JP6133668B2 - Herceptin(登録商標)補助療法 - Google Patents
Herceptin(登録商標)補助療法 Download PDFInfo
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- JP6133668B2 JP6133668B2 JP2013092728A JP2013092728A JP6133668B2 JP 6133668 B2 JP6133668 B2 JP 6133668B2 JP 2013092728 A JP2013092728 A JP 2013092728A JP 2013092728 A JP2013092728 A JP 2013092728A JP 6133668 B2 JP6133668 B2 JP 6133668B2
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Description
レセプターチロシンキナーゼのHERファミリーは、細胞の増殖、分化および生存の重要なメディエーターである。これらのレセプターファミリーは、上皮増殖因子レセプター(EGFR、ErbB1、またはHER1)、HER2(ErbB2またはp185neu)、HER3(ErbB3)およびHER4(ErbB4またはtyro2)を含む、4つの異なるメンバーを包含する。
補助療法は、その最も広い意味において、たとえ、その拡大が放射線医学試験または実験的試験によって検出することができないとしても、拡大している可能性がある任意の癌細胞を殺傷する一次治療(primary therapy)に加えて与えられる処置である。同時の臨床試験により、乳癌補助療法のための化学療法剤の効力を評価した(すなわち、BCIRG 001(パクリタキセル、ドキソルビシン、およびシクロホスファミド(TAC)を、フルオロウラシル、ドキソルビシン、およびシクロホスファミド(FAC)と比較する);CALGB 9741(用量密度治験);およびCALGC 9344(アントラサイクリン+シクロホスファミド(AC)を、AC+パクリタキセル(AC/T)と比較した)。
(項目1) 補助療法の方法であって、上記方法は、
非転移性HER2陽性乳癌を有するヒト被験体に対して、根治手術の後に、トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2のドメインIVに結合する有効量の抗体と少なくとも1種の化学療法剤とを投与して、上記被験体における無疾患生存(DFS)または全体的生存(OS)を伸長させる工程
を包含し、上記DFSまたは上記OSを、処置開始の約2年間後〜5年間後に評価する、方法。
(項目2) 項目1に記載の方法であって、上記抗体は、HER2に対するトラスツズマブ(HERCEPTIN(登録商標))の結合をブロックする、方法。
(項目3) 項目1に記載の方法であって、上記抗体は、トラスツズマブ(HERCEPTIN(登録商標))を含む、方法。
(項目4) 項目1に記載の方法であって、上記化学療法剤は、タキソイド、ビンカ、白金化合物、アロマターゼインヒビター、抗エストロゲン、エトポシド、チオテパ、シクロホスファミド、メトトレキサート、リポソームドキソルビシン、ペグ化リポソームドキソルビシン、カペシタビン、およびゲンシタビンからなる群より選択される、方法。
(項目5) 項目4に記載の方法であって、上記化学療法剤は、タキソイドである、方法。
(項目6) 項目5に記載の方法であって、上記タキソイドは、パクリタキセルまたはドセタキセルである、方法。
(項目7) 項目6に記載の方法であって、上記パクリタキセルと上記抗体とを、アントラサイクリンおよびシクロホスファミドの投与後に投与する、方法。
(項目8) 項目7に記載の方法であって、上記抗体は、トラスツズマブ(HERCEPTIN(登録商標))を含む、方法。
(項目9) 項目1に記載の方法であって、上記抗体と化学療法との投与は、被験体集団において3年目の疾患再発を、化学療法単独で処置した被験体と比較して約50%減少させる、方法。
(項目10) 項目7に記載の方法であって、上記パクリタキセルと上記抗体との投与は、被験体集団において3年目の疾患再発を、上記抗体を用いずにパクリタキセルで処置した被験体と比較して約50%減少させる、方法。
(項目11) 項目1に記載の方法であって、上記被験体は、高い癌再発リスクを有する、方法。
(項目12) 項目11に記載の方法であって、上記被験体は、約50歳未満である、方法。
(項目13) 項目11に記載の方法であって、上記被験体は、直径2cmを超える腫瘍を有する、方法。
(項目14) 項目11に記載の方法であって、上記癌は、リンパ節陽性癌である、方法。
(項目15) 項目14に記載の方法であって、上記被験体は、4〜9個の浸潤されたリンパ節を有する、方法。
(項目16) 項目15に記載の方法であって、上記被験体は、10個以上の浸潤されたリンパ節を有する、方法。
(項目17) 項目11に記載の方法であって、上記被験体は、エストロゲンレセプター(ER)陰性である、方法。
(項目18) 項目11に記載の方法であって、上記被験体は、プロゲステロンレセプター(PG)陰性である、方法。
(項目19) 項目1に記載の方法であって、上記抗体は、インタクトな裸の抗体である、方法。
(項目20) 項目1に記載の方法であって、上記DFSまたは上記OSを、処置開始の4年後に評価する、方法。
(項目21) 非転移性HER2陽性乳癌を有するヒト被験体の集団において非転移性乳癌を治癒する方法であって、上記方法は、
根治手術の後の上記被験体集団に対して、有効量のトラスツズマブ(HERCEPTIN(登録商標))およびタキソイドを投与する工程;ならびに
約4年間後に上記被験体集団を評価して、疾患再発が上記集団のうちの少なくとも約80%において生じていないことを確認する工程;
を包含する、方法。
(項目22) 項目21に記載の方法であって、上記集団は、3000人以上のヒト被験体を含む、方法。
(項目23) 非転移性HER2陽性乳癌を有するヒト被験体集団において疾患の再発を減少する方法であって、上記方法は、
有効量のトラスツズマブ(HERCEPTIN(登録商標))およびタキソイドを上記被験体に対して、根治手術の後に投与する工程、
を包含し、約3年目における疾患再発は、タキソイド単独で処置した被験体と比較して少なくとも約50%減少される、方法。
(項目24) 補助療法の方法であって、上記方法は、
非転移性HER2陽性乳癌を有するヒト被験体に対して、根治手術の後に、トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2のドメインIVに結合する抗体と少なくとも1種の化学療法剤とを、治療標準である化学療法と比較して無疾患生存(DFS)または全体的生存(OS)を伸長させるに有効な量で投与する工程
を包含し、上記DFSまたは上記OSを、処置開始の少なくとも約3年間、1年間当たり少なくとも1回評価し、上記DFSは、上記患者が生存したままであり少なくとも1年間癌の再発がない場合に伸長し、上記OSは、処置開始から少なくとも1年間生存したままである場合に伸長する、方法。
(項目25) 項目24に記載の方法であって、上記抗体は、HER2に対するトラスツズマブ(HERCEPTIN(登録商標))の結合をブロックする、方法。
(項目26) 項目24に記載の方法であって、上記抗体は、トラスツズマブ(HERCEPTIN(登録商標))を含む、方法。
(項目27) 項目24に記載の方法であって、上記化学療法剤は、タキソイドである、方法。
(項目28) 項目27に記載の方法であって、上記タキソイドは、パクリタキセルまたはドセタキセルである、方法。
(項目29) 項目24に記載の方法であって、上記抗体および化学療法剤の投与は、被験体集団において3年目における疾患再発を、上記化学療法剤単独で処置した被験体と比較して約50%減少させる、方法。
(項目30) 根治手術の後に高い癌再発リスクまたは低い生存可能性を有すると同定された非転移性HER2陽性乳癌を有するヒト被験体を指示する方法であって、上記ヒト被験体は、トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2ドメインIVに結合する抗体と少なくとも1種の化学療法剤とでの処置を受容する治療標準である化学療法によってのみ処置されている、方法。
(項目31) 項目30に記載の方法であって、上記化学療法剤は、タキソイドである、方法。
(項目32) 項目30に記載の方法であって、上記被験体を、指示される通りに処置する、方法。
(項目33) 項目32に記載の方法であって、上記処置は、少なくとも6ヶ月間継続する、方法。
(項目34) 根治手術後に高い癌再発リスクまたは低い生存可能性であると同定されるヒト被験体においてHER2陽性非転移性乳癌を処置するための宣伝方法であって、上記方法は、
(a)トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2ドメインIVに結合する抗体と組み合わせた化学療法剤;または
(b)化学療法剤と組み合わせた、トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2ドメインIVに結合する抗体;
を宣伝する工程;
を包含する、方法。
(項目35) 項目34に記載の方法であって、上記化学療法剤は、タキソイドである、方法。
(項目36) 項目34に記載の方法であって、上記宣伝は、上記化学療法剤または上記抗体の商業的処方物が付随する包装挿入物による、方法。
(項目37) 項目34に記載の方法であって、上記宣伝は、医師または健康管理供給者への文書による伝達または口頭での伝達による、方法。
(項目38) 項目34に記載の方法であって、上記宣伝の後に、上記化学療法剤と上記抗体との組み合わせを用いて上記被験体を処置することを行う、方法。
(項目39) ビジネス方法であって、上記方法は、
トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2ドメインIVに結合する抗体と組み合わせた根治手術の後に高い癌再発リスクまたは低い生存可能性であると同定されるヒト被験体においてHER2陽性非転移性乳癌を処置するための化学療法剤を販売して、上記被験体の癌再発可能性を減少するかまたは上記被験体の生存可能性を増加する工程;
を包含する、方法。
(項目40) 項目39に記載の方法であって、上記化学療法剤は、タキソイドである、方法。
(項目41) 項目39に記載の方法であって、上記販売の後に、上記化学療法剤と上記抗体との組み合わせを用いて上記被験体を処置することを行う、方法。
(項目42) ビジネス方法であって、上記方法は、
化学療法剤と組み合わせた根治手術の後に高い癌再発リスクまたは低い生存可能性であると同定されるヒト被験体においてHER2陽性非転移性乳癌を処置するためのトラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2ドメインIVに結合する抗体を販売して、上記被験体の癌再発可能性を減少するかまたは上記被験体の生存可能性を増加する工程;
を包含する、方法。
(項目43) 項目42に記載の方法であって、上記販売の後に、上記化学療法剤と上記抗体との組み合わせを用いて上記被験体を処置することを行う、方法。
(項目44) 補助療法の方法であって、上記方法は、
非転移性HER2陽性乳癌を有するヒト被験体に対して、根治手術の後に、トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2のドメインIVに結合する抗体を、単一薬剤として、無疾患生存(DFS)または全体的生存(OS)を伸長させるに有効な量で投与する工程;
を包含し、上記DFSまたは上記OSを、上記抗体の初期投与後の少なくとも約1年目に確認する、方法。
(項目45) 補助療法のための組成物であって、上記組成物は、
非転移性HER2陽性乳癌を有するヒト被験体において、根治手術の後に、無疾患生存(DFS)または全体的生存(OS)を伸長させるに有効な量の、トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2のドメインIVに結合する抗体と、少なくとも1種の化学療法剤とを、含み、上記DFSまたは上記OSは、上記処置開始の約2年後〜約5年後に評価される、組成物。
(項目46) 項目45に記載の組成物であって、上記抗体は、HER2に対するトラスツズマブ(HERCEPTIN(登録商標))の結合をブロックする、組成物。
(項目47) 項目45に記載の組成物であって、上記抗体は、トラスツズマブ(HERCEPTIN(登録商標))を含む、組成物。
(項目48) 項目45に記載の組成物であって、上記化学療法剤は、タキソイド、ビンカ、白金化合物、アロマターゼインヒビター、抗エストロゲン、エトポシド、チオテパ、シクロホスファミド、メトトレキサート、リポソームドキソルビシン、ペグ化リポソームドキソルビシン、カペシタビン、およびゲンシタビンからなる群より選択される、組成物。
(項目49) 項目48に記載の組成物であって、上記化学療法剤は、タキソイドである、組成物。
(項目50) 項目49に記載の組成物であって、上記タキソイドは、パクリタキセルまたはドセタキセルである、組成物。
(項目51) 項目50に記載の組成物であって、上記パクリタキセルと上記抗体とは、アントラサイクリンおよびシクロホスファミドの投与後に投与されるように処方されている、組成物。
(項目52) 項目51に記載の組成物であって、上記抗体は、トラスツズマブ(HERCEPTIN(登録商標))を含む、組成物。
(項目53) 項目45に記載の組成物であって、上記抗体と化学療法との投与は、被験体集団において3年目の疾患再発を、化学療法単独で処置した被験体と比較して約50%減少させる、組成物。
(項目54) 項目51に記載の組成物であって、上記パクリタキセルと上記抗体との投与は、被験体集団において3年目の疾患再発を、上記抗体を用いずにパクリタキセルで処置した被験体と比較して約50%減少させる、組成物。
(項目55) 項目45に記載の組成物であって、上記被験体は、高い癌再発リスクを有する、組成物。
(項目56) 項目55に記載の組成物であって、上記被験体は、約50歳未満である、組成物。
(項目57) 項目55に記載の組成物であって、上記被験体は、直径2cmを超える腫瘍を有する、組成物。
(項目58) 項目55に記載の組成物であって、上記癌は、リンパ節陽性癌である、組成物。
(項目59) 項目58に記載の組成物であって、上記被験体は、4〜9個の浸潤されたリンパ節を有する、組成物。
(項目60) 項目59に記載の組成物であって、上記被験体は、10個以上の浸潤されたリンパ節を有する、組成物。
(項目61) 項目55に記載の組成物であって、上記被験体は、エストロゲンレセプター(ER)陰性である、組成物。
(項目62) 項目55に記載の組成物であって、上記被験体は、プロゲステロンレセプター(PG)陰性である、組成物。
(項目63) 項目45に記載の組成物であって、上記抗体は、インタクトな裸の抗体である、組成物。
(項目64) 項目45に記載の組成物であって、上記DFSまたは上記OSを、処置開始の4年後に評価する、組成物。
(項目65) 根治手術を行った、非転移性HER2陽性乳癌を有するヒト被験体の集団において非転移性乳癌を治癒するための組成物であって、上記組成物は、
有効量のトラスツズマブ(HERCEPTIN(登録商標))およびタキソイド
を含む、組成物。
(項目66) 項目65に記載の組成物であって、上記集団は、3000人以上のヒト被験体を含む、組成物。
(項目67) 根治手術を行った、非転移性HER2陽性乳癌を有するヒト被験体集団において疾患の再発を減少するための組成物であって、上記組成物は、
有効量のトラスツズマブ(HERCEPTIN(登録商標))およびタキソイド
を含む、組成物。
(項目68) 補助療法のための組成物であって、上記組成物は、
根治手術の後の、非転移性HER2陽性乳癌を有するヒト被験体の治療標準である化学療法と比較して無疾患生存(DFS)または全体的生存(OS)を伸長させるに有効な量で、トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2のドメインIVに結合する抗体と少なくとも1種の化学療法剤とを含み、
上記DFSまたは上記OSは、処置開始の少なくとも約3年間、1年間当たり少なくとも1回評価され、上記DFSは、上記患者が生存したままであり少なくとも1年間癌の再発がない場合に伸長し、上記OSは、処置開始から少なくとも1年間生存したままである場合に伸長する、組成物。
(項目69) 項目68に記載の組成物であって、上記抗体は、HER2に対するトラスツズマブ(HERCEPTIN(登録商標))の結合をブロックする、組成物。
(項目70) 項目68に記載の組成物であって、上記抗体は、トラスツズマブ(HERCEPTIN(登録商標))を含む、組成物。
(項目71) 項目68に記載の組成物であって、上記化学療法剤は、タキソイドである、組成物。
(項目72) 項目71に記載の組成物であって、上記タキソイドは、パクリタキセルまたはドセタキセルである、組成物。
(項目73) 項目68に記載の組成物であって、上記抗体および化学療法剤の投与は、被験体集団において3年目における疾患再発を、上記化学療法剤単独で処置した被験体と比較して約50%減少させる、組成物。
(項目74) 根治手術の後に高い癌再発リスクまたは低い生存可能性を有すると同定されかつ治療標準である化学療法によってのみ処置されている非転移性HER2陽性乳癌を有するヒト被験体を指示するための、コンピュータにより実施される方法であって、上記ヒト被験体に、トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2ドメインIVに結合する抗体と少なくとも1種の化学療法剤とでの処置を受容するように、指示手段によって指示する工程、を包含する、方法。
(項目75) 項目74に記載の方法であって、上記化学療法剤は、タキソイドである、方法。
(項目76) 項目74に記載の方法であって、上記被験体を、指示される通りに処置する、方法。
(項目77) 項目76に記載の方法であって、上記処置は、少なくとも6ヶ月間継続する、方法。
(項目78) 化学療法剤を宣伝するための、コンピュータにより実施される方法であって、上記方法は、
根治手術後に高い癌再発リスクまたは低い生存可能性であると同定されるヒト被験体におけるHER2陽性非転移性乳癌の処置を、宣伝手段によって宣伝する工程、
を包含し、上記処置は、
(a)トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2ドメインIVに結合する抗体と組み合わせた化学療法剤;または
(b)化学療法剤と組み合わせた、トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2ドメインIVに結合する抗体;
を包含する、方法。
(項目79) 項目78に記載の方法であって、上記化学療法剤は、タキソイドである、方法。
(項目80) 項目78に記載の方法であって、上記宣伝は、上記化学療法剤または上記抗体の商業的処方物が付随する包装挿入物による、方法。
(項目81) 項目78に記載の方法であって、上記宣伝は、医師または健康管理供給者への文書による伝達または口頭での伝達による、方法。
(項目82) 項目78に記載の方法であって、上記宣伝の後に、上記化学療法剤と上記抗体との組み合わせを用いて上記被験体を処置することを行う、方法。
(項目83) 化学療法剤を開発するための、コンピュータにより実施される方法であって、上記方法は、
トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2ドメインIVに結合する抗体と組み合わせた根治手術の後に高い癌再発リスクまたは低い生存可能性であると同定されるヒト被験体においてHER2陽性非転移性乳癌を処置するための化学療法剤を、販売手段によって販売して、上記被験体の癌再発可能性を減少するかまたは上記被験体の生存可能性を増加する工程;
を包含する、方法。
(項目84) 項目83に記載の方法であって、上記化学療法剤は、タキソイドである、方法。
(項目85) 項目83に記載の方法であって、上記販売する工程の後に、上記化学療法剤と上記抗体との組み合わせを用いて上記被験体を処置することを行う、方法。
(項目86) 化学療法剤を開発するための、コンピュータにより実施される方法であって、上記方法は、
化学療法剤と組み合わせた根治手術の後に高い癌再発リスクまたは低い生存可能性であると同定されるヒト被験体においてHER2陽性非転移性乳癌を処置するためのトラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2ドメインIVに結合する抗体を、販売手段によって販売して、上記被験体の癌再発可能性を減少するかまたは上記被験体の生存可能性を増加する工程;
を包含する、方法。
(項目87) 項目86に記載の方法であって、上記販売する工程の後に、上記化学療法剤と上記抗体との組み合わせを用いて上記被験体を処置することを行う、方法。
(項目88) 補助療法のための組成物であって、上記組成物は、
非転移性HER2陽性乳癌を有するヒト被験体において、根治手術の後に、無疾患生存(DFS)または全体的生存(OS)を伸長させるに有効な量の、トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2のドメインIVに結合する抗体を、単一薬剤中に含み、上記DFSまたは上記OSは、上記抗体の投与開始の少なくとも約1年間後に評価される、組成物。
(項目89) 項目74〜87のうちのいずれか1項に記載の方法を、コンピュータにおいて実施するためのコンピュータプログラム。
(項目90) コンピュータ読出し可能な記憶媒体であって、上記媒体は、上記媒体中に記録されたプログラムを有し、上記プログラムは、項目74〜87に記載の方法をコンピュータに実施させる、媒体。
(項目91) 項目74〜87のうちのいずれか1項に記載の方法をコンピュータにおいて実施するためのコンピュータプログラムを含む、通信媒体。
(I.定義)
本明細書において「補助療法」とは、疾患再発の危険性を減少するように、根治手術後に与えられる治療をいい、ここで、疾患が残っている証拠は何ら検出することはできない。補助療法の目的は、癌の再発を防止し、従って、癌に関連する死亡の可能性を減少させることである。本明細書において補助療法とは、新補助療法(例えば、被験体が、根治手術前に化学療法剤および/またはHERCEPTIN(登録商標)で処置されている場合)を特に除外する。
「根治手術」とは、腫瘍および周辺組織、ならびに全ての浸潤されたリンパ節の完全な除去をいう。このような手術としては、ランペクトミー、乳房切除術(例えば、単純乳房切除術と腋窩切除、両側乳房切除術(double mastectomy)など)が挙げられる。
「ヒトエフェクター細胞」は、1つ以上のFcRを発現しそしてエフェクター機能を果たす白血球である。好ましくは、この細胞は、少なくともFcγRIIIを発現し、そしてADCCエフェクター機能を果たす。ADCCを媒介するヒト白血球の例としては、末梢血単核細胞(PBMC)、ナチュラルキラー(NK)細胞、単球、細胞傷害性T細胞および好中球が挙げられ;PBMCおよびNK細胞が好ましい。エフェクター細胞は、そのネイティブな供給源から(例えば、本明細書中に記載されるように血液またはPBMCから)単離され得る。
本発明に従って使用されるHER2抗体の産生についての例示的な技術に関して、以下に説明する。抗体の産生のために使用されるHER2抗原は、例えば、所望のエピトープを含むHER2レセプターの細胞外ドメインまたはその一部分の可溶性形態であり得る。あるいは、細胞表面でHER2を発現する細胞(例えば、HER2を過剰発現するように形質転換されたNIH−3T3細胞;またはSK−BR−3細胞のような癌細胞株、例えば、Stancovskiら、PNAS(USA)88:8691−8695(1991))が、抗体を生成するために使用され得る。抗体を生成するのに有用なHER2の他の形態は、当業者に明らかである。
ポリクローナル抗体は、好ましくは、関連抗原およびアジュバントの複数回の皮下(sc)注射または腹腔内(ip)注射によって動物において惹起される。関連抗原を、二官能剤または誘導化剤(例えば、マレイミドベンゾイルスルホスクシンイミドエステル(システイン残基を介する結合)、N−ヒドロキシスクシンイミド(リジン残基を介する)、グルタルアルデヒド、無水コハク酸、SOCl2、またはR1N=C=NR(ここで、RおよびR1は異なるアルキル基である)を使用して、免疫化される種において免疫原性であるタンパク質(例えば、キーホールリンペットヘモシニアン、血清アルブミン、ウシサイログロブリンまたはダイズトリプシンインヒビター)と結合体化させることは有用であり得る。
本明細書中におけるモノクローナル抗体を作製するための種々の方法が、当該分野で利用可能である。例えば、モノクローナル抗体は、Kohlerら、Nature、256:495(1975)によって最初に記載されたハイブリドーマ法、組換えDNA法(米国特許第4,816,567号)を使用して、作製され得る。
非ヒト抗体をヒト化するための方法は、当該分野において記載されてきた。好ましくは、ヒト化抗体は、非ヒトである供給源からその抗体に導入された一つ以上のアミノ酸残基を有する。これらの非ヒトアミノ酸残基は、しばしば、「輸入(import)」残基と称される。この残基は、代表的に「輸入」可変ドメインから得られる。ヒト化は、超可変領域配列をヒト抗体のその対応配列に置換することによって、本質的にはWinterおよび共同研究者ら(Jonesら、Nature,321:522−525(1986);Riechmannら、Nature,332:323−327(1988);Verhoeyenら、Science,239:1534−1536(1988))の方法に従って実施され得る。従って、そのような「ヒト化」抗体は、キメラ抗体であり(米国特許第4,816,567号)、ここで実質的にあまりインタクトでないヒト可変ドメインは、非ヒト種由来の対応配列によって、置換されている。実際には、ヒト化抗体は、代表的に、いくつかの超可変領域残基およびおそらくいくつかのFR残基が、げっ歯動物抗体の類似部位に由来する残基によって置換されている、ヒト抗体である。
(iv)ヒト抗体
ヒト化の代替として、ヒト抗体が生成され得る。例えば、トランスジェニック動物(例えば、マウス)であって、免疫の際に内因性免疫グロブリン産生の非存在下でヒト抗体の充分なレパートリーを生成し得るものを作製することが今や可能である。例えば、キメラおよび生殖系列変異体マウスにおける抗体重鎖結合領域(JH)遺伝子のホモ接合性欠失は、内因性抗体産生の完全阻害を生じることが記載されている。そのような生殖系列変異体マウスにおけるヒト生殖系列免疫グロブリン遺伝子のアレイの移入は、抗原攻撃(challenge)に際しヒト抗体の産生を生じる。例えば、以下を参照のこと:Jakobovitsら、Proc.Natl.Acad.Sci.USA,90:2551(1993);Jakobovitsら、Nature,362:255−258(1993);Bruggermannら、Year in Immuno.,7:33(1993);ならびに米国特許第5,591,669号、同第5,589,369号および同第5,545,807号。あるいは、ファージディスプレイ技術(McCaffertyら、Nature 348:552−553(1990))を使用して、免疫していないドナーから免疫グロブリン可変(V)ドメイン遺伝子レパートリー由来のヒト抗体および抗体フラグメントをインビトロで生成し得る。この技術に従って、抗体Vドメイン遺伝子は、糸状バクテリオファージ(例えば、M13またはfd)の主要コートタンパク質遺伝子またはマイナーなコートタンパク質遺伝子のいずれか中にインフレームでクローニングされ、そしてファージ粒子の表面上に機能的な抗体フラグメントとして提示される。糸状粒子がファージゲノムの一本鎖DNAコピーを含むことから、その抗体の機能的特性に基づく選択もまた、それらの特性を示す抗体をコードする遺伝子の選択を生じる。従って、そのファージは、B細胞の特性のいくつかを模倣する。ファージディスプレイは、種々の形式で行われ得る;それらの概説については以下を参照のこと:Johnson,Kevin S.and Chiswell,David J.,Current Opinion in Structural Biology 3:564−571(1993)。V遺伝子セグメントのいくつかの供給源をファージディスプレイのために使用し得る。Clacksonら、Nature,352:624−628(1991)は、免疫したマウスの脾臓に由来するV遺伝子の小さなランダムコンビナトリアルライブラリーからの抗オキサゾロン抗体の多様なアレイを単離した。免疫していないヒトドナーからのV遺伝子のレパートリーが構築され得、そして多様なアレイの抗原(自己抗原を含む)に対する抗体は、以下に記載される技術に本質的に従って単離され得る:Marksら、J.Mol.Biol.222:581−597(1991)、またはGriffithら、EMBO J.12:725−734(1993)。また、米国特許第5,565,332号および同第5,573,905号を参照のこと。
種々の技術が、1以上の抗原結合領域を含む抗体フラグメントの産生のために開発されてきた。伝統的には、これらのフラグメントは、インタクトな抗体のタンパク質分解消化を介して誘導された(例えば、以下を参照のこと:Morimotoら、Journal of Biochemical and Biophysical Methods 24:107−117(1992);およびBrennanら、Science,229:81(1985))。しかし、これらのフラグメントは、今や、組換え宿主細胞によって直接産生され得る。例えば、その抗体フラグメントは、上記の抗体ファージライブラリーから単離され得る。あるいは、Fab’−SHフラグメントは、E.coliから直接回収され得、化学的に結合されて、F(ab’)2フラグメントを形成し得る(Carterら、Bio/Technology 10:163−167(1992))。別のアプローチに従って、F(ab’)2フラグメントは、組換え宿主細胞培養物から直接単離され得る。抗体フラグメントの産生のための他の技術は、当業者に明白である。他の実施形態において、選り抜きの抗体は、単鎖Fvフラグメント(scFv)である。以下を参照のこと:WO 93/16185;米国特許第5,571,894号;および同第5,587,458号。この抗体フラグメントはまた、「線状抗体」(linear antibody)であり得る(例えば、米国特許第5,641,870号に記載されるとおり)。そのような線状抗体フラグメントは、単一特異性または二重特異性であり得る。
(vi)二重特異性抗体
二重特異性抗体は、少なくとも2つの異なるエピトープについての結合特異性を有する抗体である。例示的な二重特異性抗体は、HER2タンパク質の2つの異なるエピトープに結合し得る。他のそのような抗体は、HER2結合部位と、EGFR、HER3および/またはHER4についての結合部位とを組み合わせ得る。あるいは、HER2アームは、細胞防御機構をHER2発現細胞へと集中させるために、T細胞レセプター分子(例えば、CD2またはCD3)のような白血球上のトリガー分子、あるいはIgGについてのFcレセプター(FcγR(例えば、FcγRI(CD64)、FcγRII(CD32)およびFcγRIII(CD16)))に結合するアームと組み合わされ得る。二重特異性抗体はまた、HER2を発現する細胞に対して細胞傷害性因子を局在化させるために使用され得る。これらの抗体は、HER2結合アーム、および細胞傷害性因子に結合するアーム(例えば、サポリン、抗インターフェロンα、ビンカアルカロイド、リシンA鎖、メトトレキサートまたは放射性同位体ハプテン)を有する。二重特異性抗体は、全長抗体または抗体フラグメント(例えば、F(ab’)2二重特異性抗体)として調製され得る。
本明細書中に記載される抗体のアミノ酸配列改変が企図される。例えば、抗体の結合親和性および/または他の生物学的特性を改善することが好ましくあり得る。この抗体のアミノ酸配列改変体は、適切なヌクレオチド変化を抗体核酸に導入することによるか、またはペプチド合成により調製される。そのような改変としては、例えば、抗体のアミノ酸配列内の残基の欠失、および/または挿入および/または置換を包含する。欠失、挿入および置換の任意の組合せは、最終構築物に達するように作製されるが、ただし、その最終構築物は所望の特性を有する。そのアミノ酸変化はまた、その抗体の翻訳後プロセシングを変更してもよい(例えば、グリコシル化部位の数または位置の変化)。
(1)非極性:Ala(A)、Val(V)、Leu(L)、Ile(I)、Pro(P)、Phe(F)、Trp(W)、Met(M)
(2)無電荷極性:Gly(G)、Ser(S)、Thr(T)、Cys(C)、Tyr(Y)、Asn(N)、Gln(Q)
(3)酸性:Asp(D)、Glu(E)
(4)塩基性:Lys(K)、Arg(R)、His(H)。
(1)疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile;
(2)中性親水性:Cys、Ser、Thr、Asn、Gln;
(3)酸性:Asp、Glu;
(4)塩基性:His、Lys、Arg;
(5)鎖方向に影響を与える残基:Gly、Pro;
(6)芳香族性:Trp、Tyr、Phe。
抗体を産生するための技術は、上記されている。所望である場合、特定の生物学的特徴を有する抗体をさらに選択し得る。
HERCEPTIN(登録商標)組成物は概して、主要な種の抗体の混合物(配列番号5および6それぞれの軽鎖配列および重鎖配列)、およびこれらの改変形態(特に、脱アミド化した改変体を含む酸改変体)を含有する。好ましくは、組成物中のこのような酸改変体の量は、約25%未満である。米国特許第6,339,142号を参照のこと。また、カチオン交換クロマトグラフィーにより分離可能なトラスツズマブの形態(ピークA(両方の軽鎖のAspに脱アミド化したAsn30);ピークB(一方の重鎖のイソAspに脱アミド化したAsn55);ピーク1(一方の軽鎖のイソAspに脱アミド化されたAsn30);ピーク2(一方の軽鎖のAspに脱アミド化したAsp30、および一方の重鎖のイソAspに異性化されたAsp102);ピーク3(主要なピーク形態または主要な種の抗体);ピーク4(一方の重鎖のイソAspに異性体化されたAsp102)およびピークC(一方の重鎖のAsp102スクシンイミド(Asu)を含む)に関しては、Harrisら、J.Chromatography B 752:233〜245(2001)を参照のこと。このような改変形態および組成物は、本明細書の本発明に包含される。
別の局面において、本発明は、細胞傷害性薬剤(例えば、化学療法剤、薬物、増殖阻害剤、毒素(例えば、細菌、真菌、植物もしくは動物起源の酵素的に活性な毒素またはそれらのフラグメント))に結合体化した抗体、または放射性同位体に結合体化した抗体(すなわち、放射性結合体)を含む免疫結合体、または抗体−薬物結合体(ADC)を提供する。
(i)発酵または発酵産物の化学的改変、誘導体化により比較的調製しやすく、(ii)抗体に対する非ジスルフィドリンカーを介した結合に適した官能基の誘導体化を受けやすく、(iii)血漿中で安定であり、そして(iv)種々の腫瘍細胞株に対して有効であるからである。
リンカーは、1つ以上のリンカー成分から構成され得る。例示的なリンカー成分としては、6−マレイミドカプロイル(「MC」)、マレイミドプロパノイル(「MP」)、バリン−シトルリン(「val−cit」)、アラニン−フェニルアラニン(「ala−phe」)、p−アミノベンジルオキシカルボニル(「PAB」)、N−スクシンイミジル−4−(2−ピリジルチオ)ペンタノエート(「SPP」)、N−スクシンイミジル 4−(N−マレイミドメチル)シクロヘキサン−1カルボキシレート(「SMCC」)、およびN−スクシンイミジル(4−ヨード−アセチル)アミノベンゾエート(「SIAB」)が挙げられる。さらなるリンカー成分は、当該分野において公知であり、いくつかが本明細書中に記載される。
本明細書中の患者は、一般的に、HER2陽性被験体を同定するために、治療の前に診断試験に供される。例えば、診断試験は、HER2発現(過剰発現を含む)、増幅および/または活性化(リン酸化またはダイマー化を含む)を評価し得る。
スコア0 染色が観察されないか、または膜染色が、腫瘍細胞の10%未満において観察される。
スコア1+ わずかな/かすかに認識可能な膜染色が、腫瘍細胞の10%より多くにおいて検出される。細胞は、それらの膜の一部においてのみ染色される。
スコア2+ 弱い〜中程度の完全な膜の染色が、腫瘍細胞の10%より多くにおいて観察される。
スコア3+ 中程度〜強い完全な膜の染色が、腫瘍細胞の10%より多くにおいて観察される。
0=0〜10,000コピー/細胞、
1+=少なくとも約200,000コピー/細胞、
2+=少なくとも約500,000コピー/細胞、
3+=少なくとも約2,000,000コピー/細胞。
本発明に従って使用されたHER2抗体の治療的処方物は、所望の程度の純度を有する抗体を、任意の薬学的に受容可能なキャリア、賦形剤、または安定化剤(Remington’s Pharmaceutical Sciences 16th edition,Osol,A.Ed.(1980))と、一般的に凍結乾燥処方物または水溶液の形態で混合することによって、保存のために調製される。抗体結晶もまた企図される(米国特許出願2002/0136719を参照のこと)。受容可能なキャリア、賦形剤、または安定化剤は、使用される投薬量および濃度においてレシピエントに対して非毒性であり、これには、以下が挙げられる:リン酸、クエン酸および他の有機酸のような緩衝液;アスコルビン酸およびメチオニンを含む酸化防止剤;保存剤(例えば、オクタデシルジメチルベンジルアンモニウムクロリド;ヘキサメトニウムクロリド;ベンズアルコニウムクロリド、ベンズエトニウムクロリド;フェノールアルコール、ブチルアルコールまたはベンジルアルコール;メチルパラベンまたはプロピルパラベンのようなアルキルパラベン;カテコール;レゾルシノール;シクロヘキサノール;3−ペンタノール;およびm−クレゾール);低分子量(約10残基未満)ポリペプチド;血清アルブミン、ゼラチン、または免疫グロブリンのようなタンパク質;ポリビニルピロリドンのような親水性ポリマー;グリシン、グルタミン、アスパラギン、ヒスチジン、アルギニン、またはリジンのようなアミノ酸;単糖類、二糖類、および他の炭水化物(グルコース、マンノース、またはデキストリンを含む);EDTAなどのキレート剤;スクロース、マンニトール、トレハロース、またはソルビトールなどの糖;ナトリウムのような塩形成対イオン;金属複合体(例えば、亜鉛−タンパク質複合体);および/またはTWEENTM、PLURONICSTMまたはポリエチレングリコール(PEG)などの非イオン性界面活性物質が挙げられる。
本発明は、根治手術に続いて、非転移性HER2陽性乳癌を有するヒト被験体に、疾患を含まない生存(DFS)または全体的な生存(OS)を延長するのに有効な量で、トラスツズマブ(HERCEPTIN(登録商標))に結合したHER2ドメインIVに結合する抗体を投与する工程を包含する補助療法の方法を提供する。ここで、DFSまたはOSは、抗体の最初の投与の約2〜5年後に評価される。好ましくは、被験体のDFSまたはOSは、処置の開始後または最初の診断後、約3〜5年、約4〜5年、または少なくとも約4年、または少なくとも約5年で評価される。好ましくは、抗体は、トラスツズマブ(HERCEPTIN(登録商標))である。
以下のハイブリドーマ細胞株は、American Type Culture Collection,10801 University Boulevard,Manassas,VA 20110−2209,USA(ATCC)に寄託された:
抗体名称 ATCC番号 寄託日
7C2 ATCC HB−12215 1996年10月17日
7F3 ATCC HB−12216 1996年10月17日
4D5 ATCC CRL10463 1990年 5月24日
2C4 ATCC HB−12697 1999年 4月 8日
本発明のさらなる詳細は、以下の非限定的な実施例によって説明される。本明細書中の全ての引用文献の開示は、本明細書中において参考として明確に援用される。
本実施例は、National Surgical Adjuvant Breast and Bowel Project(NSABP B−31)およびNorth Central Cancer Treatment Group(NCCTG)Intergroup N9831乳癌臨床試験において処置されたヒト乳癌被験体において得られた結果のジョイントインターム(joint interm)分析に関する。NCCTG研究は、2000年6月にその最初の患者を登録し、現在まで3,406人の患者を登録している;NSABP研究は、2000年3月に登録を始め、現在まで2,085人の患者を登録している。本実施例の合間(interim)分析は、3,300人の患者からの情報に基づいた。これらの試験は、高い危険の手術可能な乳癌に対する補助療法としてのトラスツズマブ(HERCEPTIN(登録商標))の効力を評価した。
NSABP B−31研究およびNCCTG N9831研究の設計は、図4Aに示される。
集団 A:アントラサイクリン(60mg/m2)およびシクロホスファミド(600mg/m2)、3週間毎に4サイクル(q 3wk×4)、続いて、パクリタキセル(80mg/m2/wk)12週間。
これらの試験の最初の終点は、処置の意図の原理に従って分析して、疾患を含まない生存(DFS)であった。すなわち、患者は、割り当てられた治療に基づいて評価された。第2の終点は、全般的な生存(OS)および第1の遠位の再発の時間であった。明確な分析は、710のDFS事象後にスケジュールされた。最初のインターム分析は、355のDFS事象後、次いで、6ヶ月毎の後にスケジュールされた;両方の試験での395の事象の合計を本明細書中に報告する。試験は、等価物がp=0.0005(2p=0.001)で拒絶された場合のみ、停止されるべきであった。
節陽性HER2陽性乳癌について、AC化学療法に続くパクリタキセルで同時に与えられたトラスツズマブは、最初の乳癌事象の危険を3年で52%減少させた。
Claims (40)
- 根治手術およびアントラサイクリン+シクロホスファミド(AC)ベースの化学療法後にヒト被験体に医薬を投与することを特徴とする、該ヒト被験体におけるHER2陽性癌の補助療法のための医薬の調製における、トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2ドメインIVに結合する抗ErbB2抗体を含む免疫結合体の有効量の使用であって、該抗ErbB2抗体は、メイタンシノイドに結合体化される、使用。
- 前記免疫結合体が、第2の抗ErbB2抗体と組み合わせて投与するためのものであり、該第2の抗ErbB2抗体がHER2二量体化インヒビターである、請求項1に記載の使用。
- 前記メイタンシノイドに結合体化させた前記抗ErbB2抗体がhuMAb4D5−8である、請求項1または2に記載の使用。
- 前記免疫結合体が、抗体1分子につきメイタンシノイド3〜5分子を含む、請求項4に記載の使用。
- 前記抗ErbB2抗体と前記メイタンシノイドが、N−スクシンイミジル−3−(2−ピリジルジチオ)プロピオネート(SPDP)、N−スクシンイミジル−4−(2−ピリジルチオ)ペンタノエート(SPP)およびスクシンイミジル−4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(SMCC)から選択される化学リンカーによって結合体化される、請求項1または2に記載の使用。
- 前記抗ErbB2抗体と前記メイタンシノイドが、スクシンイミジル−4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(SMCC)によって結合体化される、請求項6に記載の使用。
- 前記抗ErbB2抗体と前記メイタンシノイドが、N−スクシンイミジル−3−(2−ピリジルジチオ)プロピオネート(SPDP)、N−スクシンイミジル−4−(2−ピリジルチオ)ペンタノエート(SPP)およびスクシンイミジル−4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(SMCC)から選択される化学リンカーによって結合体化される、請求項3に記載の使用。
- 前記抗ErbB2抗体と前記メイタンシノイドが、スクシンイミジル−4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(SMCC)によって結合体化される、請求項8に記載の使用。
- 前記抗ErbB2抗体と前記メイタンシノイドが、N−スクシンイミジル−3−(2−ピリジルジチオ)プロピオネート(SPDP)、N−スクシンイミジル−4−(2−ピリジルチオ)ペンタノエート(SPP)およびスクシンイミジル−4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(SMCC)から選択される化学リンカーによって結合体化される、請求項4に記載の使用。
- 前記抗ErbB2抗体と前記メイタンシノイドが、スクシンイミジル−4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(SMCC)によって結合体化される、請求項10に記載の使用。
- 前記第2の抗ErbB2抗体がペルツズマブである、請求項2に記載の使用。
- 前記第2の抗ErbB2抗体がペルツズマブである、請求項3に記載の使用。
- 前記第2の抗ErbB2抗体がペルツズマブである、請求項11に記載の使用。
- 前記HER2陽性癌がHER2陽性乳癌である、請求項1または2に記載の使用。
- 前記HER2陽性乳癌が非転移性HER2陽性乳癌である、請求項15に記載の使用。
- 前記HER2陽性癌がHER2陽性乳癌である、請求項3に記載の使用。
- 前記HER2陽性乳癌が非転移性HER2陽性乳癌である、請求項17に記載の使用。
- 前記HER2陽性癌がHER2陽性乳癌である、請求項14に記載の使用。
- 前記HER2陽性乳癌が非転移性HER2陽性乳癌である、請求項19に記載の使用。
- トラスツズマブ(HERCEPTIN(登録商標))により結合されるHER2ドメインIVに結合する抗ErbB2抗体を含む免疫結合体の有効量を含む組成物であって、該抗ErbB2抗体は、メイタンシノイドに結合体化されており、該組成物は、根治手術およびアントラサイクリン+シクロホスファミド(AC)ベースの化学療法後に、HER2陽性癌を有するヒト被験体に投与されることを特徴とする、組成物。
- 前記免疫結合体が、第2の抗ErbB2抗体と組み合わせて投与するためのものであり、該第2の抗ErbB2抗体がHER2二量体化インヒビターである、請求項21に記載の組成物。
- 前記メイタンシノイドに結合体化させた前記抗ErbB2抗体がhuMAb4D5−8である、請求項21または22に記載の組成物。
- 前記免疫結合体が、抗体1分子につきメイタンシノイド3〜5分子を含む、請求項24に記載の組成物。
- 前記抗ErbB2抗体と前記メイタンシノイドが、N−スクシンイミジル−3−(2−ピリジルジチオ)プロピオネート(SPDP)、N−スクシンイミジル−4−(2−ピリジルチオ)ペンタノエート(SPP)およびスクシンイミジル−4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(SMCC)から選択される化学リンカーによって結合体化される、請求項21または22に記載の組成物。
- 前記抗ErbB2抗体と前記メイタンシノイドが、スクシンイミジル−4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(SMCC)によって結合体化される、請求項26に記載の組成物。
- 前記抗ErbB2抗体と前記メイタンシノイドが、N−スクシンイミジル−3−(2−ピリジルジチオ)プロピオネート(SPDP)、N−スクシンイミジル−4−(2−ピリジルチオ)ペンタノエート(SPP)およびスクシンイミジル−4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(SMCC)から選択される化学リンカーによって結合体化される、請求項23に記載の組成物。
- 前記抗ErbB2抗体と前記メイタンシノイドが、スクシンイミジル−4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(SMCC)によって結合体化される、請求項28に記載の組成物。
- 前記抗ErbB2抗体と前記メイタンシノイドが、N−スクシンイミジル−3−(2−ピリジルジチオ)プロピオネート(SPDP)、N−スクシンイミジル−4−(2−ピリジルチオ)ペンタノエート(SPP)およびスクシンイミジル−4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(SMCC)から選択される化学リンカーによって結合体化される、請求項24に記載の組成物。
- 前記抗ErbB2抗体と前記メイタンシノイドが、スクシンイミジル−4−(N−マレイミドメチル)シクロヘキサン−1−カルボキシレート(SMCC)によって結合体化される、請求項30に記載の組成物。
- 前記第2の抗ErbB2抗体がペルツズマブである、請求項22に記載の組成物。
- 前記第2の抗ErbB2抗体がペルツズマブである、請求項23に記載の組成物。
- 前記第2の抗ErbB2抗体がペルツズマブである、請求項31に記載の組成物。
- 前記HER2陽性癌がHER2陽性乳癌である、請求項21または22に記載の組成物。
- 前記HER2陽性乳癌が非転移性HER2陽性乳癌である、請求項35に記載の組成物。
- 前記HER2陽性癌がHER2陽性乳癌である、請求項23に記載の組成物。
- 前記HER2陽性乳癌が非転移性HER2陽性乳癌である、請求項37に記載の組成物。
- 前記HER2陽性癌がHER2陽性乳癌である、請求項34に記載の組成物。
- 前記HER2陽性乳癌が非転移性HER2陽性乳癌である、請求項39に記載の組成物。
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JP2022075920A Pending JP2022093642A (ja) | 2005-05-13 | 2022-05-02 | Herceptin(登録商標)補助療法 |
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JP2006316040A (ja) | 2006-11-24 |
CA2790058A1 (en) | 2006-11-13 |
US20120003217A1 (en) | 2012-01-05 |
MX344809B (es) | 2017-01-09 |
JP2022093642A (ja) | 2022-06-23 |
US8597654B2 (en) | 2013-12-03 |
JP2020094061A (ja) | 2020-06-18 |
JP2019011374A (ja) | 2019-01-24 |
AR108615A2 (es) | 2018-09-12 |
US20140086940A1 (en) | 2014-03-27 |
AR054254A1 (es) | 2007-06-13 |
AR088110A2 (es) | 2014-05-07 |
US20060275305A1 (en) | 2006-12-07 |
JP2017132805A (ja) | 2017-08-03 |
JP2015187168A (ja) | 2015-10-29 |
US20200155701A1 (en) | 2020-05-21 |
AR109246A2 (es) | 2018-11-14 |
BRPI0601736A (pt) | 2007-05-15 |
US8591897B2 (en) | 2013-11-26 |
CA2540547C (en) | 2016-08-16 |
US20180236093A1 (en) | 2018-08-23 |
CA2540547A1 (en) | 2006-11-13 |
CA2790058C (en) | 2019-01-15 |
JP2013144718A (ja) | 2013-07-25 |
JP2013163694A (ja) | 2013-08-22 |
JP2017132806A (ja) | 2017-08-03 |
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