JP2014507384A - Mdm2阻害剤とのアフコシル化cd20抗体の併用療法 - Google Patents
Mdm2阻害剤とのアフコシル化cd20抗体の併用療法 Download PDFInfo
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Abstract
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モノクローナル抗体の細胞媒介性エフェクター機能は、Umana, P.等, Nature Biotechnol. 17 (1999) 176-180及び米国特許第6602684号に記載されているように、そのオリゴ糖成分を操作することによって亢進せしめることができる。癌免疫療法において最もよく使用される抗体であるIgG1型抗体は、保存されたN結合型グリコシル化部位を各CH2ドメインのAsn297に有する糖タンパク質である。Asn297に結合した2つの複合型二分岐オリゴ糖は、CH2ドメイン間に埋もれて、ポリペプチド主鎖との広範囲の接触面を形成し、その存在は、抗体が抗体依存性細胞傷害性(ADCC)のようなエフェクター機能を媒介するために必須である(Lifely, M.R.等, Glycobiology 5 (1995) 813-822;Jefferis, R.等, Immunol. Rev. 163 (1998) 59-76;Wright, A.及びMorrison, S.L., Trends Biotechnol. 15 (1997) 26-32)。Umana, P.等, Nature Biotechnol. 17 (1999) 176-180及び国際公開第99/154342号は、2つに分岐したオリゴ糖の形成を触媒するグリコシルトランスフェラーゼであるβ(1,4)-N-アセチルグルコサミニルトランスフェラーゼIII(「GnTIII」)のチャイニーズハムスター卵巣(CHO)細胞における過剰発現が、抗体のインビトロでのADCC活性を有意に増大せしめることを示している。N297炭水化物の組成の改変又はその除去もまたFcγR及びC1qへのFc結合に影響を及ぼす(Umana, P.等, Nature Biotechnol. 17 (1999) 176-180;Davies, J.等, Biotechnol. Bioeng. 74 (2001) 288-294;Mimura, Y.等, J. Biol. Chem. 276 (2001) 45539-45547;Radaev, S.等, J. Biol. Chem. 276 (2001) 16478-16483;Shields, R.L.等, J. Biol. Chem. 276 (2001) 6591-6604;Shields, R.L.等, J. Biol. Chem. 277 (2002) 26733-26740;Simmons, L.C.等, J. Immunol. Methods 263 (2002) 133-147)。
CD20分子(ヒトBリンパ球限定分化抗原又はBp35とも称される)は、広く記載されているプレB細胞及び成熟Bリンパ球上に位置する疎水性膜貫通タンパク質である(Valentine, M.A.等, J. Biol. Chem. 264 (1989) 11282-11287;及びEinfeld, D.A.等, EMBO J. 7 (1988) 711-717;Tedder, T.F.等, Proc. Natl. Acad. Sci. U.S.A. 85 (1988) 208-212;Stamenkovic, I.等, J. Exp. Med. 167 (1988) 1975-1980;Tedder, T.F.等, J. Immunol. 142 (1989) 2560-2568)。CD20は、90%を越えるB細胞非ホジキンリンパ腫(NHL)で発現している(Anderson, K.C.等, Blood 63 (1984) 1424-1433)が、造血幹細胞、プロB細胞、正常形質細胞、又は他の正常組織には見いだせない(Tedder, T.F.等, J, Immunol. 135(1985) 973-979)。
例えばトシツモマブ(B1)、11B8、AT80又はヒト化B-Ly1抗体等のII型抗体は、同時のホスファチジルセリン曝露でカスパーゼ非依存性アポトーシスを介して標的細胞死を効率的に開始せしめる。
MDM2(同義語:E3ユビキチン-タンパク質リガーゼMdm2 p53結合タンパク質)はp53関連タンパク質である(Oliner, J.D.等, Nature 358 (1992) 80-83;Momand, J.等, Cell 69 (1992) 1237-1245;Chen, J.等, Mol. Cell. Biol. 13 (1993) 4107-4114;及びBueso-Ramos, C.E.等, Blood 82 (1993) 2617-2623)。それは腫瘍タンパク質p53に結合し、自己調節性の負のフィードバックループの一部として腫瘍タンパク質p53によるトランス活性化を阻害する核リンタンパク質である。この遺伝子又はタンパク質の過剰発現は腫瘍タンパク質p53の過剰な不活化を生じ得、その腫瘍抑制因子機能を減じる。このタンパク質は、プロテアソーム分解のために腫瘍タンパク質p53を標的とするE3ユビキチンリガーゼ活性を有している。このタンパク質はまた網膜芽細胞腫1及びリボソームタンパク質L5を含む他のタンパク質との相互作用を介した細胞周期、アポトーシス及び腫瘍形成にも影響を及ぼす。40を越える異なった選択的スプライス転写バリアントが腫瘍及び正常双方の組織から単離されている。
1)該アッセイは、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知られている標的細胞を使用する;
2)該アッセイは、エフェクター細胞として、無作為に選択された健常なドナーの血液から単離されたヒト末梢血単核細胞(PBMC)を使用する;
3)該アッセイは、次のプロトコルに従って実施される:
i)標準的な密度遠心分離手順を使用してPBMCを単離し、5×106細胞/mlの濃度でRPMI細胞培養培地に懸濁させる;
ii)標準的な組織培養法により標的細胞を増殖させ、生存率が90%を越える対数増殖期に回収し、RPMI細胞培養培地で洗浄し、100マイクロキュリーの51Crで標識し、細胞培養培地で2回洗浄し、105細胞/mlの密度で細胞培養培地に再懸濁させる;
iii)100マイクロリットルの上記の最終的な標的細胞懸濁物を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)抗体を細胞培養培地で4000ng/mから0.04ng/mlに連続希釈し、50マイクロリットルの得られた抗体溶液を96ウェルマイクロタイタープレート中の標的細胞に添加し、上記の全濃度範囲をカバーする様々な抗体濃度で3回試験する;
v)最大放出(MR)コントロールに対して、標識された標的細胞を含むプレート中の更なる3つのウェルに、抗体溶液(上記のiv項)に代えて、50マイクロリットルの非イオン性洗浄剤(Nonidet, Sigma, St. Louis)の2%(VN)水溶液を添加する;
vi)自然放出(SP)コントロールに対して、標識された標的細胞を含むプレート中の更なる3つのウェルに、抗体溶液(上記のiv項)に代えて、50マイクロリットルのRPMI細胞培養培地を添加する;
vii)ついで、96ウェルマイクロタイタープレートを50xgで1分間遠心分離し、1時間4℃でインキュベートする;
viii)エフェクター:標的細胞の比率が25:1となるように各ウェルに50マイクロリットルのPBMC懸濁液(上記のi項)を添加して、該プレートを37℃、5%CO2のインキュベーター中に4時間配する;
ix)各ウェルから無細胞の上清を回収し、ガンマカウンターを使用して、実験的に放出された放射能(ER)を定量する;
x)特定の細胞溶解の割合を、各抗体濃度について、式(ER−MR)/(MR−SR)×100に従って計算する。ここで、ERは、各抗体濃度で定量(上記のix項を参照)された平均放射能であり、MRは、MRコントロール(上記のv項を参照)において定量(上記のix項を参照)された平均放射能であり、SRは、SRコントロール(上記のvi項)において定量(上記のix項を参照)された平均放射能である;
4)「増加したADCC」は、上記の試験された抗体濃度範囲内で観察される特定の細胞溶解の最大割合の増加、及び/又は上記の試験された抗体濃度範囲内で観察される特定の細胞溶解の最大割合の半分を達成するのに必要な抗体濃度の減少の何れかとして定義される。ADCCの増加は、上記アッセイで測定され、当業者に知られている同じ標準的な生産、精製、製剤化及び保存法を使用して同じ種類の宿主細胞により産生された同じ抗体により媒介されるものであるが、GnTIIIを過剰発現するように操作された宿主細胞により産生されたものではないADCCと比較したものである。
p53とMDM2タンパク質との相互作用を阻害する化合物の能力は、組換えGSTタグMDM2がp53のMDM2相互作用領域に類似したペプチドに結合する、HTRF(均一時間分解型蛍光)アッセイにより測定される(Lane等)。GST-MDM2タンパク質とp53ペプチド(そのN末端でビオチン化される)の結合は、ユーロピウム(Eu)標識抗GST抗体とストレプトアビジンコンジュゲートアロフィコシアニン(APC)との間のFRET(蛍光共鳴エネルギー転移)により記録される。黒色の平底384ウェルプレート(Costar)において、90nMのビオチン化ペプチド、160ng/mlのGST-MDM2、20nMのストレプトアビジン-APC(PerkinElmerWallac)、2nMのEu標識抗GST抗体(PerkinElmerWallac)、0.2%のウシ血清アルブミン(BSA)、1mMのジチオスレイトール(DTT)及び20mMのトリス-ボレート生理食塩水(TBS)バッファーを含む全容量40uL中で、次のようにして試験が実施される:反応バッファー中の10uLのGST-MDM2(640ng/mlのワーキング溶液)を各ウェルに添加する。10uLの希釈化合物(反応バッファー中に1:5希釈)を各ウェルに添加し、振揺して混合する。反応バッファー中の20uLのビオチン化p53ペプチド(180nMのワーキング溶液)を各ウェルに添加し、振揺機で混合する。37℃で1時間インキュベートする。0.2%のBSAを含むTBSバッファー中の20uLのストレプトアビジン-APC及びEu-抗GST抗体混合物(6nMのEu-抗GST及び60nMのストレプトアビジン-APCワーキング溶液)を添加し、室温で30分振揺させ、665及び615nmでTRF可能なプレートリーダーを使用して読み取る(Victor 5, Perkin ElmerWallac)。特定されない場合は、試薬はSigma Chemical社から購入した。この発明の主題事項の化合物に適用される生物学的活性を示すIC50は約1nMから約1000nMの範囲である。
薬学的組成物は、この発明に係る抗CD20抗体及び/又はMDM2阻害剤を、薬学的に許容可能な無機又は有機担体とプロセシングすることによって得ることができる。ラクトース、コーンスターチ又はその誘導体、タルク、ステアリン酸又はその塩等を、例えば錠剤、被覆錠剤、糖衣錠及び硬質ゼラチンカプセルのかかる担体として使用することができる。軟質ゼラチンカプセルのための適切な担体は、例えば植物油、ロウ、脂肪、半固形及び液体ポリオール等である。しかしながら、活性物質の性質に応じて、軟質ゼラチンカプセルの場合、通常は担体は必要とされない。溶液及びシロップの製造のための適切な担体は例えば水、ポリオール、グリセロール、植物油等である。坐薬に対して適切な担体は例えば天然又は硬化油、脂肪、半液体又は液体ポリオール等である。
配列番号1:マウスモノクローナル抗CD20抗体B-Ly1の重鎖の可変領域(VH)のアミノ酸配列。
配列番号2:マウスモノクローナル抗CD20抗体B-Ly1の軽鎖の可変領域(VL)のアミノ酸配列。
配列番号3−19:ヒト化B-Ly1抗体(B-HH2からB-HH9、B-HL8、及びB-HL10からB-HL17)の重鎖の可変領域(VH)のアミノ酸配列。
配列番号20:ヒト化B-Ly1抗体B-KV1の軽鎖の可変領域(VL)のアミノ酸配列。
アフコシル化抗CD20抗体のMDM2阻害剤との併用処置中のCLL細胞における直接の細胞死/アポトーシス誘導
試験化合物:
− GA101:(=アフコシル化II型抗CD20抗体B-HH6-B-KV1 GE(=ヒト化B-Ly1,糖操作B-HH6-B-KV1,国際公開第2005/044859号及び国際公開第2007/031875号を参照)
− ヌトリン,ヌトリン-3とも呼ばれる:(=4-[4,5-ビス(4-クロロフェニル)-2-(2-イソプロポキシ-4-メトキシ-フェニル)-4,5-ジヒドロ-イミダゾール-1-カルボニル]-ピペラジン-2-オン)
CLL患者(NCI−WGガイドラインに従って診断された)から末梢血を採取した。末梢血単核細胞(PBMC)を密度勾配遠心法(Pharmacia Biotech, Roosendaal, オランダ)により単離し、直ぐに使用するか液体窒素で保存した。全インビトロ実験中、細胞は培地(10%の熱失活ウシ胎仔血清(FCS)、100U/mlのペニシリン、100μg/mlのゲンタマイシン及び0.00036%のβ−メルカプトエタノールを補填したIscove改変ダルベッコ培地)に維持した。全てのサンプルはフローサイトメトリーによって評価して少なくとも90%のCD5+/CD19+細胞を含んでいた。患者サンプルのp53機能障害を、先に記載されているように(32)、p53標的遺伝子誘導のマルチプレックス定量と組み合わせて細胞遺伝学(Del17p13)を用いて評価した。研究は施設内治験審査委員会によって承認され、1975年(1983年改訂)のヘルシンキ宣言に従って実施した。
CLL患者からのPBMC(>90%のCD5+CD19+細胞)を、先に記載されたようにして(5)、CD40リガンド(CD40L)トランスフェクトNIH3T3(3T40L)細胞で刺激した。簡潔に述べると、5106のCLL細胞/ウェルを、照射した(30Gy)CD40LトランスフェクトNIH3T3細胞をコートした6ウェルプレートに加えた。非トランスフェクト3T3細胞をネガティブコントロールとして使用した。3日後、CLL細胞を線維芽細胞層から静かに取り除き、更なる実験に使用した。
直接の細胞死/アポトーシスの誘導に対して、3T3又は3T40L刺激CLL細胞(1.5・106/mlの濃度)を標記の抗CD20mAbs(10μg/ml)と共にインキュベートした。架橋GAH(ヤギ抗ヒト)抗体(XLと標記)(50μg/ml)を、CD20mAbsmの30分後に加えた。併用実験では、細胞を5及び10μMのGA101及びヌトリンと共に48時間インキュベートした。
直接の細胞死/アポトーシスを、製造者の推奨に従ってMitoTrackerオレンジ(Molecular probes, Leiden, オランダ)を用いてミトコンドリア膜電位を評価するか又は過去に記載されたように(34)アネキシンV/PI染色によって分析した。アポトーシス細胞パーセントは次のようにして計算した:100%−annV−/PI−(生存)細胞。ある実験では、データを(基底アポトーシスの不均一なレベルのため)特定の細胞死として表し、これを、刺激細胞中の細胞死%−培地コントロール中の細胞死%と、定義した。
GA101とMDM2阻害剤(ヌトリン)の併用処置による薬剤耐性CLL細胞における相加的細胞死誘導。我々は、変異(n=7)及び非変異(n=5)IgVH遺伝子を持つCD40刺激CLL細胞及びp53機能障害CLL細胞(n=3)においてGA101のMDM2阻害剤(ヌトリン)との併用処置の効果を試験した。
アフコシル化抗CD20抗体のMDM2阻害剤との併用処置のインビボ抗腫瘍効果
実験手順
II型抗CD20抗体(B-HH6-B-KV1 GE)のMDM2阻害剤(4S,5R)-1-[[4-[[4,5-ビス(4-クロロフェニル)-2-[4-(tert-ブチル)-2-エトキシ-フェニル]-4,5-ジメチル-4,5-ジヒドロ-1H-イミダゾール-1-イル]]-カルボニル]-4-[3-(メチルスルホニル)プロピル]-ピペラジンとの併用処置の抗腫瘍活性
−GA101:(=アフコシル化II型抗CD20抗体B-HH6-B-KV1 GE(=ヒト化B-Ly1,糖操作B-HH6-B-KV1、国際公開第2005/044859号及び国際公開第2007/031875号を参照)がグリクアート(Schlieren, スイス)から原液(c=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。抗体溶液は注射前に原液からPBSに適当に希釈した。
−MDM2阻害剤 (4S,5R)-1-[[4-[[4,5-ビス(4-クロロフェニル)-2-[4-(tert-ブチル)-2-エトキシ-フェニル]-4,5-ジメチル-4,5-ジヒドロ-1H-イミダゾール-1-イル]]-カルボニル]-4-[3-(メチルスルホニル)プロピル]-ピペラジンがホフマン・ラ・ロシュ社(Nutley, 米国)から提供された。
ヒトZ138マントル細胞リンパ腫細胞株を、8%のCO2の水飽和雰囲気中、37℃で10%のウシ胎仔血清(PAA Laboratories, オーストリア)及び2mMのL−グルタミンを補填したDMEMにおいて常套的に培養する。細胞にマトリゲルを同時注入した。
雌SCIDベージュマウス;到着時7週齢(Charles River(Sulzfeld, ドイツ)から購入) を、委員会のガイドライン(GV-Solas; Felasa; TierschG)に従って12時間明所/12時間暗所の毎日のサイクルを伴う特定病原体除去条件下に維持した。実験研究プロトコルはレビューされ地方自治体によって承認された。到着後、動物は新しい環境に慣れさせ、また観察のために、動物設備の検疫部に維持した。連続的な健康モニタリングは規則的な規準で実施した。食餌(Provimi Kliba 3337)と水(酸性化pH2.5−3)を適宜与えた。
動物は臨床的徴候と副作用の検出について毎日管理した。実験全体を通じてのモニタリングでは、動物の体重を毎週2回記録し、腫瘍体積をステージング後にノギスで測定した。
動物の処置は腫瘍細胞接種から17日後の無作為化した日に開始した。ヒト化II型抗CD20抗体B-HH6-B-KV1 GE(=GA101)又はリツキシマブを、それぞれ0.5mg/kg又は1mg/kgの用量で3週間の間毎週一回q7dでi.p.単剤として投与した。対応するビヒクルを同じ日に投与した。MDM2阻害剤(4S,5R)-1-[[4-[[4,5-ビス(4-クロロフェニル)-2-[4-(tert-ブチル)-2-エトキシ-フェニル]-4,5-ジメチル-4,5-ジヒドロ-1H-イミダゾール-1-イル]]-カルボニル]-4-[3-(メチルスルホニル)プロピル]-ピペラジン(=ヌトリン,図2及び3を参照)を75mg/kg又は150mg/kgの用量で18日にわたって週に3回、一日1回p.o.投与した。
腫瘍細胞接種から35日目に、コントロール群に比較して、それぞれ75mg/kg(図2)又は150mg/kg(図3)のリツキシマブ、抗CD20抗体B−HH6−B−KV1 GE又はMDM2阻害剤を与えた動物において44%、59%、35%又は78%の腫瘍増殖阻害があった。
75mg/kg(図2)又は150mg/kg(図3)のMDM2阻害剤とのリツキシマブの併用はそれぞれ79%又は101%の腫瘍増殖阻害を生じた。
75mg/kg(図2)又は150mg/kg(図3)のMDM2阻害剤との抗CD20抗体B−HH6−B−KV1 GEの併用はそれぞれ87%又は106%の腫瘍増殖阻害を生じた。
Claims (19)
- MDM2阻害剤と併用される癌治療のための、フコース量がAsn297におけるオリゴ糖(糖類)の全量の60%以下であるアフコシル化抗CD20抗体。
- 上記癌がCD20発現癌であることを特徴とする請求項1に記載の抗体。
- 上記CD20発現癌がリンパ腫又はリンパ性白血病であることを特徴とする請求項1から2の何れか一項に記載の抗体。
- 上記抗CD20抗体がヒト化B-Ly1抗体であることを特徴とする請求項1から3の何れか一項に記載の抗体。
- 上記MDM2阻害剤が、
a) 4-[4,5-ビス(4-クロロフェニル)-2-(2-イソプロポキシ-4-メトキシ-フェニル)-4,5-ジヒドロ-イミダゾール-1-カルボニル]-ピペラジン-2-オン;
b)(4S,5R)-1-[[4-[[4,5-ビス(4-クロロフェニル)-2-[4-(tert-ブチル)-2-エトキシ-フェニル]-4,5-ジメチル-4,5-ジヒドロ-1H-イミダゾール-1-イル]]-カルボニル]-4-[3-(メチルスルホニル)プロピル]-ピペラジン;
c) 2-{4-[(4S,5R)-2-(6-tert-ブチル-4-エトキシ-ピリジン-3-イル)-4,5-ビス-(4-クロロ-フェニル)-4,5-ジメチル-4,5-ジヒドロ-イミダゾール-1-カルボニル]-ピペラジン-1-イル}-N,N-ビス-(2-メトキシエチル)-アセトアミド;又は
d) 2-{1-[(4S,5R)-2-(6-tert-ブチル-4-エトキシ-ピリジン-3-イル)-4,5-ビス-(4-クロロ-フェニル)-4,5-ジメチル-4,5-ジヒドロ-イミダゾール-1-カルボニル]-ピペリジン-4-イル}-アセトアミド
であることを特徴とする請求項1から4の何れか一項に記載の抗体。 - 一又は複数の更なる他の細胞傷害、化学治療又は抗癌剤、又は該薬剤の効果を亢進させる化合物又は電離放射線が投与されることを特徴とする請求項1から5の何れか一項に記載の抗体。
- フコース量がAsn297におけるオリゴ糖(糖類)の全量の60%以下であるアフコシル化されたヒト化B-Ly1抗体と、
a) 4-[4,5-ビス(4-クロロフェニル)-2-(2-イソプロポキシ-4-メトキシ-フェニル)-4,5-ジヒドロ-イミダゾール-1-カルボニル]-ピペラジン-2-オン;
b) (4S,5R)-1-[[4-[[4,5-ビス(4-クロロフェニル)-2-[4-(tert-ブチル)-2-エトキシ-フェニル]-4,5-ジメチル-4,5-ジヒドロ-1H-イミダゾール-1-イル]]-カルボニル]-4-[3-(メチルスルホニル)プロピル]-ピペラジン;
c) 2-{4-[(4S,5R)-2-(6-tert-ブチル-4-エトキシ-ピリジン-3-イル)-4,5-ビス-(4-クロロ-フェニル)-4,5-ジメチル-4,5-ジヒドロ-イミダゾール-1-カルボニル]-ピペラジン-1-イル}-N,N-ビス-(2-メトキシエチル)-アセトアミド;又は
d) 2-{1-[(4S,5R)-2-(6-tert-ブチル-4-エトキシ-ピリジン-3-イル)-4,5-ビス-(4-クロロ-フェニル)-4,5-ジメチル-4,5-ジヒドロ-イミダゾール-1-カルボニル]-ピペリジン-4-イル}-アセトアミド
からなる群から選択されるMDM2阻害剤とを含有する、癌の治療のための組成物。 - フコース量がAsn297におけるオリゴ糖(糖類)の全量の60%以下であるアフコシル化された抗CD20抗体をMDM2阻害剤と併用して、治療を必要とする患者に投与することにより、癌に罹患した患者を治療する方法。
- 上記癌がCD20発現癌であることを特徴とする請求項8に記載の方法。
- 上記CD20発現癌がリンパ腫又はリンパ性白血病であることを特徴とする請求項8から9の何れか一項に記載の抗体。
- 上記抗CD20抗体がヒト化B-Ly1抗体であることを特徴とする請求項8から10の何れか一項に記載の抗体。
- 上記MDM2阻害剤が、
a) 4-[4,5-ビス(4-クロロフェニル)-2-(2-イソプロポキシ-4-メトキシ-フェニル)-4,5-ジヒドロ-イミダゾール-1-カルボニル]-ピペラジン-2-オン;
b) (4S,5R)-1-[[4-[[4,5-ビス(4-クロロフェニル)-2-[4-(tert-ブチル)-2-エトキシ-フェニル]-4,5-ジメチル-4,5-ジヒドロ-1H-イミダゾール-1-イル]]-カルボニル]-4-[3-(メチルスルホニル)プロピル]-ピペラジン;
c) 2-{4-[(4S,5R)-2-(6-tert-ブチル-4-エトキシ-ピリジン-3-イル)-4,5-ビス-(4-クロロ-フェニル)-4,5-ジメチル-4,5-ジヒドロ-イミダゾール-1-カルボニル]-ピペラジン-1-イル}-N,N-ビス-(2-メトキシエチル)-アセトアミド;又は
d) 2-{1-[(4S,5R)-2-(6-tert-ブチル-4-エトキシ-ピリジン-3-イル)-4,5-ビス-(4-クロロ-フェニル)-4,5-ジメチル-4,5-ジヒドロ-イミダゾール-1-カルボニル]-ピペリジン-4-イル}-アセトアミド
からなる群から選択されることを特徴とする請求項11に記載の方法。 - 一又は複数の更なる他の細胞傷害、化学治療又は抗癌剤、又は該薬剤の効果を亢進させる化合物又は電離放射線が投与されることを特徴とする請求項8から12の何れか一項に記載の方法。
- MDM2阻害剤と併用される癌の治療のための医薬の製造における、フコース量がAsn297におけるオリゴ糖(糖類)の全量の60%以下であるアフコシル化された抗CD20抗体の使用。
- 上記癌がCD20発現癌であることを特徴とする請求項14に記載の使用。
- 上記CD20発現癌がリンパ腫又はリンパ性白血病であることを特徴とする請求項14から15の何れか一項に記載の抗体。
- 上記抗CD20抗体がヒト化B-Ly1抗体であることを特徴とする請求項14から16の何れか一項に記載の抗体。
- MDM2阻害剤が、
a) 4-[4,5-ビス(4-クロロフェニル)-2-(2-イソプロポキシ-4-メトキシ-フェニル)-4,5-ジヒドロ-イミダゾール-1-カルボニル]-ピペラジン-2-オン;
b) (4S,5R)-1-[[4-[[4,5-ビス(4-クロロフェニル)-2-[4-(tert-ブチル)-2-エトキシ-フェニル]-4,5-ジメチル-4,5-ジヒドロ-1H-イミダゾール-1-イル]]-カルボニル]-4-[3-(メチルスルホニル)プロピル]-ピペラジン;
c) 2-{4-[(4S,5R)-2-(6-tert-ブチル-4-エトキシ-ピリジン-3-イル)-4,5-ビス-(4-クロロ-フェニル)-4,5-ジメチル-4,5-ジヒドロ-イミダゾール-1-カルボニル]-ピペラジン-1-イル}-N,N-ビス-(2-メトキシエチル)-アセトアミド;又は
d) 2-{1-[(4S,5R)-2-(6-tert-ブチル-4-エトキシ-ピリジン-3-イル)-4,5-ビス-(4-クロロ-フェニル)-4,5-ジメチル-4,5-ジヒドロ-イミダゾール-1-カルボニル]-ピペリジン-4-イル}-アセトアミド
であることを特徴とする請求項14から17の何れか一項に記載の使用。 - 一又は複数の更なる他の細胞傷害剤、化学療法剤もしくは抗癌剤、又は該薬剤の効果を亢進させる化合物又は電離放射線が投与されることを特徴とする請求項14から18の何れか一項に記載の使用。
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