JP2016166203A - トリプルネガティブおよび基底様乳癌の治療におけるerbb3阻害剤の使用 - Google Patents
トリプルネガティブおよび基底様乳癌の治療におけるerbb3阻害剤の使用 Download PDFInfo
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Abstract
【解決手段】トリプルネガティブ乳癌の治療の方法において使用するためのErbB3阻害剤であって、特定のVH,VL配列を有する抗ErbB3抗体である、ErbB3阻害剤。更に追加のErbB3阻害剤ではない抗癌剤を投与することが好ましい、ErbB3阻外剤の使用方法。
【選択図】なし
Description
本出願は、2010年3月11日に出願された米国特許仮出願第61/312895号、表題「Use of ErbB3 Inhibitors in the Treatment of Triple Negative and Basal−Like Breast Cancers」に対する優先権を主張し、ここで参照することによりその全体が本明細書に組み込まれる。
[本発明1001]
トリプルネガティブ乳癌の治療のための薬剤を製造するための、ErbB3阻害剤の使用。
[本発明1002]
トリプルネガティブ乳癌細胞の成長を抑制する方法であって、前記細胞を有効量のErbB3阻害剤と接触させる工程を含む、方法。
[本発明1003]
患者のトリプルネガティブ乳癌腫瘍の成長を抑制する方法であって、有効量のErbB3阻害剤を前記患者に投与する工程を含む、方法。
[本発明1004]
患者のトリプルネガティブ乳癌腫瘍を治療する方法であって、有効量のErbB3阻害剤を前記患者に投与する工程を含む、方法。
[本発明1005]
トリプルネガティブ乳癌腫瘍のある患者を選択する工程と、
有効量のErbB3阻害剤を前記患者に投与する工程と
を含む、患者の乳癌腫瘍を治療する方法。
[本発明1006]
前記ErbB3阻害剤が、抗ErbB3抗体である、本発明1001〜1005のいずれかの方法。
[本発明1007]
前記抗ErbB3抗体が、MM−121である、本発明1006の方法。
[本発明1008]
前記抗ErbB3抗体が、
アミノ末端からカルボキシ末端の順で、それぞれ配列番号3〜5に示されるVH CDR1、2、および3の配列と、アミノ末端からカルボキシ末端の順で、それぞれ配列番号6〜8に示されるVL CDR1、2、および3の配列とを含む抗体
を含む、本発明1006の方法。
[本発明1009]
前記抗ErbB3抗体が、
それぞれ配列番号9および10に示されるVHおよびVL配列を含むAb#3
を含む、本発明1006の方法。
[本発明1010]
前記抗ErbB3抗体が、
それぞれ配列番号17および18に示されるVHおよびVL配列を含むAb#14
を含む、本発明1006の方法。
[本発明1011]
前記抗ErbB3抗体が、
それぞれ配列番号25および26に示されるVHおよびVL配列を含むAb#17
を含む、本発明1006の方法。
[本発明1012]
前記抗ErbB3抗体が、
それぞれ配列番号33および34に示されるVHおよびVL配列を含むAb#19
を含む、本発明1006の方法。
[本発明1013]
前記抗ErbB3抗体が、mAb1B4C3、mAb2D1D12、およびヒト化mAb8B8から成る群から選択される、本発明1006の方法。
[本発明1014]
前記トリプルネガティブ乳癌腫瘍が、基底様発現型を有すると病理組織学的に特徴付けられる、本発明1001〜1005のいずれかの方法。
[本発明1015]
前記トリプルネガティブ乳癌腫瘍が、基底様以外の発現型を有すると病理組織学的に特徴付けられる、本発明1001〜1005のいずれかの方法。
[本発明1016]
ErbB3阻害剤ではない少なくとも1つの追加の抗癌剤の有効量を前記患者に投与する工程をさらに含む、本発明1003〜1015のいずれかの方法。
[本発明1017]
前記少なくとも1つの追加の抗癌剤が、少なくとも1つの化学療法薬を含む、本発明1016の方法。
[本発明1018]
前記少なくとも1つの追加の抗癌剤が、白金系化学療法薬、タキサン、チロシンキナーゼ阻害剤、抗EGFR抗体、抗ErbB2抗体、およびそれらの組み合わせから成る群から選択される、本発明1017の方法。
[本発明1019]
前記少なくとも1つの化学療法薬が、パクリタキセルである、本発明1018の方法。
[本発明1020]
前記ErbB3阻害剤が、
それぞれ配列番号3、4、および5に示されるVH CDR1、2、および3の配列と、それぞれ配列番号6、7、および8に示されるVL CDR1、2、および3の配列とを含む抗ErbB3抗体
である、本発明1019の方法。
[本発明1021]
前記ErbB3阻害剤が、MM−121である、本発明1019の方法。
[本発明1022]
前記少なくとも1つの追加の抗癌剤が、EGFR阻害剤を含む、本発明1016の方法。
[本発明1023]
前記EGFR阻害剤が、抗EGFR抗体を含む、本発明1022の方法。
[本発明1024]
前記抗EGFR抗体が、セツキシマブを含む、本発明1023の方法。
[本発明1025]
前記抗EGFR抗体が、マツズマブ、パニツムマブ、ニモツズマブ、およびmAb806から成る群から選択される、本発明1023の方法。
[本発明1026]
前記EGFR阻害剤が、EGFRシグナル伝達の小分子阻害剤である、本発明1022の方法。
[本発明1027]
前記EGFRシグナル伝達の小分子阻害剤が、ゲフィチニブ、ラパチニブ、カネルチニブ、ペリチニブ、エルロチニブHCL、PKI−166、PD158780、およびAG1478から成る群から選択される、本発明1026の方法。
[本発明1028]
前記少なくとも1つの追加の抗癌剤が、VEGF阻害剤を含む、本発明1016の方法。
[本発明1029]
前記VEGF阻害剤が、抗VEGF抗体を含む、本発明1028の方法。
[本発明1030]
前記抗VEGF抗体が、ベバシズマブである、本発明1029の方法。
[本発明1031]
前記トリプルネガティブ乳癌腫瘍は、
腫瘍細胞が、エストロゲン受容体(ER)およびプロゲステロン受容体に関してマイナスの得点を取り、多クローン性抗HER2一次抗体を使用する半定量的免疫組織化学的アッセイを使用して、0または1+の試験結果を得る腫瘍
である、本発明1001〜1005のいずれかの方法。
[本発明1032]
前記トリプルネガティブ乳癌腫瘍は、
腫瘍細胞が、エストロゲン受容体(ER)およびプロゲステロン受容体に関してマイナスの得点を取り、多クローン性抗HER2一次抗体を使用する半定量的免疫組織化学アッセイを使用して、2+の試験結果を得る腫瘍
である、本発明1001〜1005のいずれかの方法。
[本発明1033]
前記腫瘍細胞が、HER2遺伝子増幅に関してFISHネガティブである、本発明1032の方法。
[本発明1034]
基底様乳癌の治療のための薬剤を製造するための、ErbB3阻害剤の使用。
[本発明1035]
基底様乳癌細胞の成長を抑制する方法であって、前記細胞を有効量のErbB3阻害剤と接触させる工程を含む、方法。
[本発明1036]
患者の基底様乳癌腫瘍の成長を抑制する方法であって、有効量のErbB3阻害剤を前記患者に投与する工程を含む、方法。
[本発明1037]
基底様乳癌腫瘍について患者を治療する方法であって、有効量のErbB3阻害剤を前記患者に投与する工程を含む、方法。
[本発明1038]
基底様乳癌腫瘍のある患者を選択する工程と、
有効量のErbB3阻害剤を前記患者に投与する工程と
を含む、患者の乳癌腫瘍を治療する方法。
[本発明1039]
前記ErbB3阻害剤が、抗ErbB3抗体である、本発明1034〜1038のいずれかの方法。
[本発明1040]
前記抗ErbB3抗体が、MM−121である、本発明1039の方法。
[本発明1041]
前記抗ErbB3抗体が、
それぞれ配列番号3〜5に示されるVH CDR1、2、および3の配列と、それぞれ配列番号6〜8に示されるVL CDR1、2、および3の配列とを含む抗体
を含む、本発明1039の方法。
[本発明1042]
前記抗ErbB3抗体が、
それぞれ配列番号9および10に示されるVHおよびVL配列を含むAb#3
を含む、本発明1039の方法。
[本発明1043]
前記抗ErbB3抗体が、
それぞれ配列番号17および18に示されるVHおよびVL配列を含むAb#14
を含む、本発明1039の方法。
[本発明1044]
前記抗ErbB3抗体が、
それぞれ配列番号25および26に示されるVHおよびVL配列を含むAb#17
を含む、本発明1039の方法。
[本発明1045]
前記抗ErbB3抗体が、
それぞれ配列番号33および34に示されるVHおよびVL配列を含むAb#19
を含む、本発明1039の方法。
[本発明1046]
前記抗ErbB3抗体が、mAb1B4C3、mAb2D1D12、AMG−888、およびヒト化mAb8B8から成る群から選択される、本発明1039の方法。
[本発明1047]
ErbB3阻害剤ではない少なくとも1つの追加の抗癌剤の有効量を前記患者に投与する工程をさらに含む、本発明1035〜1040のいずれかの方法。
[本発明1048]
前記少なくとも1つの追加の抗癌剤が、パクリタキセルである、本発明1047の方法。
[本発明1049]
ErbB3阻害剤ではない少なくとも1つの追加の抗癌剤による基底様乳癌またはトリプルネガティブ乳癌の治療とともに、基底様乳癌またはトリプルネガティブ乳癌を治療するための薬剤を製造するための、ErbB3阻害剤の使用。
[本発明1050]
前記少なくとも1つの追加の抗癌剤が、パクリタキセルである、本発明1049の方法。
[本発明1051]
前記追加の抗癌剤が、トラスツズマブまたはペルツズマブである抗ErbB2抗体である、本発明1018または本発明1044の方法。
[本発明1052]
前記少なくとも1つの追加の抗癌剤が、ラパチニブである、本発明1018または本発明1047の方法。
[本発明1053]
前記半定量的免疫組織化学アッセイが、HercepTest(登録商標)キットを含むアッセイである、本発明1031または本発明1032の方法。
本明細書では、トリプルネガティブおよび基底様乳癌を治療するための方法、ならびにそのような方法を実施する際に使用することができる薬学的組成物が提供される。実施例でさらに説明されるように、現在、ErbB3阻害剤、特に抗ErbB3抗体が、生体内でTN乳癌細胞の成長を抑制できることが証明されている。したがって、本明細書では、ErbB3阻害剤を使用して、患者においてTN乳癌およびBL乳癌の成長を抑制するための方法、ならびにそのような乳癌を治療する方法が提供される。
本明細書で使用する、「トリプルネガティブ」または「TN」という用語は、腫瘍(例えば、癌)、通常、***腫瘍を指し、腫瘍細胞は、エストロゲン受容体(ER)およびプロゲステロン受容体(PR)についてネガティブのスコアを取り(すなわち、従来の病理組織学的方法を使用して)、いずれも核受容体であり(すなわち、それらは主に細胞核に位置する)、腫瘍細胞は、上皮成長因子受容体2型(HER2またはErbB2)について増幅せず、受容体は、通常、細胞表面上に位置する。腫瘍細胞は、標準免疫組織化学的技法を使用して、腫瘍細胞核の5%未満がERおよびPR発現について染色される場合、ERおよびPRの発現についてネガティブであると考えられる。腫瘍細胞は、HER2(「HER23+」)について、大幅に増幅すると考えられる。HercepTest(商標)キット(コードK5204、Dako North America,Inc.、Carpinteria CA)を用いて、ポリクローナル抗HER2一次抗体を使用する半定量的免疫組織化学アッセイを試験するとき、蛍光インサイツハイブリダイゼーション(FISH)によって、試験結果スコア3+または試験HER2ポジティブを生じる。本明細書で使用する、腫瘍細胞は、それらが試験結果スコア0、1+、または2+を生じる場合、またはそれらがHER2FISHネガティブである場合、HER2の過剰発現についてネガティブであると考えられる。
本明細書でさらに詳述されるように、本明細書に提供される方法および組成物は、1つまたは複数のErbB3阻害剤の使用を伴う。
一態様では、TN乳癌またはBL乳癌の治療用の薬剤を製造するためのErbB3阻害剤の使用が提供される。
TNまたはBL乳癌腫瘍のある患者を選択する工程と、
有効量のErbB3阻害剤を患者に投与する工程とを含む。
別の態様では、本明細書に開示される方法で使用することができる薬学的組成物、すなわち、TNまたはBL乳癌腫瘍を治療するための薬学的組成物が提供される。
ある実施形態では、TN乳癌細胞の成長を抑制するため、またはTN***腫瘍もしくはBL***腫瘍のある患者を治療するための本明細書に提供される方法および使用は、ErbB3阻害剤、およびErbB3阻害剤ではない少なくとも1つの追加の抗癌剤の投与を含み得る。
log10細胞死滅=T−C(日数)/3.32xTd
式中、T−Cは、細胞成長の遅延を表し、治療群(T)の腫瘍および対照群(C)の腫瘍が、既定値(例えば、1gまたは10mL)に到達するまでの平均時間(日数)であり、Tdは、対照動物において腫瘍の体積を二倍にするために必要な時間(日数)を表す。この方法を適用するとき、製品は、log10細胞死滅が0.7以上である場合に活性であると考えられ、log10細胞死滅が2.8を超えると非常に活性であると考えられる。
担癌マウスのMM−121治療の抗腫瘍有効性および耐性に関する分析は、NMRIヌードマウスにおいて、トリプルネガティブヒト乳癌異種移植片MAXF449(ONCOTEST GmbH、Frieburg、Germany)を使用して行われる。MAXF449は、ヌードマウスの連続継代において皮下注射を介して確立された、ヒト腫瘍外植片である(外植片に関して、固形の侵襲性管として組織学的に説明され、明らかに定義されていない)。これらの実験で使用されるMAXF449細胞は、22回継代された。NMRIヌードマウスは、Taconic farms、Charles River Laboratories InternationalまたはHarlan Laboratoriesから取得される。マウスは、温度と湿度が調整された部屋にある、個別に換気されたTecniplastポリカーボネート(Macrolon)ケージ(IVC)セットに収容され、食餌と酸性水に自由にアクセスできる。
一般的な麻酔下、バルブ/cヌードマウスに107MDA−MB−231ヒトトリプルネガティブ乳癌細胞(ATCC)を、側腹部に皮下的に、または***脂肪体の中のいずれかに注射する。次に、確立された腫瘍のあるマウス(すなわち、細胞注射に続く腫瘍成長の7〜10日後)を、実施例1に記載されるように、PBSまたはMM−121のいずれかを用いて、3日毎に600μg MM−121/マウスで腹腔内治療する。実施例1に記載されるように、腫瘍体積を1週間に2回測定する。
抗ErbB抗体の解離定数は、表面プラズモン共鳴アッセイおよび細胞結合アッセイという2つの独立した技法のいずれか、または両方を使用して測定されてもよい。
表面プラズモン共鳴アッセイは、Wassafら(2006)のAnalytical Biochem.,351:241〜253に記載のとおり行う。1つの実装では、組み換えErbBタンパク質を検体として、および抗ErbB抗体をリガンドとして使用するBIACORE3000器具(GE Healthcare)を使用する。KD値は、式KD=Kd/Kaに基づいて計算する。
MALME−3M細胞(ATCC)を使用して、ErbB3結合について細胞結合アッセイを行う。アッセイは、実質的に以下のとおり行う。
方法:
バルブ/cヌードマウス(雌、Charles River Labからの4〜5週齢)の***体に10x106個の細胞を同所移植する。腫瘍のサイズを平均100mm3に到達させた後、同様の腫瘍サイズ分布を有するマウスを含む、10匹のマウスの4群にランダム化する。各群のマウスは、1)MM−121(150μg/マウス、腹腔内、Q3D)、2)媒体対照(PBS、腹腔内)、3)パクリタキセル(5mg/kg LC Lab)、または4)パクリタキセル(5mg/kg)およびMM−121(150μg/マウス)で治療する。治療は4週間継続する。1週間に2回腫瘍を測定し、腫瘍体積は、p/6x長さx幅2として計算する(幅は短い方の測定値である)。
MDA−MB−231トリプルネガティブ乳癌異種移植片モデルにおいて、上記の方法またはそのマイナー変化を使用して、MM−121とパクリタキセルの複合を生体内で調査した。マウスを準最適用量のMM−121、パクリタキセル、MM−121およびパクリタキセルの複合、または媒体対照で治療する(図3)。MM−121およびパクリタキセルはいずれも、それぞれ生体内で腫瘍成長を阻害するが、MM−121およびパクリタキセルの複合療法を受けるマウスは、個別の治療のそれぞれから得られたものと比較して、腫瘍成長阻害の向上を呈した。腫瘍成長阻害の向上は、治療的相乗効果を呈し、複合の単剤それぞれから得られる向上と比較して、少なくともほぼ付加的であった。
方法:
バルブ/cヌードマウス(雌、Charles River Labからの4〜5週齢)の***体に10x106個の細胞を同所移植する。腫瘍のサイズを平均150mm3に到達させた後、同様の腫瘍サイズ分布を有するマウスを含む、8匹のマウスの9群にランダム化する。各群のマウスを、1)MM−121(300μg/マウス、腹腔内、Q3D)、2)媒体対照(PBS、腹腔内)、3)パクリタキセル(10mg/kg LC Labs)、4)エルロチニブ(50mg/kg PO 5XQD)、5)セツキシマブ(2mg/kg Q3D)、6)エルロチニブ(50mg/kg)およびMM−121(300μg/マウス)との複合療法、7)セツキシマブ(2mg/kg)およびMM−121(300μg/マウス)との複合療法、8)エルロチニブ(50mg/kg)およびMM−121(300μg/マウス)およびパクリタキセル(10mg/kg)との複合療法、または9)セツキシマブ(2mg/kg)およびMM121(300μg/マウス)およびパクリタキセル(10mg/kg)の投与で治療する。治療は4週間継続する。1週間に2回腫瘍を測定し、腫瘍体積は、p/6x長さx幅2として計算する(幅は短い方の測定値である)。
当業者であれば、単なる日常実験を使用して、本明細書に記載される特定実施形態の多くの均等物を認識するか、または確認することができるであろう。そのような均等物は、以下の請求項によって包含されるものとする。従属請求項に開示される実施形態のあらゆる組み合わせは、本発明の範囲内であると考えられる。
本明細書で言及される発行済み特許、特許出願、および公開のそれぞれおよびすべては、参照することによりその全体が本明細書に組み込まれる。
Claims (15)
- トリプルネガティブ乳癌の治療の方法において使用するためのErbB3阻害剤であって、抗ErbB3抗体である、ErbB3阻害剤。
- 前記抗ErbB3抗体が、
アミノ末端からカルボキシ末端の順で、
配列番号3に示されるVH CDR1の配列、
配列番号4に示されるVH CDR2の配列、および
配列番号5に示されるVH CDR3の配列、ならびに
アミノ末端からカルボキシ末端の順で、
配列番号6に示されるVL CDR1の配列、
配列番号7に示されるVL CDR2の配列、および
配列番号8に示されるVL CDR3の配列
を含む、請求項1に記載の使用のための請求項1に記載の阻害剤。 - 前記抗ErbB3抗体が以下:
(a)配列番号1に示されるVH配列と配列番号2に示されるVL配列とを含む抗体;
(b)配列番号9に示されるVH配列と配列番号10に示されるVL配列とを含む抗体;
(c)配列番号17に示されるVH配列と配列番号18に示されるVL配列とを含む抗体;および
(d)配列番号25に示されるVH配列と配列番号26に示されるVL配列とを含む抗体
より選択される、請求項1に記載の使用のための請求項1に記載の阻害剤。 - 前記トリプルネガティブ乳癌腫瘍が以下:
(i)基底様発現型;または
(ii)基底様以外の発現型
を有すると病理組織学的に特徴付けられる、請求項1〜3のいずれか一項に記載の使用のための請求項1〜3のいずれか一項に記載の阻害剤。 - 前記方法が、少なくとも1つの追加の抗癌剤を投与する工程をさらに含む、請求項1〜4のいずれか一項に記載の使用のための請求項1〜4のいずれか一項に記載の阻害剤。
- 前記追加の抗癌剤が、ErbB3阻害剤ではない、請求項5に記載の使用のための請求項5に記載の阻害剤。
- 前記少なくとも1つの追加の抗癌剤が、白金系化学療法薬、タキサン、チロシンキナーゼ阻害剤、抗EGFR抗体、抗ErbB2抗体、それらの組み合わせ、EGFR阻害剤、およびVEGF阻害剤から選択される、請求項5または6に記載の使用のための請求項5または6に記載の阻害剤。
- 前記少なくとも1つの追加の抗癌剤が、パクリタキセルである、請求項7に記載の使用のための請求項7に記載の阻害剤。
- 前記少なくとも1つの追加の抗癌剤が、抗EGFR抗体である、請求項7に記載の使用のための請求項7に記載の阻害剤。
- 前記抗EGFR抗体が、セツキシマブ、マツズマブ、パニツムマブ、ニモツズマブ、およびmAb806から選択される、請求項9に記載の使用のための請求項9に記載の阻害剤。
- 前記EGFR阻害剤が、ゲフィチニブ、ラパチニブ、カネルチニブ、ペリチニブ、エルロチニブHCL、PKI−166、PD158780、およびAG1478から選択されるEGFRシグナル伝達の小分子阻害剤である、請求項7に記載の使用のための請求項7に記載の阻害剤。
- 前記VEGF阻害剤が、ベバシズマブを含む、請求項7に記載の使用のための請求項7に記載の阻害剤。
- 前記トリプルネガティブ乳癌腫瘍は、
腫瘍細胞が、エストロゲン受容体(ER)およびプロゲステロン受容体に関してネガティブのスコアを取り、ポリクローナル抗HER2一次抗体を使用する半定量的免疫組織化学的アッセイを使用して、0、1+、または2+の試験結果を得る腫瘍
である、請求項1〜3のいずれか一項に記載の使用のための請求項1〜3のいずれか一項に記載の阻害剤。 - 前記腫瘍細胞が、HER2遺伝子増幅に関して蛍光インサイツハイブリダイゼーション(FISH)ネガティブである、請求項13に記載の使用のための請求項13に記載の阻害剤。
- トリプルネガティブ乳癌の治療のための薬剤を製造するためのErbB3阻害剤の使用であって、該阻害剤がErbB3抗体である、ErbB3阻害剤の使用。
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