JP2018515583A - 抗CD20抗体のBcl−2阻害剤及びMDM2阻害剤との併用療法 - Google Patents
抗CD20抗体のBcl−2阻害剤及びMDM2阻害剤との併用療法 Download PDFInfo
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- RCINICONZNJXQF-XAZOAEDWSA-N taxol® Chemical compound O([C@@H]1[C@@]2(CC(C(C)=C(C2(C)C)[C@H](C([C@]2(C)[C@@H](O)C[C@H]3OC[C@]3(C21)OC(C)=O)=O)OC(=O)C)OC(=O)[C@H](O)[C@@H](NC(=O)C=1C=CC=CC=1)C=1C=CC=CC=1)O)C(=O)C1=CC=CC=C1 RCINICONZNJXQF-XAZOAEDWSA-N 0.000 description 1
- 229940063683 taxotere Drugs 0.000 description 1
- NRUKOCRGYNPUPR-QBPJDGROSA-N teniposide Chemical compound COC1=C(O)C(OC)=CC([C@@H]2C3=CC=4OCOC=4C=C3[C@@H](O[C@H]3[C@@H]([C@@H](O)[C@@H]4O[C@@H](OC[C@H]4O3)C=3SC=CC=3)O)[C@@H]3[C@@H]2C(OC3)=O)=C1 NRUKOCRGYNPUPR-QBPJDGROSA-N 0.000 description 1
- 229960001278 teniposide Drugs 0.000 description 1
- BGMJVNFYEKYBGI-VZEIJFLTSA-N tert-butyl 4-[[(2r,3s,4r,5s)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino]-2-fluorobenzoate Chemical compound C1([C@H]2[C@@H](N[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)NC=2C=C(F)C(C(=O)OC(C)(C)C)=CC=2)=CC=CC(Cl)=C1F BGMJVNFYEKYBGI-VZEIJFLTSA-N 0.000 description 1
- DCEDSWOGVFTKRM-ZKHUUIOXSA-N tert-butyl 4-[[(2r,3s,4r,5s)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino]-4-methylpiperidine-1-carboxylate Chemical compound C1([C@H]2[C@@H](N[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)NC2(C)CCN(CC2)C(=O)OC(C)(C)C)=CC=CC(Cl)=C1F DCEDSWOGVFTKRM-ZKHUUIOXSA-N 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- NDVNFEUPKWYRTI-ZFHKOKEKSA-N tert-butyl n-[[4-[[(2r,3s,4r,5s)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino]phenyl]methyl]carbamate Chemical compound C1([C@H]2[C@@H](N[C@H]([C@]2(C#N)C=2C(=CC(Cl)=CC=2)F)CC(C)(C)C)C(=O)NC=2C=CC(CNC(=O)OC(C)(C)C)=CC=2)=CC=CC(Cl)=C1F NDVNFEUPKWYRTI-ZFHKOKEKSA-N 0.000 description 1
- QEMXHQIAXOOASZ-UHFFFAOYSA-N tetramethylammonium Chemical compound C[N+](C)(C)C QEMXHQIAXOOASZ-UHFFFAOYSA-N 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 229960001196 thiotepa Drugs 0.000 description 1
- 201000002510 thyroid cancer Diseases 0.000 description 1
- 229960003087 tioguanine Drugs 0.000 description 1
- MNRILEROXIRVNJ-UHFFFAOYSA-N tioguanine Chemical compound N1C(N)=NC(=S)C2=NC=N[C]21 MNRILEROXIRVNJ-UHFFFAOYSA-N 0.000 description 1
- 125000003944 tolyl group Chemical group 0.000 description 1
- UCFGDBYHRUNTLO-QHCPKHFHSA-N topotecan Chemical compound C1=C(O)C(CN(C)C)=C2C=C(CN3C4=CC5=C(C3=O)COC(=O)[C@]5(O)CC)C4=NC2=C1 UCFGDBYHRUNTLO-QHCPKHFHSA-N 0.000 description 1
- 229960000303 topotecan Drugs 0.000 description 1
- 229960005267 tositumomab Drugs 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- 238000013518 transcription Methods 0.000 description 1
- 230000035897 transcription Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 238000011830 transgenic mouse model Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- LENZDBCJOHFCAS-UHFFFAOYSA-N tris Chemical compound OCC(N)(CO)CO LENZDBCJOHFCAS-UHFFFAOYSA-N 0.000 description 1
- 239000012588 trypsin Substances 0.000 description 1
- 208000029729 tumor suppressor gene on chromosome 11 Diseases 0.000 description 1
- 239000000225 tumor suppressor protein Substances 0.000 description 1
- 108010003137 tyrosyltyrosine Proteins 0.000 description 1
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- 229950000815 veltuzumab Drugs 0.000 description 1
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- GBABOYUKABKIAF-GHYRFKGUSA-N vinorelbine Chemical compound C1N(CC=2C3=CC=CC=C3NC=22)CC(CC)=C[C@H]1C[C@]2(C(=O)OC)C1=CC([C@]23[C@H]([C@]([C@H](OC(C)=O)[C@]4(CC)C=CCN([C@H]34)CC2)(O)C(=O)OC)N2C)=C2C=C1OC GBABOYUKABKIAF-GHYRFKGUSA-N 0.000 description 1
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- 125000000391 vinyl group Chemical group [H]C([*])=C([H])[H] 0.000 description 1
- 201000005102 vulva cancer Diseases 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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- 125000005023 xylyl group Chemical group 0.000 description 1
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Abstract
Description
アフコシル化抗体
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., et al., 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。がん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., et al., Glycobiology 5 (1995) 813-822; Jefferis, R., et al., Immunol. Rev. 163 (1998) 59-76; Wright, A., and Morrison, S.L., Trends Biotechnol. 15 (1997) 26-32)。Umana, P., et al.. 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., et al., Nature Biotechnol. 17 (1999) 176-180; Davies, J., et al., Biotechnol. Bioeng. 74 (2001) 288-294; Mimura, Y., et al., J. Biol. Chem. 276 (2001) 45539-45547; Radaev, S., et al., J. Biol. Chem. 276 (2001) 16478-16483; Shields, R.L., et al., J. Biol. Chem. 276 (2001) 6591-6604; Shields, R.L., et al., J. Biol. Chem. 277 (2002) 26733-26740; Simmons, L.C., et al., 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)はプレB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り、詳しく記述されている(Valentine, M.A., et al., J. Biol. Chem. 264 (1989) 11282-11287; and Einfeld, D.A., et al., EMBO J. 7 (1988) 711-717; Tedder, T.F., et al., Proc. Natl. Acad. Sci. U.S.A. 85 (1988) 208-212; Stamenkovic, I., et al., J. Exp. Med. 167 (1988) 1975-1980; Tedder, T.F., et al., J. Immunol. 142 (1989) 2560-2568)。CD20は90%を超えるB細胞非ホジキンリンパ腫(NHL)に発現する(Anderson, K.C., et al., Blood 63(6) (1984) 1424-1433))が、造血幹細胞、プロB細胞、正常な形質細胞、又はその他正常な組織には見られない(Tedder, T.F., et al., J. Immunol. 135(2) (1985) 973- 979)。
タンパク質p53は、がんの発達に対する保護において中心的役割を果たす腫瘍抑制タンパク質である。p53は、細胞の完全性を保護し、増殖停止又はアポトーシスの誘導によって細胞の恒久的損傷を受けたクローンの増殖を防止する。分子レベルでは、p53は、細胞周期及びアポトーシスの調節に関係する遺伝子パネルを活性化することができる転写因子である。p53は、細胞レベルでMDM2により厳しく制御されている強力な細胞周期阻害因子である。MDM2とp53はフィードバック制御ループを形成する。MDM2は、p53に結合し、p53制御遺伝子を転写活性化するその能力を阻害し得る。また、MDM2は、p53のユビキチン依存性分解を媒介する。p53は、MDM2遺伝子の発現を活性化することができ、それによってMDM2タンパク質の細胞レベルを上昇させる。このフィードバック制御ループは、MDM2とp53の両方が、正常な増殖細胞において低いレベルに維持されることを保証する。MDM2は、細胞周期制御において中心的な役割を果たすE2Fのコファクターでもある。
Bcl−2タンパク質は、多くの疾患、特にがん、白血病、免疫及び自己免疫疾患において役割を果たす。Bcl−2タンパク質は、膀胱がん、脳がん、乳がん、骨髄がん、子宮頸がん、慢性リンパ性白血病、結腸直腸がん、食道がん、肝細胞がん、リンパ芽球性白血病、濾胞性リンパ腫、T細胞又はB細胞起源のリンパ系悪性腫瘍、メラノーマ、骨髄性白血病、骨髄腫、口腔がん、卵巣がん、非小細胞肺がん、前立腺がん、小細胞肺がん、脾臓がんに関与していると言われている。Bcl−2タンパク質の過剰発現は、様々ながん及び免疫系の障害における化学療法に対する耐性、臨床転帰、疾患の進行、全体的な予後、又はそれらの組み合わせと相関する。
本発明は、Bcl−2阻害剤及びMDM2阻害剤と併用するがんの治療のための、I型抗CD20抗体、又はAsn297においてオリゴ糖(糖類)の総量の60%以下のフコース量を有するIgG1又はIgG3アイソタイプのアフコシル化抗CD20抗体を含む。
1)該アッセイは、抗体の抗原結合領域によって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、次のプロトコー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、5x106細胞/ml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%を越える指数増殖期から回収し、RPMI細胞培養培地中で洗浄し、100マイクロキュリーの51Crで標識し、細胞培養培地で二回洗浄し、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標的細胞懸濁物を96ウェル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)次いで、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雰囲気下で4時間インキュベーター内に配置する;
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)特異的溶解の百分率を、各抗体濃度について、式(ER−MR)/(MR−SR)×100[式中、ERはその抗体濃度について定量された平均放射活性(上記ix項参照)であり、MRはMRコントロール(上記v項参照)について定量された平均放射活性(上記ix項参照)であり、SRはSRコントロール(上記vi項参照)について定量された平均放射活性(上記ix項参照)である]に従って計算する。
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異的溶解の最大百分率の増加、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異的溶解の最大百分率の半分を達成するのに必要な抗体濃度の低下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、当該技術分野において当業者に知られている同じ標準的な生産、精製、製剤化及び保存の方法を使用して同じ型の宿主細胞により産生された同じ抗体によって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。
[式中、
Xは、H、F、Cl、Br、I、シアノ、ニトロ、エチニル、シクロプロピル、メチル、エチル、イソプロピル、ビニル及びメトキシからなる群より選択され、
Yは、H、F、Cl、Br、I、CN、OH、ニトロ、低級アルキル、シクロアルキル、低級アルコキシ、低級アルケニル、シクロアルケニル、低級アルキニル、アリール、ヘテロアリール、複素環、COOR’、OCOR’、CONR’R”、NR’COR”、NR”SO2R’、SO2NR’R”及びNR’R”からなる群より独立して選択される1つ〜4つの基であり、ここで
R’及びR”は、H、低級アルキル、置換低級アルキル、低級シクロアルキル、置換低級シクロアルキル、低級アルケニル、置換低級アルケニル、低級シクロアルケニル、置換低級シクロアルケニル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環、又は置換複素環から独立して選択され、
R’とR”が独立して結合し、置換若しくは無置換シクロアルキル、置換若しくは無置換シクロアルケニル、置換若しくは無置換ヘテロアリール又は置換若しくは無置換複素環から選択される環状構造を形成する場合、
R1は、低級アルキル、置換低級アルキル、低級アルケニル、置換低級アルケニル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環、置換複素環、シクロアルキル、置換シクロアルキル、シクロアルケニル、及び置換シクロアルケニルからなる群より選択され、
R2は水素又は低級アルキルであり、
R3はH又は低級アルキルであり,
R5は、低級アルキル、置換低級アルキル、低級アルケニル、置換低級アルケニル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環、置換複素環、シクロアルキル、置換シクロアルキル、シクロアルケニル、及び置換シクロアルケニルからなる群より選択され、
R4は水素であり、
R6及びR7は、(CH2)n−R’、(CH2)n−NR’R”、(CH2)n−NR’COR”、(CH2)n−NR’SO2R”、(CH2)n−COOH、(CH2)n−COOR’、(CH2)n−CONR’R”、(CH2)n−OR’、(CH2)n−SR’、(CH2)n−SOR’、(CH2)n−SO2R’、(CH2)n−COR’、(CH2)n−SO3H、(CH2)n−SONR’R”、(CH2)n−SO2NR’R”、(CH2CH2O)m−(CH2)n−R’、(CH2CH2O)m−(CH2)n−OH、(CH2CH2O)m−(CH2)n−OR’、(CH2CH2O)m−(CH2)n−NR’R”、(CH2CH2O)m−(CH2)n−NR’COR”、(CH2CH2O)m−(CH2)n−NR’SO2R”、(CH2CH2O)m−(CH2)n−COOH、(CH2CH2O)m−(CH2)n−COOR’、(CH2CH2O)m−(CH2)n−CONR’R”、(CH2CH2O)m−(CH2)n−SO2R’、(CH2CH2O)m−(CH2)n−COR’、(CH2CH2O)m−(CH2)n−SONR’R”、(CH2CH2O)m−(CH2)n−SO2NR’R”、(CH2)p−(CH2CH2O)m−(CH2)n−R’、(CH2)p−(CH2CH2O)m−(CH2)n−OH、(CH2)p−(CH2CH2O)m−(CH2)n−OR’、(CH2)p−(CH2CH2O)m−(CH2)n−NR’R”、(CH2)p−(CH2CH2O)m−(CH2)n−NR’COR”、(CH2)p−(CH2CH2O)m−(CH2)n−NR’SO2R”、(CH2)p−(CH2CH2O)m−(CH2)n−COOH、(CH2)p−(CH2CH2O)m−(CH2)n−COOR’、(CH2)p−(CH2CH2O)m−(CH2)n−CONR’R”、(CH2)p−(CH2CH2O)m−(CH2)n−SO2R’、(CH2)p−(CH2CH2O)m−(CH2)n−COR’、(CH2)p−(CH2CH2O)m−(CH2)n−SONR’R”、(CH2)p−(CH2CH2O)m−(CH2)n−SO2NR’R”、−COR’、−SOR’及びSO2R’からなる群より選択され、
ここでR’及びR’’は上記の通りであり、
m、n及びpは、独立して0から6である]、
及びその薬学的に許容される塩及びエステル。
[式中、
XはF、Cl又はBrであり、
Yは、H、F、Cl、Br、I、CN、OH、ニトロ、低級アルキル、シクロアルキル、低級アルコキシ、低級アルケニル、低級シクロアルケニル、及び低級アルキニルからなる群より独立して選択される1つ〜2つの基であり、
R1は、低級アルキル、置換低級アルキル、低級アルケニル、置換低級アルケニル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環、置換複素環、シクロアルキル、置換シクロアルキル、シクロアルケニル、及び置換シクロアルケニルからなる群より選択され、
R2は水素であり、
R3はHであり、
R5は、アリール、置換アリール、ヘテロアリール及び置換ヘテロアリールからなる群より選択され、
R4は水素であり、
R6及びR7は、(CH2)n−R’、(CH2)n−NR’R”、(CH2)n−NR’COR”、(CH2)n−NR’SO2R”、(CH2)n−COOH、(CH2)n−COOR’、(CH2)n−CONR’R”、(CH2)n−OR’、(CH2)n−SR’、(CH2)n−SOR’、(CH2)n−SO2R’、(CH2)n−COR’、(CH2)n−SO3H、(CH2)n−SONR’R”、(CH2)n−SO2NR’R”、(CH2CH2O)m−(CH2)n−R’、(CH2CH2O)m−(CH2)n−OH、(CH2CH2O)m−(CH2)n−OR’、(CH2CH2O)m−(CH2)n−NR’R”、(CH2CH2O)m−(CH2)n−NR’COR”、(CH2CH2O)m−(CH2)n−NR’SO2R”、(CH2CH2O)m−(CH2)n−COOH、(CH2CH2O)m−(CH2)n−COOR’、(CH2CH2O)m−(CH2)n−CONR’R”、(CH2CH2O)m−(CH2)n−SO2R’、(CH2CH2O)m−(CH2)n−COR’、(CH2CH2O)m−(CH2)n−SONR’R”、(CH2CH2O)m−(CH2)n−SO2NR’R”、(CH2)p−(CH2CH2O)m−(CH2)n−R’、(CH2)p−(CH2CH2O)m−(CH2)n−OH、(CH2)p−(CH2CH2O)m−(CH2)n−OR’、(CH2)p−(CH2CH2O)m−(CH2)n−NR’R”、(CH2)p−(CH2CH2O)m−(CH2)n−NR’COR”、(CH2)p−(CH2CH2O)m−(CH2)n−NR’SO2R”、(CH2)p−(CH2CH2O)m−(CH2)n−COOH、(CH2)p−(CH2CH2O)m−(CH2)n−COOR’、(CH2)p−(CH2CH2O)m−(CH2)n−CONR’R”、(CH2)p−(CH2CH2O)m−(CH2)n−SO2R’、
(CH2)p−(CH2CH2O)m−(CH2)n−COR’、(CH2)p−(CH2CH2O)m−(CH2)n−SONR’R”、(CH2)p−(CH2CH2O)m−(CH2)n−SO2NR’R”、−COR’、−SOR’及びSO2R’からなる群より選択され、ここで
R’及びR”は、H、低級アルキル、置換低級アルキル、低級シクロアルキル、置換低級シクロアルキル、低級アルケニル、置換低級アルケニル、低級シクロアルケニル、置換低級シクロアルケニル、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環、又は置換複素環から独立して選択され、R’とR”はまた独立して結合し、置換若しくは無置換シクロアルキル、置換若しくは無置換シクロアルケニル、置換若しくは無置換ヘテロアリール又は置換若しくは無置換複素環から選択される環状構造を形成する場合があり、
m、n及びpは、独立して0から6である]、
及びその薬学的に許容される塩及びエステルである。
[式中、
XはF、Cl又はBrであり、
Yは、H又はFから選択される一置換基であり、
R1は、低級アルキル、置換低級アルキル、低級アルケニル、置換低級アルケニル、複素環、置換複素環、シクロアルキル、置換シクロアルキル、シクロアルケニル、及び置換シクロアルケニルからなる群より選択される。
から選択される置換低級アルキルであり、
ここで、R8、R9は両方ともメチルであるか、又は結合してシクロプロピル、シクロブチル、シクロペンチル又はシクロヘキシル基を形成し、
R10は(CH2)m−R11であり、
mは、0、1又は2であり、
R11は、水素、ヒドロキシル、低級アルキル、低級アルコキシ、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環又は置換複素環から選択され、
R2はHであり、
R3はHであり、
R5は
から選択される置換フェニルであり:
上式中、WはF、Cl又はBrであり、
VはH又はFであり、
R4は水素であり、
R6及びR7の一方は水素であり、他方は(CH2)n−R’であり、
nは、0又は1であり、
R’は、アリール、置換アリール、ヘテロアリール、置換ヘテロアリール、複素環又は置換複素環から選択される。
ここで、R6及びR6についての定義において言及されている全ての変数及び置換基は、上記の式Iについて与えられた意味を有する。
ここで、R6は(CH2)n−R’であり、
R’は、シクロヘキシルであるか、又は
1つ又は2つの炭素原子がN、S又はOによって置換されてよく、かつ前述のシクロヘキシル又は芳香族炭化水素が、低級アルキル、低級−アルケニル、低級−アルキニル、ジオキソ−低級−アルキレン(例えば、ベンゾジオキシル基を形成する)、ハロゲン、ヒドロキシ、CN、CF3、NH2、N(H、低級−アルキル)、N(低級−アルキル)2、アミノカルボニル、カルボキシ、NO2、低級−アルコキシ、チオ−低級−アルコキシ、低級−アルキルスルホニル、アミノスルホニル、低級−アルキルカルボニル、低級−アルキルカルボニルオキシ、低級−アルコキシカルボニル、低級−アルキル−カルボニル−NH、フルオロ−低級−アルキル、フルオロ−低級−アルコキシ、低級−アルコキシ−カルボニル−低級−アルコキシ、カルボキシ−低級−アルコキシ、カルバモイル−低級−アルコキシ、ヒドロキシ−低級−アルコキシ、NH2−低級−アルコキシ、N(H、低級−アルキル)−低級−アルコキシ、N(低級−アルキル)2−低級−アルコキシ、低級−アルキル−1−オキシラニル−低級−アルコキシ−低級−アルキル、2−オキソ−ピロリジン−1−イル、(1,1−ジオキソ)−2−イソチアゾリジン、3−低級−アルキルスルフィニル、置換又は無置換複素環式環、置換又は無置換アリール環、置換又は無置換ヘテロアリール環、トリフルオロ−低級−アルキルスルホニルアミノ−アリール、低級−アルキルスルホニルアミノカルボニル、低級−アルキルスルホニルアミノカルボニル−アリール、ヒドロキシカルバモイル−フェニル、ベンジルオキシ−低級−アルコキシ、モノ−又はジ−低級アルキル置換アミノ−スルホニル及びハロゲン、ヒドロキシ、NH2、N(H、低級アルキル)又はN(低級アルキル)2で置換されてもよい低級−アルキルから独立に選択される基により一度又は二度置換可能である、5〜10員の単環式又は二環式芳香族炭化水素であり;
nは、0又は1である。
ここで、
R6は(CH2)n−R’であり、
R’は、それぞれ無置換であるか、又はハロゲン、C1−6アルコキシ、C1−6アルキル、ヒドロキシカルボニル、カルボキシ、カルボキシC1−6アルコキシ、オキソ及びCNから独立して選択される置換基により一度又は二度置換可能である、フェニル、ピリジニル、ピラジニル又はピリミジニルであり;
nは0である。
rac−4−({[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−メチル)−シクロヘキサンカルボン酸メチルエステル、
rac−4−({[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−メチル)−シクロヘキサンカルボン酸、
rac−4−({[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−メチル)−2−メトキシ−安息香酸メチルエステル、
rac−4−({[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−メチル)−2−メトキシ−安息香酸、
rac−4−({[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−メチル)−2−フルオロ−安息香酸メチルエステル、
rac−4−({[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−メチル)−2−フルオロ−安息香酸、
キラル5−({[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−メチル)−ピリジン−2−カルボン酸メチルエステル、
キラル5−({[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−メチル)−ピリジン−2−カルボン酸、
キラル6−({[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−メチル)−ニコチン酸エチルエステル、
キラル6−({[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−メチル)−ニコチン酸、
rac−4−{[(2R、3S、4R、5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−2,2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−2−エトキシ−安息香酸、
キラル(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−ヒドラジノカルボニル−フェニル)−アミド、
キラル[2−(4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−フェニル)−エチル]−カルバミン酸tert−ブチルエステル、
キラル(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸[4−(2−アミノ−エチル)−フェニル]−アミド、
キラル5−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−ピラジン−2−カルボン酸、
キラル4−(((2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド)メチル)−2−メトキシ安息香酸、
キラル−4−({[(2S,3R,4S,5R)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−
シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−メチル)−2−メトキシ−安息香酸、
キラルメチル3−(4−((2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド)フェニル)プロパノアート、
キラル3−(4−((2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド)フェニル)プロパン酸、
キラル−4−(((2S,3R,4S,5R)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド)メチル)−2−フルオロ安息香酸、
キラル4−(((2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド)メチル)−2−フルオロ安息香酸、
キラル(2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−N−(2−モルホリノピリミジン−5−イル)−5−ネオペンチルピロリジン−2−カルボキサミド、
キラル(2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチル−N−(ピリミジン−5−イル)ピロリジン−2−カルボキサミド、
キラル(2S,3R,4S,5R)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−ジメチルアミノメチル−フェニル)−アミド、(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−ジメチルアミノメチル−フェニル)−アミド、
キラルメチル5−((2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド)−1H−ベンゾ[d]イミダゾール−2−カルボキシラート、
キラル−5−((2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド)−1H−ベンゾ[d]イミダゾール−2−カルボン酸、
キラル−メチル5−((2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド)ベンゾフラン−2−カルボキシラート、
キラル−5−((2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド)ベンゾフラン−2−カルボン酸、
キラル−メチル4−(4−((2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド)フェニル)ブタノアート、
キラル−4−(4−((2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド)フェニル)ブタン酸、
キラルメチル5−((2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド)ベンゾ[d]オキサゾール−2−カルボキシラート、
キラル−5−((2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド)ベンゾ[d]オキサゾール−2−カルボン酸、
キラル−(2R,3S,4R,5S)−N−(ベンゾ[d]オキサゾール−5−イル)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド、
rac−(4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−ベンジル)−カルバミン酸tert−ブチルエステル、
rac−(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−アミノメチル−フェニル)−アミド、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸[4−(メタンスルホニルアミノ−メチル)−フェニル]−アミド、
1−(4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−フェニル)−ピペリジン−4−カルボン酸エチルエステル、
1−(4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−フェニル)−ピペリジン−4−カルボン酸、
rac−(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−ジメチルアミノメチル−フェニル)−アミド、
rac−5−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−2−ピロリジン−1−イル−安息香酸、
rac−4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−4−メチル−ピペリジン−1−カルボン酸tert−ブチルエステル、
rac−(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−メチル−ピペリジン−4−イル)−アミド、
rac−(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(1−メタンスルホニル−4−メチル−ピペリジン−4−イル)−アミド、
メチル1−(4−((2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド)フェニル)ピロリジン−2−カルボキシラート、
1−(4−((2R,3S,4R,5S)−3−(3−クロロ−2−フルオロフェニル)−4−(4−クロロ−2−フルオロフェニル)−4−シアノ−5−ネオペンチルピロリジン−2−カルボキサミド)フェニル)ピロリジン−2−カルボン酸、
キラル5−{[(2R,3S,4R,5S)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−1H−ピロール−2−カルボン酸、
キラル5−{[(2R,3S,4R,5S)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−1H−ピロール−2−カルボン酸エチルエステル、
キラル(R)−2−(4−{[(2R,3S,4R,5S)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−フェニル)−酪酸、
キラル(S)−2−(4−{[(2R,3S,4R,5S)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−フェニル)−酪酸、
キラル(S)−2−{[(2R,3S,4R,5S)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−チアゾール−4−イル−プロピオン酸メチルエステル、
キラル(S)−2−{[(2S,3R,4S,5R)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−チアゾール−4−イル−プロピオン酸メチルエステル、
キラル(S)−2−{[(2R,3S,4R,5S)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−チアゾール−4−イル−プロピオン酸、
キラル(S)−2−{[(2S,3R,4S,5R)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−チアゾール−4−イル−プロピオン酸、
キラル4−{[(2R,3S,4R,5S)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−1H−インドール−2−カルボン酸、
rac(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(5−ヨード−ピリジン−2−イル)−アミド、
2−クロロ−4−{[(2R,3S,4R,5S)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−安息香酸、
6−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−ニコチン酸、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸ピリジン−2−イルアミド、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸ピリジン−4−イルアミド、
5−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−ピリジン−2−カルボン酸、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸ピリジン−3−イルアミド、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−ヨード−3,5ジメチル−フェニル)−アミド、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−2−フルオロ−安息香酸tert−ブチルエステル、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−2−フルオロ−安息香酸、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−フルオロ−安息香酸、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−2−トリフルオロメチル−安息香酸、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−ヨード−2−トリフルオロメトキシ−フェニル)−アミド、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−トリフルオロメトキシ−安息香酸メチルエステル、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−トリフルオロメトキシ−安息香酸、
6−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−ニコチン酸、
6−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−ニコチン酸メチルエステル、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(6−ヨード−ピリジン−3−イル)−アミド、
5−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−ピリジン−2−カルボン酸メチルエステル、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−メトキシ−安息香酸メチルエステル、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−メトキシ−安息香酸、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(6−カルバモイル−ナフタレン−2−イル)−アミド、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−カルバモイル−3−クロロ−フェニル)−アミド、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−カルバモイル−3−トリフルオロメチル−フェニル)−アミド、
5−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−ピリジン−2−カルボン酸、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−フルオロ−安息香酸メチルエステル、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−クロロ−安息香酸メチルエステル、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−クロロ−安息香酸、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−カルバモイル−2−フルオロ−フェニル)−アミド、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−カルバモイル−2−メトキシ−フェニル)−アミド、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−2,5−ジフルオロ−安息香酸メチルエステル、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−2,5−ジフルオロ−安息香酸、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−2,5−ジフルオロ−安息香酸、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−カルバモイル−3−トリフルオロメチル−フェニル)−アミド、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−2,6−ジフルオロ−安息香酸、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−ヒドロキシ−安息香酸、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−カルバモイル−3−メトキシ−フェニル)−アミド、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−カルバモイル−3−トリフルオロメトキシ−フェニル)−アミド、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−カルバモイル−3−フルオロ−フェニル)−アミド、
(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸(4−カルバモイル−2−クロロ−フェニル)−アミド、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−2−フルオロ−5−メトキシ−安息香酸メチルエステル、
4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−2−フルオロ−5−メトキシ−安息香酸、
2−(4−{[(2R,3S,4R,5S)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−フェニル)−4−メチル−ペンタン酸、
キラル2−(4−{[(2S,3R,4S,5R)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−フェニル)−2−メチル−プロピオン酸メチルエステル、
キラル2−(4−{[(2R,3S,4R,5S)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−フェニル)−2−メチル−プロピオン酸、
キラル(2S,3R,4S,5R)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸[4−(1−メチル−1−メチルカルバモイル−エチル)−フェニル]−アミド、
キラル(2S,3R,4S,5R)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸{4−[1−(3−ヒドロキシ−プロピルカルバモイル)−1−メチル−エチル]−フェニル}アミド、及び
キラル(2S,3R,4S,5R)−3−(3−クロロ−2−フルオロ−フェニル)−4−(4−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボン酸[4−(1−カルバモイル−1−メチル−エチル)−フェニル]−アミド。
本発明によるMDM2阻害剤の調製は、国際公開第2011/098398号に開示されているように実施される。
薬学的組成物は、本発明による抗CD20抗体及び/又はBcl−2阻害剤及びMDM2阻害剤を、薬学的に許容される無機又は有機の担体と共に加工することにより得ることができる。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などを、例えば、錠剤、コーティングされた錠剤、ドラフェ及び硬質ゼラチンカプセルのためのこのような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に適した担体は、例えば、植物油、ワックス、油脂、半固体及び液体ポリオールなどである。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。溶液及びシロップ剤生成ための適切な担体は、例えば、水、ポリオール、グリセロール、植物油などである。坐剤に適した担体は、例えば、天然油又は硬化油、ワックス、油脂、半液状又は液体ポリオールなどである。
配列番号1 マウスモノクローナル抗CD20抗体B−Ly1の重鎖(VH)の可変領域のアミノ酸配列。
配列番号2 マウスモノクローナル抗CD20抗体B−Ly1の軽鎖(VL)の可変領域のアミノ酸配列。
配列番号3−19 ヒト化B−Ly1抗体(B−HH2〜B−HH9、B−HL8、及びB−HL10〜B−HL17)の重鎖可変領域(VH)のアミノ酸配列
配列番号20 ヒト化B−Ly1抗体B−KV1の軽鎖可変領域(VL)のアミノ酸配列
実施例1:
実施例
in vivo抗腫瘍効果
bcl−2阻害剤GDC−0199及びMDM2阻害剤RG7388と併用するCD20特異的抗体のオビヌツズマブのin vivo抗腫瘍効果を、DOHH2 DLBCL異種移植片(CD20+、p53wt)に対して評価した。本明細書中で使用される場合、オビヌツズマブは、RO5072759及びB−HH6−B−KV1 GEと同義に使用される。本明細書中で使用される場合、前記bcl−2阻害剤GDC−0199は以下の化合物である:4−(4−{[2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エン−1−イル]メチル}ピペラジン−l−イル)−2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−N−({4−[(テトラヒドロ−2H−ピラン−4−イルメチル)アミノ]−3−[(トリフルオロメチル)スルホニル]フェニル}スルホニル)ベンズアミド又はその塩若しくは多形体。本明細書中で使用される場合、前記MDM2阻害剤RG7388は以下の化合物である:4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−メトキシ−安息香酸又はその塩若しくは多形体。
CD20抗体であるオビヌツズマブは、Roche、Basel、Switzerlandからストック溶液として提供された。抗体緩衝液ははヒスチジンが含んでいた。抗体溶液を注射前のストックから緩衝液で適切に希釈した。MDM2(4)阻害剤は、Roche、Basel、SwitzerlandからSDP製剤として提供され、使用前に再懸濁された。Bcl−2阻害剤GDC−0199は、GNE、SSF、USAによって提供され、使用前に処方された。
元のDOHH−2ヒトB細胞NHL細胞株(DLBCL)はNCIで樹立され、ATCC(Manassas、VA、USA)から購入した。移植のための腫瘍細胞の増殖は、プロトコールに従ってTAP CompacT CellBase Cell Culture Roboterによって行った。腫瘍細胞株を、常套的に、RPMI1640培地、FCS10%及びL−グルタミン2mM中、37℃、5%CO2の水飽和雰囲気中で培養した。培養継代は、トリプシン/EDTA 1xスプリットを週2回、継代2を移植に用いて行った。
到着時に6〜7週齢の雌SCIDベージュマウスは、特異的病原体を含まない条件下で、確約されたガイドラインに従って12時間明/12時間暗のサイクルで保持された。実験研究プロトコールが審査され、地方自治体により承認された。動物は、到着後1週間、新しい環境への馴致及び観察のために動物施設で保持された。継続的な健康モニタリングが定期的に実施された。規制食及びオートクレーブ水は自由に与えられた。
動物は、臨床症状及び副作用の検出のために毎日管理された。実験を通してのモニタリングのために、動物の体重を記録した。
腫瘍サイズの中央値が約200mm3のときに無作為化後に動物の治療が開始された。CD20抗体オビヌツズマブを、週1回13日目、21日目及び27日目に、10mg/kgを腹腔内に単剤及び組み合わせて投与した。対応するビヒクルを同じ日に投与した。MDM2(4)阻害剤RG7388の30mg/kgでの経口治療は、13〜17、20〜24及び27〜29日に単剤として及び組み合わせて行った。最後に、bcl−2阻害剤GDC−0199を、13〜29日目に100mg/kgで単剤として及び組み合わせで経口投与した。
DOHH−2ヒトびまん性大B細胞リンパ腫(DLBCL)細胞(CD20+、p53wt)を、雌のSCIDベージュマウスにマトリゲルとともに皮下接種した。腫瘍を有するマウスを、13日後に示された研究グループに無作為化し、化合物による治療を開始した。腫瘍を有する動物は、単剤として、ビヒクルコントロールで、MDM2(4)阻害剤RO5503781(RG7388)を30mg/kgで、抗CD20抗体オビヌツズマブを10mg/kgで、又はbcl−2阻害剤GDC−0199(100mg/kg)で処置された。更に、1つの研究群は、MDM2阻害剤RG7388、CD20抗体オビヌツズマブ及びbcl−2阻害剤GDC−0199の三重併用を受けた。その結果、単剤として与えられた全ての化合物は、DOHH−2異種移植片に対して有意な抗腫瘍効果を示した。より詳細には、MDM2(4)阻害剤RO5503781(RG7388)による治療は、コントロールと比較してp53wt DOHH2異種移植片に対して56%の腫瘍増殖阻害をもたらした。同様の効果が、bcl−2阻害剤GDC−0199による治療後に認められるが(60%TGI)、一方単剤としての最良の効果は、抗CD20抗体であるオビヌツズマブによる治療後に達成され、ほぼ腫瘍停止(TGI 90%)に到達した。しかしながら、MDM2阻害剤RG7388+CD20抗体オビヌツズマブ+bcl−2阻害剤GDC−0199を含む三重併用群では、優れた効果が観察された。より詳細には、三重併用アプローチは、初期に実質的に腫瘍退縮を誘導し、これは最終的に90%に達し、30%が完全な腫瘍寛解に達した。三重併用治療群の強力な効果は、それぞれの単剤治療群と比較して相乗的に優れていた。
bcl−2阻害剤GDC−0199及びMDM2阻害剤RG7388と併用するCD20特異的抗体オビヌツズマブ。
試験薬剤
II型抗CD20抗体B−HH6−B−KV1 GE(=ヒト化B−Ly1、糖鎖操作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)は、GlycArt、Schlieren、Switzerlandからヒスチジン、トレハロース及びポリソルベート20緩衝液中でストック溶液(c=9.4mg/ml)として提供される。抗体を、in−vivo適用の前にPBSで希釈した。
Bcl−2阻害剤GDC−0199は、Genentech Inc.、CA、USAから得た。
MDM2(4)アンタゴニストRG7388(RO5503781)は、Hoffmann−La Roche、Basel、Switzerlandの小分子プロセス研究開発ユニット(Small Molecule Process Research and Development unit)によって提供された。
ヒトZ138マントル細胞リンパ腫細胞株を、10%ウシ胎児血清(PAA Laboratories、Austria)及び2mMのL−グルタミンを補充したDMEM中、37℃、5%CO2の水飽和大気中で培養した。in−vivo異種移植実験のために、細胞にマトリゲルを同時注入した。
到着時に4〜5週齢の雌SCIDベージュマウス(Charles River、Sulzfeld、Germanyから購入)を動物施設の隔離部分で1週間保持し、その後ガイドライン(GV−Solas;Felasa;TierschG)に従って、12時間明/12時間暗の毎日のサイクルで特定の病原体を含まない条件下で保持した。Rocheと地方自治体が実験的研究プロトコールをレビューし承認した(Regierung von Oberbayern、登録番号55.2−1−54−2531.2−26−09)。規制食(KLIBA NAFAG 3807)及び水(濾過)は自由に与えられた。
動物は、臨床症状及び副作用の検出のために毎日モニターされた。実験の間、動物の体重を週に2回確認し、腫瘍体積をノギスで測定した。
動物の治療は腫瘍細胞接種の18日後の無作為化の日に開始された。ヒト化II型抗CD20抗体RO5072759 B−HH6−B−KV1 GE(オビヌツズマブ)を、単剤として腹腔内に(i.p.)q7dで3週間週1回(18、25、32日目)、0.5mg/kgの投与量で投与した。bcl−2阻害剤GDC−0199を経口で(p.o.)19日間にわたり1日1回(18日目〜36日目)100mg/kgの投与量で与えた。MDM2アンタゴニストRG7388(RO5503781)を経口で(p.o.)18日目から22日目まで5日間にわたり1日1回、100mg/kg(活性化合物)の投与量で与え、25日目〜36日目まで12日間にわたり80mg/kg(活性化合物)の投与量で投与した。23日目及び24日目には治療はなかった。併用群において、RO5072759 B−HH6−B−KV1 GE、MDM2(4)及びGDC−0199を同じ投与量で同じ日に投与した。対応するビヒクルを同じ日に投与した。
RO5072759、GDC−0199又はRG7388(RO5503781)を用いた単独療法は、それぞれ47%、53%又は67%の腫瘍増殖阻害をもたらした。RO5072759とGDC−0199又はRG7388(RO5503781)との組み合わせは、それぞれ85%又は86%の腫瘍増殖阻害をもたらした。RG7388(RO5503781)とGDC−0199との組み合わせ及び三重併用は、腫瘍細胞接種後32日目に腫瘍退縮(TGI>100%)を示した。
配列番号1
マウスモノクローナル抗CD20抗体B−Ly1の重鎖(VH)の可変領域のアミノ酸配列
Gly Pro Glu Leu Val Lys Pro Gly Ala Ser Val Lys Ile Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Lys Leu Arg Pro Gly Gln Gly Leu Glu Trp Ile Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Lys Ala Thr Leu Thr Ala Asp Lys Ser Ser Asn Thr Ala Tyr Met Gln Leu Thr Ser Leu Thr Ser Val Asp Ser Ala Val Tyr Leu Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ala
マウスモノクローナル抗CD20抗体B−Ly1の軽鎖(VL)の可変領域のアミノ酸配列
Asn Pro Val Thr Leu Gly Thr Ser Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro Asp Arg Phe Ser Ser Ser Gly Ser Gly Thr Asp Phe Thr Leu Arg Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Leu Glu Ile Lys Arg
ヒト化B−Ly1抗体(B−HH2)の重鎖の可変領域(VH)のアミノ酸配列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HH3)の重鎖の可変領域(VH)のアミノ酸配列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Leu Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HH4)の重鎖の可変領域(VH)のアミノ酸配列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Val Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HH5)の重鎖の可変領域(VH)のアミノ酸配列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Met Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HH6)の重鎖の可変領域(VH)のアミノ酸配列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Ile Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HH7)の重鎖の可変領域(VH)のアミノ酸配列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ala Phe Ser Tyr Ser Trp Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HH8)の重鎖の可変領域(VH)のアミノ酸配列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HH9)の重鎖の可変領域(VH)のアミノ酸配列
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HL8)の重鎖の可変領域(VH)のアミノ酸配列
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HL10)の重鎖の可変領域(VH)のアミノ酸配列
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ala Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HL11)の重鎖の可変領域(VH)のアミノ酸配列
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HL12)の重鎖の可変領域(VH)のアミノ酸配列
Glu Val Gln Leu Val Glu Ser Gly Ala Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HL13)の重鎖の可変領域(VH)のアミノ酸配列
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HL14)の重鎖の可変領域(VH)のアミノ酸配列
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Lys Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HL15)の重鎖の可変領域(VH)のアミノ酸配列
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Ser Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HL16)の重鎖の可変領域(VH)のアミノ酸配列
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Val Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体(B−HL17)の重鎖の可変領域(VH)のアミノ酸配列
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Tyr Ser Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Met Gly Arg Ile Phe Pro Gly Asp Gly Asp Thr Asp Tyr Asn Gly Lys Phe Lys Gly Arg Val Thr Ile Thr Ala Asp Lys Ser Thr Ser Thr Ala Tyr Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys Ala Arg Asn Val Phe Asp Gly Tyr Trp Leu Val Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
ヒト化B−Ly1抗体B−KV1の軽鎖可変領域(VL)のアミノ酸配列
Asp Ile Val Met Thr Gln Thr Pro Leu Ser Leu Pro Val Thr Pro Gly Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Lys Ser Leu Leu His Ser Asn Gly Ile Thr Tyr Leu Tyr Trp Tyr Leu Gln Lys Pro Gly Gln Ser Pro Gln Leu Leu Ile Tyr Gln Met Ser Asn Leu Val Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Ala Gln Asn Leu Glu Leu Pro Tyr Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg Thr Val
Claims (26)
- Bcl−2阻害剤及びMDM2阻害剤と併用するがんの治療のための抗CD20抗体。
- 前記CD20抗体が、I型抗CD20抗体又はAsn297においてオリゴ糖(糖類)の総量の60%以下のフコース量を有するアフコシル化抗CD20抗体であることを特徴とする、請求項1に記載の抗体。
- 前記がんがCD20を発現するがんであることを特徴とする、請求項1又は2に記載の抗体。
- 前記CD20を発現するがん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3の何れか一項に記載の抗体。
- 前記アフコシル化抗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4の何れか一項に記載の抗体。
- 前記アフコシル化抗CD20抗体がオビヌツズマブであ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。
- 前記I型抗CD20抗体がリツキシマブであ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。
- Bcl−2阻害剤が、4−(4−{[2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エン−1−イル]メチル}ピペラジン−l−イル)−2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−N−({4−[(テトラヒドロ−2H−ピラン−4−イルメチル)アミノ]−3−[(トリフルオロメチル)スルホニル]フェニル}スルホニル)ベンズアミドであることを特徴とする、請求項1から7の何れか一項に記載の抗体。
- MDM2阻害剤が、4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−メトキシ−安息香酸であることを特徴とする、請求項1から7の何れか一項に記載の抗体。
- 一又は複数の付加的な他の細胞傷害性剤、化学療法剤若しくは抗がん剤、又はかかる薬剤の効果を亢進する化合物若しく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9の何れか一項に記載の抗体。
- がんの治療のための、I型抗CD20抗体又はAsn297においてオリゴ糖(糖類)の総量の60%以下のフコース量でアフコシル化されたヒト化B−Ly1抗体の、4−(4−{[2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エン−1−イル]メチル}ピペラジン−l−イル)−2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−N−({4−[(テトラヒドロ−2H−ピラン−4−イルメチル)アミノ]−3−[(トリフルオロメチル)スルホニル]フェニル}スルホニル)ベンズアミド、及び4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−メトキシ−安息香酸又はその塩との組み合わせを含む、薬学的組成物。
- Bcl−2阻害剤及びMDM2阻害剤と併用して、I型抗CD20抗体又はAsn297においてオリゴ糖(糖類)の総量の60%以下のフコース量を有するアフコシル化抗CD20抗体をがんの治療を必要とする患者に投与することによる、がんに罹患している患者の治療方法。
- 前記がんがCD20を発現するがんであることを特徴とする、請求項12に記載の方法。
- 前記CD20を発現するがん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12又は13に記載の方法。
- 前記アフコシル化抗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12から14の何れか一項に記載の方法。
- 前記I型抗CD20抗体がリツキシマブであることを特徴とする、請求項12から15の何れか一項に記載の方法。
- Bcl−2阻害剤が、4−(4−{[2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エン−1−イル]メチル}ピペラジン−l−イル)−2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−N−({4−[(テトラヒドロ−2H−ピラン−4−イルメチル)アミノ]−3−[(トリフルオロメチル)スルホニル]フェニル}スルホニル)ベンズアミド又はその塩若しくは多形体であることを特徴とする、請求項12から16の何れか一項に記載の方法。
- MDM2阻害剤が、4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−メトキシ−安息香酸又はその塩若しくは多形体であることを特徴とする、請求項12から17の何れか一項に記載の方法。
- 一又は複数の付加的な他の細胞傷害性剤、化学療法剤若しくは抗がん剤、又はかかる薬剤の効果を亢進する化合物若しくは電離放射線が投与されることを特徴とする、請求項12から18の何れか一項に記載の方法。
- Bcl−2阻害剤及びMDM2阻害剤と併用するがんの治療用医薬の製造のための、I型CD20抗体、又はAsn297においてオリゴ糖(糖類)の総量の60%以下のフコース量を有するアフコシル化抗CD20抗体の使用。
- 前記がんがCD20を発現するがんであることを特徴とする、請求項20に記載の使用。
- 前記CD20を発現するがん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20又は21に記載の使用。
- 前記アフコシル化抗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20から22の何れか一項に記載の使用。
- Bcl−2阻害剤が、4−(4−{[2−(4−クロロフェニル)−4,4−ジメチルシクロヘキサ−1−エン−1−イル]メチル}ピペラジン−l−イル)−2−(1H−ピロロ[2,3−b]ピリジン−5−イルオキシ)−N−({4−[(テトラヒドロ−2H−ピラン−4−イルメチル)アミノ]−3−[(トリフルオロメチル)スルホニル]フェニル}スルホニル)ベンズアミド又はその塩若しくは多形体であることを特徴とする、請求項20から23の何れか一項に記載の使用。
- MDM2阻害剤が、4−{[(2R,3S,4R,5S)−4−(4−クロロ−2−フルオロ−フェニル)−3−(3−クロロ−2−フルオロ−フェニル)−4−シアノ−5−(2,2−ジメチル−プロピル)−ピロリジン−2−カルボニル]−アミノ}−3−メトキシ−安息香酸又はその塩若しくは多形体であることを特徴とする、請求項20から24の何れか一項に記載の使用。
- 一又は複数の付加的な他の細胞傷害性剤、化学療法剤若しくは抗がん剤、又はかかる薬剤の効果を亢進する化合物若しくは電離放射線が投与されることを特徴とする、請求項20から25の何れか一項に記載の使用。
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WO2019246317A1 (en) | 2018-06-20 | 2019-12-26 | Progenity, Inc. | Treatment of a disease or condition in a tissue originating from the endoderm |
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GEP20237460B (en) * | 2018-07-31 | 2023-01-25 | Ascentage Pharma Suzhou Co Ltd | Synergistic antitumor effect of bcl-2 inhibitor combined with rituximab and/or bendamustine or bcl-2 inhibitor combined with chop |
US20220249814A1 (en) | 2018-11-19 | 2022-08-11 | Progenity, Inc. | Methods and devices for treating a disease with biotherapeutics |
WO2021119482A1 (en) | 2019-12-13 | 2021-06-17 | Progenity, Inc. | Ingestible device for delivery of therapeutic agent to the gastrointestinal tract |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
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MX2013006739A (es) * | 2010-12-16 | 2013-07-17 | Roche Glycart Ag | Terapia combinada de anticuerpo cd20 afucosilado con inhibidor de mdm2. |
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Non-Patent Citations (8)
Title |
---|
ANR(ADVANCES IN NEUROBLASTOMA RESEARCH) COLOGNE 20, vol. Meeting Abstract, JPN6018037386, 2014, pages No.8071660 * |
BLOOD, vol. Vol.124,No.21, JPN6018037379, 2014, pages Abstract No.2162 * |
BLOOD, vol. Vol.124,No.21, JPN6018037381, 2014, pages Abstract No.4687 * |
BLOOD, vol. Vol.124,No.21, JPN6018037382, 2014, pages Abstract No.325 * |
BLOOD, vol. Vol.124,No.21, JPN6018037385, 2014, pages Abstract No.1780 * |
CANCER RESEARCH, vol. Vol.74,No.19 Suppl., JPN6018037377, 2014, pages Abstract No.5505 * |
JOURNAL OF CLINICAL ONCOLOGY, vol. Vol.32,No.15 Suppl., JPN6018037383, 2014, pages Abstract No.7013 * |
ONCOLOGY RESEARCH AND TREATMENT, vol. Vol.38,No.4, JPN6018037374, 31 March 2015 (2015-03-31), pages p185−192 * |
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