)p’‐、‐C(=O)‐O‐もしくは‐O‐C(=O)‐であり;
p’は1〜10の整数であり;
QはH、電荷をもつ置換基、またはイオン化できる基であり;
R9、R10、R11、R12及びR13はそれぞれ独立してHまたは任意に置換されたアルキルであり;ならびに
q及びrはそれぞれ独立して0〜10の整数である
細胞毒性化合物またはその塩。 - Qが、i)H;ii)‐SO3H、‐Z’‐SO3H、‐OPO3H2、‐Z’‐OPO3H2、‐PO3H2、‐Z’‐PO3H2、‐CO2H、‐Z’‐CO2H、‐NR11R12もしくは‐Z’‐NR11R12、もしくはそれらの薬学的に許容できる塩;またはiii)‐N+R14R15R16Xーもしくは‐Z’‐N+R14R15R16Xーであり;Z’は任意に置換されたアルキレン、任意に置換されたシクロアルキレンまたは任意に置換されたフェニレンであり;R14〜R16は、それぞれ独立して任意に置換されたアルキルであり;ならびにX−は陰イオンである請求項19または20に記載の細胞毒性化合物。
- JCBがマレイミドである請求項22に記載の細胞毒性化合物。
- Zが‐C(=O)‐NR9‐または‐NR9‐C(=O)‐である請求項19〜23のいずれか1項に記載の細胞毒性化合物。
- Ra、Rb、Rc及びReがそれぞれHであり;Z’が任意に置換されたアルキレンであり;ならびにR9がHである請求項19〜24のいずれか1項に記載の細胞毒性化合物。
- Qが、Hまたは‐SO3Hもしくはその塩である請求項19〜25のいずれか1項に記載の細胞毒性化合物。
- 以下の式:
式中、
JCBは、マレイミド、X’‐CRbRc‐C(=O)‐、X’‐CRbRc‐C(=O)‐NRe‐、Ra‐C(=O)‐、Ra‐C(=O)‐Ar‐、NH2‐NRe‐、NH2‐NRe‐C(=O)‐、NH2‐NRe‐Ar‐、NH2‐O‐、
X’はハロゲンであり;
Ra、Rb、Rc及びReはそれぞれ独立してHまたは任意に置換されたアルキルであり;
Zは存在しないか、または‐SO2NR9‐、‐NR9SO2‐、‐C(=O)‐NR9‐、‐NR9‐C(=O)‐、‐C(=O)‐O‐、‐O‐C(=O)‐、‐C(=O)‐NR9‐(CH2CH2O)p‐、‐NR9‐C(=O)‐(CH2CH2O)p‐、‐(OCH2CH2)p‐C(=O)NR9‐もしくは‐(OCH2CH2)p‐NR9‐C(=O)‐であり;
pは1〜1000の整数であり;
Z1は存在しないか、または‐SO2NR9‐、‐NR9SO2‐、‐C(=O)‐NR9‐、‐NR9‐C(=O)‐、‐(CH2CH2)p’NR9‐C(=O)‐、‐C(=O)‐NR9(CH2CH2)p’、‐(CH2CH2)p’‐C(=O)NR9‐、‐NR9C(=O)(CH2CH2)p’‐、‐C(=O)‐O‐もしくは‐O‐C(=O)‐であり;QはH、電荷をもつ置換基、またはイオン化できる基であり;
p’は1〜10の整数であり;
R9、R10、R11、R12及びR13はそれぞれ独立してHまたは任意に置換されたアルキルであり;
q及びrはそれぞれ独立して0〜10の整数であり;ならびに
JDは‐SH、‐SSRdまたは‐SC(=O)Rgであり、Rdはフェニル、ニトロフェニル、ジニトロフェニル、カルボキシニトロフェニル、ピリジルまたはニトロピリジルであり;及び、Rgはアルキルである
リンカー化合物またはその塩。 - ‐SHまたは‐SSRdである請求項28記載のリンカー化合物。
- Qが、i)H;ii)‐SO3H、‐Z’‐SO3H、‐OPO3H2、‐Z’‐OPO3H2、‐PO3H2、‐Z’‐PO3H2、‐CO2H、‐Z’‐CO2H、‐NR11R12もしくは‐Z’‐NR11R12、もしくはそれらの薬学的に許容できる塩;またはiii)‐N+R14R15R16Xーもしくは‐Z’‐N+R14R15R16Xーであり;Z’は任意に置換されたアルキレン、任意に置換されたシクロアルキレンまたは任意に置換されたフェニレンであり;R14〜R16は、それぞれ独立して任意に置換されたアルキルであり;ならびにX−は陰イオンである請求項28または29に記載のリンカー化合物。
- JCBがマレイミドである請求項31記載のリンカー化合物。
- Zが‐C(=O)‐NR9‐または‐NR9‐C(=O)‐である請求項28〜32のいずれか1項に記載のリンカー化合物。
- Ra、Rb、Rc及びReがそれぞれHであり;Z’が任意に置換されたアルキレンであり;ならびにR9がHである請求項28〜33のいずれか1項に記載のリンカー化合物。
- Qが、Hまたは‐SO3Hもしくはその塩である請求項28〜34のいずれか1項に記載のリンカー化合物。
- 請求項1〜18のいずれか1項に記載の複合体または請求項19〜27のいずれか1項に記載の化合物;及び薬学的に許容できる担体を含む医薬組成物。
- 異常細胞増殖の阻害方法または哺乳動物における増殖性障害、自己免疫性障害、破壊性骨障害、感染症、ウイルス性疾患、線維性疾患、神経変性障害、膵炎もしくは腎疾患の治療方法であって、該方法が、請求項1〜18のいずれか1項に記載の複合体、請求項19〜27のいずれか1項に記載の化合物、または請求項37記載の組成物;及び任意に第2治療薬の治療有効量を、前記哺乳動物に投与することを含む方法。
- 前記第2治療薬を前記哺乳動物に、順次にまたは連続して投与する請求項38記載の方法。
- 前記方法が、がん、関節リウマチ、多発性硬化症、移植片対宿主疾患、移植片拒絶、狼瘡、筋炎、感染症及び免疫不全から成る群より選択される状態の治療方法である請求項38または39記載の方法。
- 前記状態ががんである請求項40記載の方法。
- 前記がんが乳癌、結腸癌、脳癌、前立腺癌、腎臓癌、膵癌、卵巣癌、頭部及び頸部癌、メラノーマ、結腸直腸癌、胃癌、扁平上皮癌、小細胞肺癌、非小細胞肺癌、精巣癌、メルケル細胞癌、神経膠芽腫、神経芽細胞腫、リンパ器官癌、ならびに造血器腫瘍から成る群より選択される請求項41記載の方法。
- 以下の式:
式中、
CBAは細胞結合剤であり;
JCB’は、
Ra、Rb、Rc及びReはそれぞれ独立してHまたは任意に置換されたアルキルであり;
Zは存在しないか、または‐SO2NR9‐、‐NR9SO2‐、‐C(=O)‐NR9‐、‐NR9‐C(=O)‐、‐C(=O)‐O‐、‐O‐C(=O)‐、‐C(=O)‐NR9‐(CH2CH2O)p‐、‐NR9‐C(=O)‐(CH2CH2O)p‐、‐(OCH2CH2)p‐C(=O)NR9‐もしくは‐(OCH2CH2)p‐NR9‐C(=O)‐であり;
pは1〜1000の整数であり;
Z1は存在しないか、または‐SO2NR9‐、‐NR9SO2‐、‐C(=O)‐NR9‐、‐NR9‐C(=O)‐、‐(CH2CH2)p’NR9‐C(=O)‐、‐C(=O)‐NR9(CH2CH2)p’、‐(CH2CH2)p’‐C(=O)NR9‐、‐NR9C(=O)(CH2CH2)p’‐、‐C(=O)‐O‐もしくは‐O‐C(=O)‐であり;
p’は1〜10の整数であり;
QはH、電荷をもつ置換基、またはイオン化できる基であり;
R9、R10、R11、R12及びR13はそれぞれ独立してHまたは任意に置換されたアルキルであり;
q及びrはそれぞれ独立して0〜10の整数であり;
JDは‐SH、‐SSRdまたは‐SC(=O)Rgであり、Rdはフェニル、ニトロフェニル、ジニトロフェニル、カルボキシニトロフェニル、ピリジルまたはニトロピリジルであり;及び、Rgはアルキルであり;ならびに
wは1〜20の整数である
修飾細胞結合剤またはその塩。 - JDが‐SHまたは‐SSRdである請求項43記載の修飾細胞結合剤。
- Qが、i)H;ii)‐SO3H、‐Z’‐SO3H、‐OPO3H2、‐Z’‐OPO3H2、‐PO3H2、‐Z’‐PO3H2、‐CO2H、‐Z’‐CO2H、‐NR11R12もしくは‐Z’‐NR11R12、もしくはそれらの薬学的に許容できる塩;またはiii)‐N+R14R15R16Xーもしくは‐Z’‐N+R14R15R16Xーであり;Z’は任意に置換されたアルキレン、任意に置換されたシクロアルキレンまたは任意に置換されたフェニレンであり;R14〜R16は、それぞれ独立して任意に置換されたアルキルであり;ならびにX−は薬学的に許容できる陰イオンである請求項43または44に記載の修飾細胞結合剤。
- Zが‐C(=O)‐NR9‐または‐NR9‐C(=O)‐である請求項43〜47のいずれか1項に記載の修飾細胞結合剤。
- Ra、Rb、Rc及びReがそれぞれHであり;Z’が任意に置換されたアルキレンであり;ならびにR9がHである請求項43〜48のいずれか1項に記載の修飾細胞結合剤。
- Qが、Hまたは‐SO3Hもしくはその薬学的に許容できる塩である請求項43〜49のいずれか1項に記載の修飾細胞結合剤。
- 前記細胞結合剤が抗体、単鎖抗体、標的細胞に特異的に結合する抗体断片、モノクローナル抗体、単鎖モノクローナル抗体、標的細胞に特異的に結合するモノクローナル抗体断片、キメラ抗体、標的細胞に特異的に結合するキメラ抗体断片、ドメイン抗体、標的細胞に特異的に結合するドメイン抗体断片、リンホカイン、ホルモン、ビタミン、増殖因子、コロニー刺激因子または栄養輸送分子である請求項43〜51のいずれか1項に記載の修飾細胞結合剤。
- 前記細胞結合剤がモノクローナル抗体、単鎖モノクローナル抗体または標的細胞に特異的に結合するモノクローナル抗体断片である請求項52記載の修飾細胞結合剤。
- 前記抗体が表面再形成抗体、表面再形成単鎖抗体または表面再形成抗体断片である請求項52または53に記載の修飾細胞結合剤。
- 前記抗体がヒト化抗体、ヒト化単鎖抗体またはヒト化抗体断片である請求項52〜54のいずれか1項に記載の修飾細胞結合剤。
- 前記細胞結合剤がミニボディ、二重特異性抗体(diabody)、三重特異性抗体、四重特異性抗体、ナノボディ、プロボディ、ドメインボディ、ユニボディ、二重特異性抗体(bispecific antibody)、アンキリン反復タンパク質(例えば、DARPin)、センチリンまたはAvibodyである請求項43〜51のいずれか1項に記載の修飾細胞結合剤。
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BIOCONJUGATE CHEMISTRY, 2011, VOL. 22, NO. 4, PP. 717-727, JPN6017046865, ISSN: 0003864247 * |
CANCER RESEARCH, 2006, VOL. 66, NO. 8, PP. 4426-4433, JPN6017046862, ISSN: 0003864244 * |
CHEMICAL BIOLOGY & DRUG DESIGN, 2013.01, VOL. 81, NO. 1, PP. 113-121, JPN6017046866, ISSN: 0003864248 * |
JOURNAL OF MEDICINAL CHEMISTRY, 2011, VOL. 54, NO. 10, PP. 3606-3623, JPN6017046864, ISSN: 0003864246 * |
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JP2019059782A (ja) | 2019-04-18 |
US20150359903A1 (en) | 2015-12-17 |
EP3566750A2 (en) | 2019-11-13 |
JP6494533B2 (ja) | 2019-04-03 |
EP3566750A3 (en) | 2020-04-08 |
WO2014134483A3 (en) | 2014-10-23 |
EP2961434A2 (en) | 2016-01-06 |
US9999680B2 (en) | 2018-06-19 |
WO2014134483A2 (en) | 2014-09-04 |
HK1219422A1 (zh) | 2017-04-07 |
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