JP2020063279A - タイプII抗CD20抗体と選択的Bcl−2インヒビターの併用療法 - Google Patents
タイプII抗CD20抗体と選択的Bcl−2インヒビターの併用療法 Download PDFInfo
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Abstract
Description
(a)アミノ酸残基26−32(L1)、50−52(L2)、91−96(L3)、26−32(H1)、53−55(H2)及び96−101(H3)に存在する超可変ループ(Chothia and Lesk,J.Mol.Biol.,196:901−917(1987));
(b)アミノ酸残基24−34(L1)、50−56(L2)、89−97(L3)、31−35b(H1)、50−65(H2)及び95−102(H3)に存在するCDR(Kabatら,Sequences of Proteins of Immunological Interest,5th Ed.,Public Health Service,National Institutes of Health,Bethesda、MD(1991));
(c)アミノ酸残基27c−36(L1)、46−55(L2)、89−96(L3)、30−35b(H1)、47−58(H2)及び93−101(H3)に存在する抗原コンタクト(MacCallumら,J.Mol.Biol.,262:732−745(1996));及び
(d)HVRアミノ酸残基46−56(L2)、47−56(L2)、48−56(L2)、49−56(L2)、26−35(H1)、26−35b(H1)、49−65(H2)、93−102(H3)及び94−102(H3)を含めた(a)、(b)及び/または(c)の組合せ;
が含まれる。
1)アッセイは、抗体の抗原結合領域により認識される標的抗原を発現することが公知の標的細胞を使用する;
2)アッセイは、ランダムに選択した健康なドナーの血液から単離したヒト末梢血単核細胞(PBMC)をエフェクター細胞として使用する;
3)アッセイは以下のプロトコルに従って実施する:
i)PBMCを標準の密度遠心手順を用いて単離し、RPMI細胞培地中に5×106細胞/mlで懸濁させる;
ii)標的細胞を標準組織培養方法により増殖させ、90%を超える生存度で指数的増殖期から収集し、RPMI細胞培地で洗浄し、100マイクロキューリーの51Crで標識し、細胞培地で2回洗浄し、細胞培地に105細胞/mlの密度で再懸濁させる;
iii)100μlの上記最終標的細胞懸濁液を96ウェルのマイクロタイタープレートの各ウェルに移す;
iv)抗体を細胞培地で4000ng/mlから0.04ng/mlに連続希釈し、50μlの生じた抗体溶液を96ウェルのマイクロタイタープレート中の標的細胞に添加し、上記に記載した全濃度範囲をカバーする各種抗体濃度で3回試験する;
v)最大放出(MR)対照のために、標識標的細胞を収容しているプレート中の3つの追加ウェルに抗体溶液(上のポイントiv)の代わりに50μlの非イオン性洗剤(Nonidet,セントルイスに所在のSigma)の2%(VN)水溶液を入れる;
vi)自然放出(SR)対照のために、標識標的細胞を収容しているプレート中の3つの追加ウェルに抗体溶液(上のポイントiv)の代わりに50μlのRPMI細胞培地を入れる;
vii)次いで、96ウェルのマイクロタイタープレートを50×gで1分間遠心し、4℃で1時間インキュベートする;
viii)25:1のエフェクター:標的細胞比を生ずるように各ウェルに50μlのPBMC懸濁液(上のポイントi)を添加し、プレートをインキュベータ中に5% CO2雰囲気下37℃で4時間置く;
ix)各ウェルからの無細胞上清を収集し、実験的に放出させた放射能(ER)をガンマカウンターを用いて定量化する;
x)抗体濃度毎に特異的溶解のパーセンテージを式(ER−MR)/(MR−SR)×100に従って計算する。ここで、ERはその抗体濃度について定量した平均放射能(上のポイントixを参照されたい)であり、MRはMR対照(上のポイントVを参照されたい)について定量した平均放射能(上のポイントixを参照されたい)であり、SRはSR対照(上のポイントviを参照されたい)について定量した平均放射能(上のポイントixを参照されたい)である。
4)「高いADCC」は、上で試験した抗体濃度範囲内で観察された特異的溶解の最大パーセンテージの増加、及び/または上で試験した抗体濃度範囲内で観察された特異的溶解の最大パーセンテージの半分を達成するのに必要な抗体の濃度の減少として定義される。1つの実施形態では、ADCCの増加は、コンパレーター抗体(高いADCCを欠く)をGnTIIIを過剰発現するように工学処理した及び/またはフコシルトランスフェラーゼ8(FUT8)遺伝子からの低い発現を有するように工学処理した(例えば、FUT8ノックアウトについて工学処理したものを含む)宿主細胞より産生されなかったことを除いて、当業者に公知の同一の標準産生、精製、処方及び保存方法を用いて上記アッセイで調べ、同一抗体により媒介され、同一タイプの宿主細胞により産生されたADCCに対している。
CD20発現癌疾患、好ましくはB細胞非ホジキンリンパ腫(NHL)に対する方法としての併用療法の使用に関する添付文書を含み得る。
医薬組成物は、本発明に従うタイプII抗CD20抗体または抗Bcl−2活性物質を医薬的に許容され得る無機または有機担体を用いて加工することにより得られ得る。錠剤、コーティング錠、糖衣錠及び硬ゼラチンカプセル剤用の担体として、例えばラクートース、トウモロコシ澱粉またはその誘導体、タルク、ステアリン酸またはその塩等が使用され得る。軟ゼラチンカプセル剤用の適当な担体は、例えば植物油、ワックス、脂肪、半固体及び液体ポリオール等である。しかしながら、軟ゼラチンカプセル剤の場合活性物質の種類に応じて担体は通常必要でない。溶液剤及びシロップ剤を製造するための適当な担体は、例えば水、ポリオール、グリセロール、植物油等である。座剤用の適当な担体は、例えば天然または硬化油、ワックス、脂肪、半液体または液体ポリオール等である。
1.品目1、2、3及び4を混合し、精製水を用いて造粒する;
2.顆粒を50℃で乾燥する;
3.顆粒を適当な粉砕装置に通す;
4.品目5を添加し、3分間混合し、適当なプレスを用いて圧縮する。
1.品目1、2及び3を適当なミキサーを用いて30分間混合する;
2.品目4及び5を添加し、3分間混合する;
3.適当なカプセルに充填する。
非臨床データから、GDC−0199及びGA101(この場合、オビヌツズマブ)の組合せが各薬物を単独で投与したときよりも高い抗腫瘍活性を示すという仮説が裏付けられる。本研究は、侵襲性リンパ腫の非ホジキンリンパ腫(NHL)異種移植片モデル、びまん性大細胞型B細胞リンパ腫(DLBCL)由来細胞株SU.DHL−4を使用した。オビヌツズマブを1mg/kgの用量で1週間に1回、3週間IV投与し、腫瘍静止後増殖の遅延が見られた。GDC−0199を100mg/kg QDで21日間投与し、同様に腫瘍静止後増殖の遅延が見られた。しかしながら、GDC−0199及びオビヌツズマブの組合せは相加効果を超える効果を誘導して、腫瘍が退縮した(8例のうち5例で部分退縮(PR);図1を参照されたい)。3週間の併用療法により、単剤投与で76%(GA101)及び80%(GDC 0199)の腫瘍増殖抑制(TGI)が観察されたのに比して高いTGI(118% TGI)が生じた(図1を参照されたい)。GA101をGDC 0199と組み合わせたときには、単剤投与に比して高い腫瘍退縮(5PR)も観察された。加えて、31日目(投与終了から10日後)に単剤としてのGA101で30% TGI、GDC 0199で25% TGIであったのに対して116% TGIが観察されたので、併用療法群ではTGIが治療を21日目に終了させた後持続された。要するに、NHL異種移植片モデルにおいて各剤を別々に投与したときに比してGA101をGDC 0199と組み合わせると高いTGI及び腫瘍退縮が生じた。
2つのスケジュールを評価する:スケジュールA(図2)では最初のオビヌツズマブ注入前にGDC−0199を漸増用量で3週間投与し、スケジュールB(図3)ではまずオビヌツズマブを投与した後漸増用量レベルのGDC−0199を投与した。スケジュールA及びスケジュールBのコホート1は平行して登録する。加えて、用量設定段階は、最初のオビヌツズマブ注入前にGDC−0199を投与する(スケジュールA)と注入反応の頻度が低下し、それによりオビヌツズマブ及びコルチコステロイドの前投薬の分割用量の必要性が減らせるかどうかを評価する。
タイプII抗CD20抗体はGA101抗体IgG1(WO 2005/044859に開示されているキメラヒト化IgG1抗体(ここでは、B−HH6−B−KV1 GEと称されており、オビヌツズマブまたはRO5072759としても公知)であり、スイス国シュリーレンのRoche GlycArtからストック溶液(濃度9.4mg/ml)として提供された。抗体バッファーはヒスチジン、トレハロース及びポリソルベート20を含んでいた。注入前に抗体溶液をストックからPBSで適切に希釈した。GDC−0199は米国カリフォルニア州のGenentech Inc.から入手した。
ヒトZ138マントル細胞リンパ腫細胞株を10% ウシ胎児血清(オーストリアのPAA Laboratories)及び2mM L−グルタミンを補充したDMEMにおいて37℃、5% CO2で水飽和雰囲気中でルーチン通りに培養する。細胞をMATRIGELと共注射した。
到着時(ドイツ国ズルツフェルトのCharles Riverから購入)5〜6週令の雌SCIDベージュマウスを関係しているガイドライン(GV−Solas;Felasa;TierschG)に従って12時間の明暗の1日周期で特別の病原体を含まない条件下で維持した。実験研究プロトコルを再検討し、地方自治体(Regierung von Oberbayern;登録番号55.2−1−54−2531.2−26−09)により容認された。到着後、新しい環境に慣らし、観察のために、動物を動物施設の隔離部分で1週間維持した。継続的健康モニタリングを定期的に実施した。餌(英国Altromin Spezialfutter GmbH & Co.)及び(濾過した)水は自由に与えた。
臨床症状及び副作用の検出のために動物を毎日管理した。実験を通してモニターするために、動物の体重を1週間に2回記録し、腫瘍体積をステージング後カリバスにより測定した。
動物治療を腫瘍細胞接種から18日後にランダム化の日に開始した。RO5072759またはリツキシマブを単剤として1mg/kgの用量で1週間に1回(18、25、32日目)、3週間i.p.投与した。対応するビヒクルは同日に投与した。GCD−0199を100mg/kgの用量で1日1回、17日間にわたり(18日目から34日目まで)p.o.投与した。併用療法群では、抗体及びGDC−0199を同一用量で同日に投与した。
治療の腫瘍体積拡大に対する結果を図4に示す。腫瘍細胞接種から35日目に、リツキシマブ、GDC−0199、RO5072759、GDC−0199+リツキシマブの組合せ、またはGDC−0199+RO5072759の組合せを投与された動物において対照群と比較してそれぞれ32%、59%、73%、96%または106%の腫瘍増殖抑制が観察された。
本実施例は上記実施例1に検討したDLBCL SU−DHL−4異種移植片モデルを用いて結果を記載する。最初、GDC−0199を1mg/kgのGA101(この例では、オビヌツズマブ)と一緒に連続21日間、3週間経口投与した。後者により、各々の薬剤のみで観察された54%(GA101)及び24%(GDC−0199) TGIと比較して高いTGI(91%)が生じた(図5)。22日目に、併用コホートの担腫瘍マウスにGDC−0199のみを100mg/kgで更に24日間投与し続けた。後者により、GA101及びGDC−0199の組合せで21日間治療したマウスと比較して腫瘍再増殖の有意な遅延が生じた(併用コホートの腫瘍進行までの時間=38日対GDC−0199での継続治療=45日(図5)。よって、GA101との併用後のGDC−0199での単剤治療はインビボで有効性を持続している。これらの結果により、GDC−0199での維持治療に対するベネフィットが裏付けられる。
Claims (29)
- 治療を要するヒトに対して有効量のGA101抗体、または2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドまたはその医薬的に許容され得る塩を1つ以上の投与期間中投与した後、有効量の前記GA101抗体及び2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドまたはその医薬的に許容され得る塩を1つ以上の投与期間中共投与することを含む前記ヒトにおける癌の治療方法。
- 治療を要するヒトに対して有効量のGA101抗体、または2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドまたはその医薬的に許容され得る塩を0、1、2、3、4、5、6、7、8、9、10、11、12、13または14日間投与した後、有効量の前記GA101抗体及び2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドまたはその医薬的に許容され得る塩を1つ以上の投与期間中共投与することを含む前記ヒトにおける癌の治療方法。
- 有効量の前記GA101抗体を1、2、3、4、5または6つのサイクル中投与期間毎に1回投与した後、有効量の前記GA101抗体を投与期間毎に1回、2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドまたはその医薬的に許容され得る塩を1つ以上の投与期間中1日1〜3回共投与することを含む請求項1に記載の方法。
- 有効量の2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドまたはその医薬的に許容され得る塩を1、2、3、4、5または6つの投与期間中1日1〜3回投与した後、有効量の前記GA101抗体を投与期間毎に1回、2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドまたはその医薬的に許容され得る塩を1つ以上の投与期間中1日1〜3回共投与することを含む請求項1に記載の方法。
- 前記GA101抗体の有効量は約500mg〜約3000mgであり、2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドまたはその医薬的に許容され得る塩の有効量は約20mg〜約500mgである請求項2〜4のいずれか1項に記載の方法。
- 前記GA101抗体の有効量は800、900、1000、1100、1200、1300、1400、1500mgであり、2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドまたはその医薬的に許容され得る塩の有効量は50、60、70、80、90、100、110、120、130、140、150、160、170、180、190、200、210、220、230、240、250、260、270、280、290または300mgである請求項2〜4のいずれか1項に記載の方法。
- 前記GA101抗体及び2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドまたはその医薬的に許容され得る塩を各投与期間中順次共投与し、各投与期間は1、2、3、4、5、6、7、8、9、10、11、12、13または14日間である請求項1〜6のいずれか1項に記載の方法。
- 前記GA101抗体は配列番号1のアミノ酸配列を含むHVR−H1、配列番号2のアミノ酸配列を含むHVR−H2、配列番号3のアミノ酸配列を含むHVR−H3、配列番号4のアミノ酸配列を含むHVR−L1、配列番号5のアミノ酸配列を含むHVR−L2、及び配列番号6のアミノ酸配列を含むHVR−L3を含む抗ヒトCD20抗体である請求項1〜7のいずれか1項に記載の方法。
- 前記GA101抗体は更に配列番号7のアミノ酸配列を含むVHドメイン及び配列番号8のアミノ酸配列を含むVLドメインを含む請求項8に記載の方法。
- 前記GA101抗体は配列番号9のアミノ酸配列及び配列番号10のアミノ酸配列を含む請求項1〜7のいずれか1項に記載の方法。
- 前記GA101抗体はオビヌツズマブとして公知である請求項1〜8のいずれか1項に記載の方法。
- 前記GA101抗体は配列番号9のアミノ酸配列と少なくとも95%の配列同一性を有するアミノ酸配列を含み、配列番号10のアミノ酸配列と少なくとも95%の配列同一性を有するアミノ酸配列を含む請求項1〜8のいずれか1項に記載の方法。
- 前記癌はCD20発現癌である請求項1〜12のいずれか1項に記載の方法。
- 前記癌は非固形腫瘍である請求項13に記載の方法。
- 前記癌はリンパ腫または白血病である請求項13に記載の方法。
- 前記白血病は慢性リンパ球性白血病(CLL)である請求項13に記載の方法。
- 前記患者は再発性、難治性または未治療の慢性リンパ球性白血病を患っている請求項16に記載の方法。
- 治療を要するヒトに対して投与期間中有効量のGA101抗体及び2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドを共投与することを含む前記ヒトにおける癌の治療方法であって、前記GA101抗体を500〜3000mgで毎週投与し、2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドを50〜300mgで投与期間中1日1〜3回投与する前記方法。
- 治療を要するヒトに対してGA101抗体及び2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドを複数投与サイクルで投与することを含む前記ヒトにおける癌の治療方法であって、各投与サイクルは少なくとも2、3、4、5または6週間であり、500mg〜3000mgの前記GA101抗体を複数の投与サイクルの1つ以上の投与サイクル中に1投与サイクルあたり1回投与し、10mg〜300mgの2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドを複数の投与サイクルの1つ以上の投与サイクル中に1投与サイクルあたり毎日投与する前記方法。
- 前記GA101抗体及び2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドの両方を患者に対して複数の投与サイクルの少なくとも2、3、4、5、6、7、8または8を超える投与サイクルで投与する請求項19に記載の方法。
- 複数の投与サイクルの最後の投与サイクルの後、GA101抗体を患者に対して投与することなく、2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドの用量を患者に対して投与する請求項19に記載の方法。
- 前記GA101抗体の非存在下で患者に対して投与される2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドの用量は約10mg〜約300mgの2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドである請求項21に記載の方法。
- 前記GA101抗体の非存在下で患者に対して投与される2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドの用量を患者に対して少なくとも3、4、5、6、7、8日間、または10日間以上、20日間以上、または30日間以上投与する請求項22に記載の方法。
- 複数の投与サイクルは、2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−4−(4−((2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エニル)メチル)ピペラジン−1−イル)−N−(3−ニトロ−4−((テトラヒドロ−2H−ピラン−4−イル)メチルアミノ)フェニルスルホニル)ベンズアミドを患者に対して段階的投与サイクルの間、漸増1日用量で投与する段階的投与サイクルを含む請求項19に記載の方法。
- 前記漸増1日用量は10mgの初期1日用量および、300mgの最終1日用量を含む請求項24に記載の方法。
- 前記癌は非固形腫瘍である請求項19〜25のいずれか1項に記載の方法。
- 前記癌は慢性リンパ球性白血病(CLL)である請求項19〜25のいずれか1項に記載の方法。
- 前記癌は非ホジキンリンパ腫(NHL)である請求項13に記載の方法。
- 前記癌は急性骨髄性白血病(AML)である請求項13に記載の方法。
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