JP2023510601A - オフターゲット毒性を低下させるプロ抗体 - Google Patents
オフターゲット毒性を低下させるプロ抗体 Download PDFInfo
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Abstract
Description
該当無し。
本出願は、37CFR1.821~1.825の要求に従い、別途ファイル添付された配列リストを含む。
PP1;SPRR1B(Spr1);ST6GAL1;STAB1;STAT6;STEAP;STEAP2;サブスタンスP;TB4R2;TBX21;TCP10;TDGF1;TEK;TGFA;TGFB1;TGFB111;TGFB2;TGFB3;TGFBI;TGFBR1;TGFBR2;TGFBR3;TH1L;THBS1(トロンボスポンジン-1);THBS2;THBS4;THPO;TIE(Tie-1);TIMP3;組織因子;TLR10;TLR2;TLR3;TLR4;TLR5;TLR6;TLR7;TLR8;TLR9;TNF;TNF-a;TNFAIP2(B94);TNFAIP3;TNFRSF11A;TNFRSF1A;TNFRSF1B;TNFRSF21;TNFRSF5;TNFRSF6(Fas);TNFRSF7;TNFRSF8;TNFRSF9;TNFSF10(TRAIL);TNFSF11(TRANCE);TNFSF12(AP03L);TNFSF13(April);TNFSF13B;TNFSF14(HVEML);TNFSF15(VEGI);TNFSF18;TNFSF4(OX40リガンド);TNFSF5(CD40リガンド);TNFSF6(FasL);TNFSF7(CD27リガンド);TNFSF8(CD30リガンド);TNFSF9(4-1BBリガンド);TOLLIP;Toll様受容体;TOP2A(トポイソメラーゼIIa);TP53;TPM1;TPM2;TRADD;TRAF1;TRAF2;TRAF3;TRAF4;TRAF5;TRAF6;TREM1;TREM2;TRPC6;TSLP;TWEAK;トロンボモジュリン;トロンビン;VEGF;VEGFB;VEGFC;バーシカン;VHL C5;VLA-4;XCL1(リンホタクチン);XCL2(SCM-1b);XCR1(GPR5/CCXCR1);YY1;及びZFPM2から選択される少なくとも1つの遺伝子によりコードされるタンパク質、タンパク質の一部分、又はペプチドから選択される。別の態様では、腫瘍標的は、腫瘍標的抗原、HER1、HER2、HER3、GD2、癌胎児抗原(CEA)、上皮増殖因子受容体活性ミュータント(EGFRVIII,epidermal growth factor receptor active mutant)、CD133、線維芽細胞活性化タンパク質(FAP,Fibroblast Activation Protein)アルファ、上皮細胞接着分子(Epcam)、グリピカン3(GPC3,Glypican 3)、EPH受容体A4(EphA)、チロシン-プロテインキナーゼMet(cMET)、IL-13Ra2、ミクロソームエポキシドヒドロラーゼ(mEH,microsomal epoxide hydrolase)、MAGE、メソテリン、MUC16、MUC1、前立腺幹細胞抗原(PSCA,prostate stem cell antigen)、ウィルムス腫瘍-1(WT-1,Wilms tumor-1)、又はクローディンファミリータンパク質から選択される。別の態様では、第1の抗原結合部位又は第2の抗原結合部位は、T細胞マーカーに結合する。別の態様では、T細胞マーカーは、CTLA4、PD-1、Lag3、S15、B7H3、B7H4、TCR-アルファ、TCR-ベータ、又はTIM-3から選択される。別の態様では、第1の抗原結合部位又は第2の抗原結合部位は、T細胞アクチベーターに結合する。別の態様では、T細胞アクチベーターは、CD3、41BB、又はOX40から選択される。別の態様では、切断可能リンカーは、プロテアーゼ切断可能リンカーである。別の態様では、切断可能リンカーは、腫瘍関連のプロテアーゼ:MMP1、MMP2、MMP3、MMP7、MMP9、MMP10、MMP11、MMP12、MMP13、MMP14、MMP15、MMP16、MMP17、MMP19、MMP20、MMP21、uPA、FAPa、又はカテプシンBにより切断される。別の態様では、切断可能リンカーは、アポトーシス又は炎症関連応答期間中に上方制御されるプロテアーゼにより切断される。別の態様では、切断可能リンカーは、カスパーゼにより切断される。別の態様では、カスパーゼは、カスパーゼ1、カスパーゼ2、カスパーゼ3、カスパーゼ4、カスパーゼ5、カスパーゼ6、カスパーゼ7、カスパーゼ8、カスパーゼ9、カスパーゼ10、カスパーゼ11、及びカスパーゼ12である。別の態様では、切断可能リンカーは抗原結合部位を遮蔽しない。別の態様では、aAbは、aAbにコンジュゲートした薬剤をさらに含む。別の態様では、aAbは、aAb若しくはFc領域に結合した又はaAb若しくはFc領域を含む融合タンパク質となっているサイトカインをさらに含む。別の態様では、サイトカインは、成長ホルモン;副甲状腺ホルモン;チロキシン;インスリン;プロインスリン;リラキシン;プロリラキシン;糖タンパク質ホルモン;肝増殖因子;線維芽細胞増殖因子;プロラクチン;胎盤性ラクトゲン;TNF-a;ミュラー管抑制因子;ゴナドトロピン関連ペプチド;インヒビン;アクチビン;血管内皮増殖因子;インテグリン;トロンボポエチン(TPO,thrombopoietin);神経成長因子;血小板増殖因子;胎盤増殖因子、形質転換増殖因子(TGF,transforming growth factor);インスリン様増殖因子-1及び-11;エリスロポエチン(EPO,erythropoietin);骨誘導因子;インターフェロン;コロニー刺激因子(CSF,colony stimulating factor);リンホトキシン-アルファ;リンホトキシン-ベータ;CD27L;CD30L;FASL;4-1BBL;OX40L;TRAIL;IL-1;IL-2;IL-3;IL-4;IL-5;IL-6;IL-7;IL-8;IL-9;IL-10;IL-11;IL-12;IL-13;IL-15;IL-18;IL-21;IL-22;IL-23;IL-33;IFN-a;IFN-b;IFN-g;IFN-g誘発因子(IGIF,IFN-g inducing factor);骨形成タンパク質(BMP,bone morphogenetic protein);白血病抑制因子(LIF,leukemia inhibitory factor);又はkitリガンド(KL,kit ligand)のうちの少なくとも1つから選択される。別の態様では、aAbは、配列番号1、2、又は3から選択される。別の態様では、薬剤は、毒素又はその毒性断片;微小管阻害剤;核酸ダメージング剤;検出可能部分;又は診断用薬剤のうちの少なくとも1つである。
ケラチン19);KRT2A;KRTHB6(毛髪特異的タイプIIケラチン);L-セレクチン;LAMA5;LEP(レプチン);Lingo-p75;Lingo-Troy;LPS;LTA(TNF-b);LTB;LTB4R(GPR16);LTB4R2;LTBR;MACMARCKS;MAG又はOmgp;MAP2K7(c-Jun);MDK;MIB1;ミドカイン;MIF;MIP-2;MKI67(Ki-67);MMP2;MMP9;MS4A1;MSMB;MT3(メタロチオネクチン-III);MTSS1;MUC1(ムチン);MYC;MYD88;NCK2;ニューロカン;NKG2D;NFKB1;NFKB2;NGF;NGFB(NGF);NGFR;NgR-Lingo;NgR-Nogo66(Nogo);NgR-p75;NgR-Troy;NME1(NM23A);NOX5;NPPB;NR0B1;NR0B2;NR1D1;NR1D2;NR1H2;NR1H3;NR1H4;NRII2;NRII3;NR2C1;NR2C2;NR2E1;NR2E3;NR2F1;NR2F2;NR2F6;NR3C1;NR3C2;NR4A1;NR4A2;NR4A3;NR5A1;NR5A2;NR6A1;NRP1;NRP2;NT5E;NTN4;ODZ1;OPRD1;P2RX7;PAP;PARTI;PATE;PAWR;PCA3;PCNA;PDGFA;PDGFB;PECAM1;PF4(CXCL4);PGE2;PGF;PGR;ホスファカン;PIAS2;PIK3CG;プラスミノーゲンアクチベーター;PLAU(uPA);PLG;PLXDC1;PPBP(CXCL7);PPID;PR1;PRKCQ;PRKD1;PRL;PROC;プロテインC;PROK2;PSAP;PSCA;PTAFR;PTEN;PTGS2(COX-2);PTN;RAC2(p21Rac2);RAGE;RARB;RGS1;RGS13;RGS3;RNF110(ZNF144);ROB02;SI00A2;SCGB1D2(リポフィリンB);SCGB2A1(マンマグロビン2);SCGB2A2(マンマグロビン1);SCYE1(内皮性単球活性化サイトカイン);SDF2;SERPINA1;SERPINA3;SERPINB5(マスピン);SERPINE1(PAI-1);SERPINF1;SHBG;SLA2;SLC2A2;SLC33A1;SLC43A1;SLIT2;SPP1;SPRR1B(Spr1);ST6GAL1;STAB1;STAT6;STEAP;STEAP2;サブスタンスP;TB4R2;TBX21;TCP10;TDGF1;TEK;TGFA;TGFB1;TGFB111;TGFB2;TGFB3;TGFBI;TGFBR1;TGFBR2;TGFBR3;TH1L;THBS1(トロンボスポンジン-1);THBS2;THBS4;THPO;TIE(Tie-1);TIMP3;組織因子;TLR10;TLR2;TLR3;TLR4;TLR5;TLR6;TLR7;TLR8;TLR9;TNF-アルファ;TNFAIP2(B94);TNFAIP3;TNFRSF11A;TNFRSF1A;TNFRSF1B;TNFRSF21;TNFRSF5;TNFRSF6(Fas);TNFRSF7;TNFRSF8;TNFRSF9;TNFSF10(TRAIL);TNFSF11(TRANCE);TNFSF12(AP03L);TNFSF13(April);TNFSF13B;TNFSF14(HVEML);TNFSF15(VEGI);TNFSF18;TNFSF4(OX40リガンド);TNFSF5(CD40リガンド);TNFSF6(FasL);TNFSF7(CD27リガンド);TNFSF8(CD30リガンド);TNFSF9(4-1BBリガンド);TOLLIP;Toll様受容体;TOP2A(トポイソメラーゼIIa);TP53;TPM1;TPM2;TRADD;TRAF1;TRAF2;TRAF3;TRAF4;TRAF5;TRAF6;TREM1;TREM2;TRPC6;TSLP;TWEAK;トロンボモジュリン;トロンビン;VEGF;VEGFB;VEGFC;バーシカン;VHL C5;VLA-4;XCL1(リンホタクチン);XCL2(SCM-1b);XCR1(GPR5/CCXCR1);YY1;及びZFPM2から選択される少なくとも1つの遺伝子によりコードされるタンパク質、タンパクの一部分、又はペプチドから選択される。別の態様では、第1及び第2の抗原は、同一の抗原である;第1の抗原及び第2の抗原は異なる;又は第1の抗原及び第2の抗原は同一の抗原であるが、第1の抗原結合部位及び第2の抗原結合部位は同一の抗原の異なるエピトープに結合する;のうちの少なくとも1つに該当する。別の態様では、第1の抗原結合部位又は第2の抗原結合部位は、腫瘍標的に結合する。別の態様では、腫瘍標的は、腫瘍標的抗原、HER1、HER2、HER3、GD2、癌胎児抗原(CEA)、上皮増殖因子受容体活性ミュータント(EGFRVIII)、CD133、線維芽細胞活性化タンパク質アルファ(FAP)、上皮細胞接着分子(Epcam)、グリピカン3(GPC3)、EPH受容体A4(EphA)、チロシン-プロテインキナーゼMet(cMET)、IL-13Ra2、ミクロソームエポキシドヒドロラーゼ(mEH)、MAGE、メソテリン、MUC16、MUC1、前立腺幹細胞抗原(PSCA)、ウィルムス腫瘍-1(WT-1)、又はクローディンファミリーメンバーから選択される。別の態様では、第1の抗原結合部位又は第2の抗原結合部位は、T細胞マーカーに結合する。別の態様では、T細胞マーカーは、CTLA4、PD-1、Lag3、S15、B7H3、B7H4、TCR-アルファ、TCR-ベータ、TIM-3から選択される。別の態様では、第1の抗原結合部位又は第2の抗原結合部位は、T細胞アクチベーターに結合する。別の態様では、T細胞アクチベーターは、CD3、41BB、又はOX40から選択される。別の態様では、切断可能リンカーは、プロテアーゼ切断可能リンカーである。別の態様では、切断可能リンカーは、腫瘍関連プロテアーゼ:MMP1、MMP2、MMP3、MMP7、MMP9、MMP10、MMP11、MMP12、MMP13、MMP14、MMP15、MMP16、MMP17、MMP19、MMP20、MMP21、uPA、FAPa、又はカテプシンBにより切断される。別の態様では、切断可能リンカーは、アポトーシス又は炎症関連応答期間中に上方制御されるプロテアーゼにより切断される。別の態様では、切断可能リンカーは、カスパーゼにより切断される。別の態様では、カスパーゼは、カスパーゼ1、カスパーゼ2、カスパーゼ3、カスパーゼ4、カスパーゼ5、カスパーゼ6、カスパーゼ7、カスパーゼ8、カスパーゼ9、カスパーゼ10、カスパーゼ11、及びカスパーゼ12である。別の態様では、切断可能リンカーは、抗原結合部位を遮蔽しない。別の態様では、aAbは、aAbにコンジュゲートした薬剤をさらに含む。別の態様では、薬剤は、毒素又はその毒性断片;微小管阻害剤;核酸ダメージング剤;検出可能部分;又は診断用薬剤のうちの少なくとも1つである。別の態様では、aAbは、配列番号1、2、又は3から選択される。
タンパク質を発現させるためのDNA断片を、Genewiz社により合成し、又はPCRにより生成し、そしてアイソサーマルアセンブリ(Quantabio社)を経由してpEE6.4ベクター中にクローン化した。
Pro-抗CTLA4-Fc
MINEFSSLAGAQRQRLLGVVVVQSLVHHGAAKHVALLPSALVHCQIASESKAAVGIQHGHGGLVVVLGLAVAFPFHGDIARVEALHQTAQRHLILGQLVSAGRLGVHLRLPRLAFGLADGLLNGGGQSLVGDLALVLLAVEPVLVQHGQHGHHSICGVVLLLSGLGFGVVHFDAVHVPVKLHLGVLMADVHHHACHLGCSRDHQCILGFGREQKHGRSAQQFGSRTARNRYHRALTPIVEVAGLTRTVISRGVLGGYRVNLQKELVFRGVTGDRDTRFDRRVVIGRTFIIDETHPFNFLTWELTDPIPTITGGDGGAGNRARQAERTGRINQTRTRFFQFYLSAYVLTPPFDFQLGARTERVRIVVPLLAVVKRLVFVLNRRNGQREVGTRARTTETVRNAGVTGRRVVDQQFRRLTRLLHVPIQIVGFRVRVEQALRAFARDGRFFTRRHAQRRWRLGHHNVSGGTWNPEQQYP(配列番号1)
METDTLLLWVLLLWVPGSTGDIVMTQSPDSLAVSLGERATISCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYFYPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGSSGRSENIRTAGGSQVQLVQSGAEVKKPGSSVKVSCKASGYAFSNYLIEWVKQAPGQGLEWIGLINPGSGGTNYNEKFKGKATITADKSTSTAYMELSSLRSEDTAVYYCARVYYGNSFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号2)
METDTLLLWVLLLWVPGSTGDIVMTQSPDSLAVSLGERATISCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYFYPFTFGQGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGSSGRSENIRTAGGSQVQLVQSGAEVKKPGSSVKVSCKASGYAFSNYLIEWVKQAPGQGLEWIGLINPGSGGTNYNEKFKGKATITADKSTSTAYMELSSLRSEDTAVYYCARVYYGNSFAYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKRVEPKSCDKTHTCPPCPAPEAAGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALGAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGKGGGGSGGGGSGGGGSGGGGSQIVLTQSPAIMSASPGEKVTMTCSASSSVSYMNWYQQKSGTSPKRWIYDTSKLASGVPAHFRGSGSGTSYSLTISGMEAEDAATYYCQQWSSNPFTFGSGTKLEINGGGGSGGGGSGGGGSQVQLQQSGAELARPGASVKMSCKASGYTFTRYTMHWVKQRPGQGLEWIGYINPSRGYTNYNQKFKDKATLTTDKSSSTAYMQLSSLTSEDSAVYYCARYYDDHYCLDYWGQGTTLTVSS(配列番号3)
Claims (70)
- 下記の構造:
第1の可変軽鎖領域を含む第1の軽鎖と、
切断可能リンカーと、
第1の可変重鎖領域を含む第1の重鎖と
を順に含む、活性化可能な抗体(aAb)であって、
前記切断可能リンカーが、前記第1の軽鎖及び前記第1の重鎖が第1の抗原に対して第1の抗原結合部位を形成することを防止し又は低下させ、かつ
前記切断可能リンカーが切断されると、前記第1の重鎖が解放されて、第1の抗原に結合する前記第1の抗原結合部位の形成を可能にする、
前記aAb。 - 第2の可変軽鎖、及び第1の重鎖と接続した第2の定常軽鎖により形成された、第2の抗原に結合する第2の抗体結合部位をさらに含み、かつ前記第2の可変軽鎖と前記第2の定常軽鎖との間に可撓性非切断可能リンカーを含んでもよい、請求項1に記載のaAb。
- 第1の定常重鎖領域、第1の定常重鎖領域のうちの少なくとも1つ、又はその両方をさらに含む、請求項1に記載のaAb。
- 第1の軽鎖領域、第1の重鎖領域、又はその両方が、Fc領域、野生型Fc領域、変異したFc領域、単量体野生型Fc領域、単量体ミュータントFc領域、二量体野生型Fc領域、又は二量体ミュータントFc領域、第2の可変重鎖領域及び第2のFc領域、又は第2の可変重鎖領域及び第2のFc領域及び切断不能な可撓性リンカー及び第2の可変軽鎖領域及び第2の重鎖可変領域、又は第2のFc領域及び切断不能な可撓性リンカー及びサイトカインをさらに含む、請求項1に記載のaAb。
- 第1の抗原及び第2の抗原が、
同一の抗原である;
前記第1の抗原及び前記第2の抗原が異なる;又は
前記第1の抗原及び前記第2の抗原が同一の抗原であるが、第1の抗原結合部位及び第2の抗原結合部位が、前記同一の抗原の異なるエピトープに結合する;
のうちの少なくとも1つに該当する、請求項2に記載のaAb。 - 第1の抗原結合部位又は第2の抗原結合部位が、腫瘍標的に結合する、請求項2に記載のaAb。
- 第1の抗原が、ICAM1;VCAM1;EpCAM;フィブロネクチンのエキストラドメインB;黒色腫関連コンドロイチン硫酸プロテオグリカン(MCSP,melanoma-associated chondroitin sulfate proteoglycan);黒色腫関連プロテオグリカン(MAPG,melanoma-associated proteoglycan);高分子量黒色腫関連抗原(HMV-MAA,high molecular weight melanoma associated antigen);前立腺特異的膜抗原(PSMA,prostate specific membrane antigen);上皮増殖因子受容体(EGFR,epidermal growth factor receptor);肝細胞増殖因子受容体(HGFR,hepatocyte growth factor receptor);線維芽細胞活性化タンパク質(FAP,fibroblast activation protein);癌胎児抗原(CEA,carcinoembryonic antigen);細胞接着分子(CAM,cell-adhesion molecule);ヒトB細胞成熟標的(BCMA,B-cell maturation target);胎盤増殖因子(PLGF,placental growth factor);葉酸受容体、インスリン様増殖因子受容体(ILGFR,insulin-like growth factor receptor);CD133;CD40;CD37;CD33;CD30;CD28;CD24;CD23;CD22;CD21;CD20;CD19;CD13;CD10;HER3;HER2;非筋ミオシン重鎖タイプA(nmMHCA,nonmuscle myosin heavy chain type A);トランスフェリン;上皮細胞接着分子(EpCAM,epithelial cell adhesion molecule);アネキシンA1;ヌクレオチン(nucleotin)、テネイシン、血管内皮増殖因子受容体1(VEGFR1,vascular endothelial growth factor receptor 1)、血管内皮増殖因子受容体2;(VEGFR-2);アミノペプチダーゼN、tie-1、tie-2、又はc-Metから選択される組織特異的表面抗原である、請求項2に記載のaAb。
- 第1の抗原が、ABCF1;ACVR1;ACVR1B;ACVR2;ACVR2B;ACVRL1;ADORA2A;アグリカン;AGR2;AICDA;AIF1;AIG1;AKAP1;AKAP2;AMH;AMHR2;ANGPT1;ANGPT2;ANGPTL3;ANGPTL4;ANPEP;APC;APOC1;AR;AZGP1;B7.1;B7.2;BAD;BAFF;BAG1;BAI1;BCL2;BCL6;BDNF;BLNK;BLR1(MDR15);BlyS;BMP1;BMP2;BMP3B(GDF10);BMP4;BMP6;BMP8;BMPR1A;BMPR1B;BMPR2;BPAG1(プレクチン);BRCA1;C19orf10(IL27w);C3;C4A;C5;C5R1;CANT1;CASP1;CASP4;CAV1;CCBP2(D6/JAB61);CCL1(1-309);CCL11(エオタキシン);CCL13(MCP-4);CCL15(MIP-1d);CCL16(HCC-4);CCL17(TARC);CCL18(PARC);CCL19(MIP-3b);CCL2(MCP-1);MCAF;CCL20(MIP-3a);CCL21(MIP-2);SLC;エクソダス-2;CCL22(MDC/STC-1);CCL23(MPIF-1);CCL24(MPIF-2/エオタキシン-2);CCL25(TECK);CCL26(エオタキシン-3);CCL27(CTACK/ILC);CCL28;CCL3(MIP-1a);CCL4(MIP-1b);CCL5(RANTES);CCL7(MCP-3);CCL8(mcp-2);CCNA1;CCNA2;CCND1;CCNE1;CCNE2;CCR1(CKR1/HM145);CCR2(mcp-1RB/RA);CCR3(CKR3/CMKBR3);CCR4;CCR5(CMKBR5/ChemR13);CCR6(CMKBR6/CKR-L3/STRL22/DRY6);CCR7(CKR7/EBI1);CCR8(CMKBR8/TER1/CKR-L1);CCR9(GPR-9-6);CCRL1(VSHK1);CCRL2(L-CCR);CD164;CD19;CD1C;CD20;CD200;CD-22;CD24;CD28;CD3;CD37;CD38;CD3E;CD3G;CD3Z;CD4;CD40;CD40L;CD44;CD45RB;CD52;CD69;CD72;CD74;CD79A;CD79B;CD8;CD80;CD81;CD83;CD86;CDH1(E-カドヘリン);CDH10;CDH12;CDH13;CDH18;CDH19;CDH20;CDH5;CDH7;CDH8;CDH9;CDK2;CDK3;CDK4;CDK5;CDK6;CDK7;CDK9;CDKN1A(p21Wap1/Cip1);CDKNIB(p27Kip1);CDKNIC;CDKN2A(pl6INK4a);CDKN2B;CDKN2C;CDKN3;CEBPB;CER1;CHGA;CHGB;キチナーゼ;CHST10;CKLFSF2;CKLFSF3;CKLFSF4;CKLFSF5;CKLFSF6;CKLFSF7;CKLFSF8;CLDN3;CLDN7(クローディン-7);CLN3;CXCL10(IP-10);CXCL11(I-TAC/IP-9);CXCL12(SDF1);CXCL13;CXCL14;CXCL16;CXCL2(GR02);CXCL3(GR03);CXCL5(ENA-78/LIX);CXCL6(GCP-2);CXCL9(MIG);CXCR3(GPR9/CKR-L2);CXCR4;CXCR6(TYMSTR/STRL33/Bonzo);CYB5;CYC1;CYSLTR1;CGRP;Clq;Clr;CI;C4a;C4b;C2a;C2b;C3a;C3b;DAB2IP;DES;DKFZp451J0118;DNCL1;DPP4;E-セレクチン;E2F1;ECGF1;EDG1;EFNA1;EFNA3;EFNB2;EGF;EGFR;ELAC2;ENG;EN01;EN02;EN03;EPHB4;EPO;ERBB2(Her-2);EREG;ERK8;ESR1;ESR2;F3(TF);第VII因子;第IX因子;第V因子;第VIIa因子;第X因子;第XII因子;第XIII因子;FADD;FasL;FASN;FCER1A;FCER2;Fcガンマ受容体;FCGR3A;FGF;FGF1(aFGF);FGF10;FGF11;FGF12;FGF12B;FGFl3;FGF14;FGF16;FGF17;FGF18;FGF19;FGF2(bFGF);FGF20;FGF21;FGF22;FGF23;FGF3(int-2);FGF4(HST);FGF5;FGF6(HST-2);FGF7(KGF);FGF8;FGF9;FGFR3;FIGF(VEGFD);FIL1(エプシロン);FIL1(ゼータ);FLJ12584;FLJ25530;FLRT1(フィブロネクチン);FLT1;FOS;FOSL1(FRA-1);FY(DARC);GABRP(GABAa);GAGEB1;GAGEC1;GALNAC4S-6ST;GATA3;GDF5;GFI1;GGT1;GMCSF;GNAS1;GNRH1;GPR2(CCR10);GPR31;GPR44;GPR81(FKSG80);GRCC10(CIO);GRP;GSN(ゲルソリン);GSTP1;糖タンパク質(GP,glycoprotein)IIb/IIIa;HAVCR2;HDAC4;HDAC5;HDAC7A;HDAC9;Her2;HGF;ITGB4(b4インテグリン);JAG1;JAK1;JAK3;JUN;K6HF;KAI1;KDR;KITLG;KLF5(GC Box BP);KLF6;KLK10;KLK12;KLK13;KLK14;KLK15;KLK3;KLK4;KLK5;KLK6;KLK9;KRT1;KRT19(ケラチン19);KRT2A;KRTHB6(毛髪特異的タイプIIケラチン);L-セレクチン;LAMA5;LEP(レプチン);Lingo-p75;Lingo-Troy;LPS;LTA(TNF-b);LTB;LTB4R(GPR16);LTB4R2;LTBR;MACMARCKS;MAG又はOmgp;MAP2K7(c-Jun);MDK;MIB1;ミドカイン;MIF;MIP-2;MKI67(Ki-67);MMP2;MMP9;MS4A1;MSMB;MT3(メタロチオネクチン-III)(metallothionectin-III);MTSS1;MUC1(ムチン);MYC;MYD88;NCK2;ニューロカン;NKG2D;NFKB1;NFKB2;NGF;NGFB(NGF);NGFR;NgR-Lingo;NgR-Nogo66(Nogo);NgR-p75;NgR-Troy;NME1(NM23A);NOX5;NPPB;NR0B1;NR0B2;NR1D1;NR1D2;NR1H2;NR1H3;NR1H4;NRII2;NRII3;NR2C1;NR2C2;NR2E1;NR2E3;NR2F1;NR2F2;NR2F6;NR3C1;NR3C2;NR4A1;NR4A2;NR4A3;NR5A1;NR5A2;NR6A1;NRP1;NRP2;NT5E;NTN4;ODZ1;OPRD1;P2RX7;PAP;PARTI;PATE;PAWR;PCA3;PCNA;PDGFA;PDGFB;PECAM1;PF4(CXCL4);PGE2;PGF;PGR;ホスファカン;PIAS2;PIK3CG;プラスミノーゲンアクチベーター;PLAU(uPA);PLG;PLXDC1;PPBP(CXCL7);PPID;PR1;PRKCQ;PRKD1;PRL;PROC;プロテインC;PROK2;PSAP;PSCA;PTAFR;PTEN;PTGS2(COX-2);PTN;RAC2(p21Rac2);RAGE;RARB;RGS1;RGS13;RGS3;RNF110(ZNF144);ROB02;SI00A2;SCGB1D2(リポフィリンB);SCGB2A1(マンマグロビン2);SCGB2A2(マンマグロビン1);SCYE1(内皮性単球活性化サイトカイン);SDF2;SERPINA1;SERPINA3;SERPINB5(マスピン);SERPINE1(PAI-1);SERPINF1;SHBG;SLA2;SLC2A2;SLC33A1;SLC43A1;SLIT2;SPP1;SPRR1B(Spr1);ST6GAL1;STAB1;STAT6;STEAP;STEAP2;サブスタンスP;TB4R2;TBX21;TCP10;TDGF1;TEK;TGFA;TGFB1;TGFB111;TGFB2;TGFB3;TGFBI;TGFBR1;TGFBR2;TGFBR3;TH1L;THBS1(トロンボスポンジン-1);THBS2;THBS4;THPO;TIE(Tie-1);TIMP3;組織因子;TLR10;TLR2;TLR3;TLR4;TLR5;TLR6;TLR7;TLR8;TLR9;TNF;TNF-a;TNFAIP2(B94);TNFAIP3;TNFRSF11A;TNFRSF1A;TNFRSF1B;TNFRSF21;TNFRSF5;TNFRSF6(Fas);TNFRSF7;TNFRSF8;TNFRSF9;TNFSF10(TRAIL);TNFSF11(TRANCE);TNFSF12(AP03L);TNFSF13(April);TNFSF13B;TNFSF14(HVEML);TNFSF15(VEGI);TNFSF18;TNFSF4(OX40リガンド);TNFSF5(CD40リガンド);TNFSF6(FasL);TNFSF7(CD27リガンド);TNFSF8(CD30リガンド);TNFSF9(4-1BBリガンド);TOLLIP;Toll様受容体;TOP2A(トポイソメラーゼIIa);TP53;TPM1;TPM2;TRADD;TRAF1;TRAF2;TRAF3;TRAF4;TRAF5;TRAF6;TREM1;TREM2;TRPC6;TSLP;TWEAK;トロンボモジュリン;トロンビン;VEGF;VEGFB;VEGFC;バーシカン;VHL C5;VLA-4;XCL1(リンホタクチン);XCL2(SCM-1b);XCR1(GPR5/CCXCR1);YY1;及びZFPM2から選択される、少なくとも1つの遺伝子によりコードされるタンパク質、タンパク質の一部分、又はペプチドから選択される、請求項2に記載のaAb。
- 腫瘍標的が、腫瘍標的抗原、HER1、HER2、HER3、GD2、癌胎児抗原(CEA)、上皮増殖因子受容体活性ミュータント(EGFRVIII,epidermal growth factor receptor active mutant)、CD133、線維芽細胞活性化タンパク質アルファ(FAP)、上皮細胞接着分子(Epcam)、グリピカン3(GPC3)、EPH受容体A4(EphA)、チロシン-プロテインキナーゼMet(cMET)、IL-13Ra2、ミクロソームエポキシドヒドロラーゼ(mEH,microsomal epoxide hydrolase)、MAGE、メソテリン、MUC16、MUC1、前立腺幹細胞抗原(PSCA)、ウィルムス腫瘍-1(WT-1)、又はクローディンファミリータンパク質から選択される、請求項6に記載のaAb。
- 第1の抗原結合部位又は第2の抗原結合部位が、T細胞マーカーに結合する、請求項2に記載のaAb。
- T細胞マーカーが、CTLA4、PD-1、Lag3、S15、B7H3、B7H4、TCR-アルファ、TCR-ベータ、又はTIM-3から選択される、請求項10に記載のaAb。
- 第1の抗原結合部位又は第2の抗原結合部位が、T細胞アクチベーターに結合する、請求項2に記載のaAb。
- T細胞アクチベーターが、CD3、41BB、又はOX40から選択される、請求項12に記載のaAb。
- 切断可能リンカーが、プロテアーゼ切断可能リンカーである、請求項1に記載のaAb。
- 切断可能リンカーが、腫瘍関連のプロテアーゼ:MMP1、MMP2、MMP3、MMP7、MMP9、MMP10、MMP11、MMP12、MMP13、MMP14、MMP15、MMP16、MMP17、MMP19、MMP20、MMP21、uPA、FAPa、又はカテプシンBにより切断される、請求項1に記載のaAb。
- 切断可能リンカーが、アポトーシス又は炎症関連応答期間中に上方制御されるプロテアーゼにより切断される、請求項1に記載のaAb。
- 切断可能リンカーが、カスパーゼにより切断される、請求項16に記載のaAb。
- カスパーゼが、カスパーゼ1、カスパーゼ2、カスパーゼ3、カスパーゼ4、カスパーゼ5、カスパーゼ6、カスパーゼ7、カスパーゼ8、カスパーゼ9、カスパーゼ10、カスパーゼ11、及びカスパーゼ12である請求項17に記載のaAb。
- 切断可能リンカーが、抗原結合部位を遮蔽しない、請求項1に記載のaAb。
- aAbにコンジュゲートした薬剤をさらに含む、請求項1に記載のaAb。
- aAb若しくはFc領域に結合した又はaAb若しくはFc領域を含む融合タンパク質となっているサイトカインをさらに含む、請求項1に記載のaAb。
- サイトカインが、成長ホルモン;副甲状腺ホルモン;チロキシン;インスリン;プロインスリン;リラキシン;プロリラキシン;糖タンパク質ホルモン;肝増殖因子;線維芽細胞増殖因子;プロラクチン;胎盤性ラクトゲン;TNF-a;ミュラー管抑制因子;ゴナドトロピン関連ペプチド;インヒビン;アクチビン;血管内皮増殖因子;インテグリン;トロンボポエチン(TPO,thrombopoietin);神経成長因子;血小板増殖因子;胎盤増殖因子、形質転換増殖因子(TGF,transforming growth factor);インスリン様増殖因子-1及び-11;エリスロポエチン(EPO,erythropoietin);骨誘導因子;インターフェロン;コロニー刺激因子(CSF,colony stimulating factor);リンホトキシン-アルファ;リンホトキシン-ベータ;CD27L;CD30L;FASL;4-1BBL;OX40L;TRAIL;IL-1;IL-2;IL-3;IL-4;IL-5;IL-6;IL-7;IL-8;IL-9;IL-10;IL-11;IL-12;IL-13;IL-15;IL-18;IL-21;IL-22;IL-23;IL-33;IFN-a;IFN-b;IFN-g;IFN-g誘発因子(IGIF,IFN-g inducing factor);骨形成タンパク質(BMP,bone morphogenetic protein);白血病抑制因子(LIF,leukemia inhibitory factor);又はkitリガンド(KL,kit ligand)のうちの少なくとも1つから選択される、請求項21に記載のaAb。
- 配列番号1、2、又は3から選択される、請求項1に記載のaAb。
- 薬剤が、毒素又はその毒性断片;微小管阻害剤;核酸ダメージング剤;検出可能部分;又は診断用薬剤のうちの少なくとも1つである、請求項20に記載のaAb。
- 請求項1に記載の活性化可能なAbと、担体とを含む医薬組成物。
- 正常組織に対する抗体の結合活性を低下させ、及びがん細胞を標的とする方法であって、有効量の請求項1に記載の抗体を、それを必要としている対象に投与するステップを含む、前記方法。
- がんの症状を治療、緩和し、又はその進行を遅延させる方法であって、有効量の請求項1に記載の抗体を、それを必要としている対象に投与するステップを含む、前記方法。
- がんが、切断可能リンカーを切断する酵素を発現するがんである、請求項27に記載の方法。
- がんが、膀胱がん、骨がん、乳がん、癌様体、子宮頸がん、結腸がん、子宮内膜がん、神経膠腫、頭頸部がん、肝がん、肺がん、リンパ腫、黒色腫、卵巣がん、膵がん、前立腺がん、腎臓がん、肉腫、皮膚がん、胃がん、精巣がん、甲状腺がん、泌尿生殖器がん、又は尿路上皮がんから選択される、請求項27に記載の方法。
- がんが、急性骨髄性白血病、副腎皮質癌、B細胞リンパ腫、膀胱尿路上皮癌、乳房腺管癌、乳房小葉癌、食道の癌、去勢抵抗性前立腺がん(CRPC,castration-resistant prostate cancer)、子宮頸癌、胆管癌、慢性骨髄性白血病、結腸直腸腺癌、結腸直腸がん(CRC,colorectal cancer)、食道癌、胃腺癌、多形膠芽細胞腫、頭頸部扁平上皮癌、ホジキンリンパ腫/原発性縦隔B細胞リンパ腫、肝細胞癌(HCC,hepatocellular carcinoma)、腎色素嫌性癌、腎明細胞癌、腎乳頭状細胞癌、低悪性度神経膠腫、肺腺癌、肺扁平上皮癌、黒色腫(MEL,melanoma)、中皮腫、非扁平上皮NSCLC、卵巣漿液性腺癌、膵管腺癌、傍神経節腫及びクローム親和細胞腫、前立腺腺癌、腎細胞癌(RCC,renal cell carcinoma)、肉腫、皮膚黒色腫、頭頸部の扁平上皮癌、T細胞リンパ腫、胸腺腫、甲状腺乳頭状癌、子宮癌肉腫、子宮体類内膜癌、及びぶどう膜黒色腫からなる群から選択される、請求項27に記載の方法。
- 下記の構造:
第1の可変軽鎖領域を含む第1の軽鎖と、
切断可能リンカーと、
第1の可変重鎖領域を含む第1の重鎖と
を順に含む、活性化可能な抗体(aAb)であって、
前記切断可能リンカーが、前記第1の軽鎖及び前記第1の重鎖が第1の抗原に対して抗原結合部位を形成することを防止し又は低下させ、
前記切断可能リンカーが切断されると、前記第1の重鎖が解放されて、前記第1の軽鎖と共に第1の抗原に結合する抗体結合部位を形成する、
前記aAb。 - 第1の定常軽鎖領域又は第1の定常重鎖領域それぞれの少なくとも1つをさらに含む、請求項31に記載のaAb。
- 第1の定常重鎖領域に結合したFc領域をさらに含み、前記Fc領域が、野生型ドメイン、又はFc受容体の結合性を改変するミュータントドメインである、請求項31に記載のaAb。
- 第2の可変軽鎖と、第1の重鎖に接続した第2の定常軽鎖とにより形成された、第2の抗原に結合する第2の抗体結合部位をさらに含み、かつ前記第2の可変軽鎖と前記第2の定常軽鎖との間に可撓性非切断可能リンカーを含んでもよい、請求項31に記載のaAb。
- 第1の定常重鎖領域、第1の定常重鎖領域のうちの少なくとも1つ、又はその両方をさらに含む、請求項31に記載のaAb。
- Fc領域が、野生型Fc領域、変異したFc領域、単量体野生型Fc領域、単量体ミュータントFc領域、二量体野生型Fc領域、又は二量体ミュータントFc領域、第2の可変重鎖領域及び第2のFc領域、又は第2の可変重鎖領域及び第2のFc領域及び切断不能な可撓性リンカー及び第2の可変軽鎖領域及び第2の重鎖可変領域、又は第2のFc領域及び切断不能な可撓性リンカー及びサイトカインである、請求項33に記載のaAb。
- aAb若しくはFc領域に結合した又はaAb若しくはFc領域を含む融合タンパク質となっているサイトカインをさらに含む、請求項31に記載のaAb。
- サイトカインが、成長ホルモン;副甲状腺ホルモン;チロキシン;インスリン;プロインスリン;リラキシン;プロリラキシン;糖タンパク質ホルモン;肝増殖因子;線維芽細胞増殖因子;プロラクチン;胎盤性ラクトゲン;TNF-アルファ;ミュラー管抑制因子;ゴナドトロピン関連ペプチド;インヒビン;アクチビン;血管内皮増殖因子;インテグリン;トロンボポエチン(TPO);神経成長因子;血小板増殖因子;胎盤増殖因子、形質転換増殖因子(TGF);インスリン様増殖因子-1及び-11;エリスロポエチン(EPO);骨誘導因子;インターフェロン;コロニー刺激因子(CSF);リンホトキシン-アルファ;リンホトキシン-ベータ;CD27L;CD30L;FASL;4-1BBL;OX40L;TRAIL;IL-1;IL-2;IL-3;IL-4;IL-5;IL-6;IL-7;IL-8;IL-9;IL-10;IL-11;IL-12;IL-13;IL-15;IL-18;IL-21;IL-22;IL-23;IL-33;IFN-a;IFN-ベータ;IFN-ガンマ;IFN-ガンマ誘発因子(IGIF);骨形成タンパク質(BMP);白血病抑制因子(LIF);又はkitリガンド(KL)のうちの少なくとも1つから選択される、請求項35に記載のaAb。
- 第1の抗原が、ICAM1;VCAM1;EpCAM;フィブロネクチンのエキストラドメインB;黒色腫関連コンドロイチン硫酸プロテオグリカン(MCSP);黒色腫関連プロテオグリカン(MAPG);高分子量黒色腫関連抗原(HMV-MAA);前立腺特異的膜抗原(PSMA);上皮増殖因子受容体(EGFR);肝細胞増殖因子受容体(HGFR);線維芽細胞活性化タンパク質(FAP);癌胎児抗原(CEA);細胞接着分子(CAM);ヒトB細胞成熟標的(BCMA);胎盤増殖因子(PLGF);葉酸受容体、インスリン様増殖因子受容体(ILGFR);CD133;CD40;CD37;CD33;CD30;CD28;CD24;CD23;CD22;CD21;CD20;CD19;CD13;CD10;HER3;HER2;非筋ミオシン重鎖タイプA(nmMHCA);トランスフェリン;上皮細胞接着分子(EpCAM);アネキシンA1;ヌクレオチン、テネイシン、血管内皮増殖因子受容体1(VEGFR1)、血管内皮増殖因子受容体2;(VEGFR-2);アミノペプチダーゼN、tie-1、tie-2、又はc-Metから選択される組織特異的表面抗原である、請求項31に記載のaAb。
- 第1の抗原が、ABCF1;ACVR1;ACVR1B;ACVR2;ACVR2B;ACVRL1;ADORA2A;アグリカン;AGR2;AICDA;AIF1;AIG1;AKAP1;AKAP2;AMH;AMHR2;ANGPT1;ANGPT2;ANGPTL3;ANGPTL4;ANPEP;APC;APOC1;AR;AZGP1(亜鉛-a-糖タンパク質);B7.1;B7.2;BAD;BAFF;BAG1;BAI1;BCL2;BCL6;BDNF;BLNK;BLR1(MDR15);BlyS;BMP1;BMP2;BMP3B(GDF10);BMP4;BMP6;BMP8;BMPR1A;BMPR1B;BMPR2;BPAG1(プレクチン);BRCA1;C19orf10(IL27w);C3;C4A;C5;C5R1;CANT1;CASP1;CASP4;CAV1;CCBP2(D6/JAB61);CCL1(1-309);CCL11(エオタキシン);CCL13(MCP-4);CCL15(MIP-1d);CCL16(HCC-4);CCL17(TARC);CCL18(PARC);CCL19(MIP-3b);CCL2(MCP-1);MCAF;CCL20(MIP-3a);CCL21(MIP-2);SLC;エクソダス-2;CCL22(MDC/STC-1);CCL23(MPIF-1);CCL24(MPIF-2/エオタキシン-2);CCL25(TECK);CCL26(エオタキシン-3);CCL27(CTACK/ILC);CCL28;CCL3(MIP-1a);CCL4(MIP-1b);CCL5(RANTES);CCL7(MCP-3);CCL8(mcp-2);CCNA1;CCNA2;CCND1;CCNE1;CCNE2;CCR1(CKR1/HM145);CCR2(mcp-1RB/RA);CCR3(CKR3/CMKBR3);CCR4;CCR5(CMKBR5/ChemR13);CCR6(CMKBR6/CKR-L3/STRL22/DRY6);CCR7(CKR7/EBI1);CCR8(CMKBR8/TER1/CKR-L1);CCR9(GPR-9-6);CCRL1(VSHK1);CCRL2(L-CCR);CD164;CD19;CD1C;CD20;CD200;CD-22;CD24;CD28;CD3;CD37;CD38;CD3E;CD3G;CD3Z;CD4;CD40;CD40L;CD44;CD45RB;CD52;CD69;CD72;CD74;CD79A;CD79B;CD8;CD80;CD81;CD83;CD86;CDH1(E-カドヘリン);CDH10;CDH12;CDH13;CDH18;CDH19;CDH20;CDH5;CDH7;CDH8;CDH9;CDK2;CDK3;CDK4;CDK5;CDK6;CDK7;CDK9;CDKN1A(p21Wap1/Cip1);CDKNIB(p27Kip1);CDKNIC;CDKN2A(pl6INK4a);CDKN2B;CDKN2C;CDKN3;CEBPB;CER1;CHGA;CHGB;キチナーゼ;CHST10;CKLFSF2;CKLFSF3;CKLFSF4;CKLFSF5;CKLFSF6;CKLFSF7;CKLFSF8;CLDN3;CLDN7(クローディン-7);CLN3;CXCL10(IP-10);CXCL11(I-TAC/IP-9);CXCL12(SDF1);CXCL13;CXCL14;CXCL16;CXCL2(GR02);CXCL3(GR03);CXCL5(ENA-78/LIX);CXCL6(GCP-2);CXCL9(MIG);CXCR3(GPR9/CKR-L2);CXCR4;CXCR6(TYMSTR/STRL33/Bonzo);CYB5;CYC1;CYSLTR1;CGRP;Clq;CIRタンパク質;CI;C4a;C4b;C2a;C2b;C3a;C3b;DAB2IP;DES;DKFZp451J0118;DNCL1;DPP4;E-セレクチン;E2F1;ECGF1;EDG1;EFNA1;EFNA3;EFNB2;EGF;EGFR;ELAC2;ENG;EN01;EN02;EN03;EPHB4;EPO;ERBB2(Her-2);EREG;ERK8;ESR1;ESR2;F3(TF);第VII因子;第IX因子;第V因子;第VIIa因子;第X因子;第XII因子;第XIII因子;FADD;FasL;FASN;FCER1A;FCER2;Fcガンマ受容体;FCGR3A;FGF;FGF1(aFGF);FGF10;FGF11;FGF12;FGF12B;FGF13;FGF14;FGF16;Fgf17;Fgf18;FGF19;FGF2(bFGF);FGF20;FGF21;FGF22;FGF23;FGF3(int-2);FGF4(HST);FGF5;FGF6(HST-2);FGF7(KGF);FGF8;FGF9;FGFR3;FIGF(VEGFD);FIL1(エプシロン);FIL1(ゼータ);FLJ12584;FLJ25530;FLRT1(フィブロネクチン);FLT1;FOS;FOSL1(FRA-1);FY(DARC);GABRP(GABAa);GAGEB1;GAGEC1;GALNAC4S-6ST;GATA3;GDF5;GFI1;GGT1;GMCSF;GNAS1;GNRH1;GPR2(CCR10);GPR31;GPR44;GPR81(FKSG80);GRCC10(CIO);GRP;GSN(ゲルソリン);GSTP1;糖タンパク質IIb;糖タンパク質IIIa;HAVCR2;HDAC4;HDAC5;HDAC7A;HDAC9;Her2;HGF;HIF1A;HIP1;ヒスタミン及びヒスタミン受容体;HLA-A;HLA-DRA;HM74;HMGB1;HMOX1;HUMCYT2A;ICEBERG;ICOSL;ID2;IFN-アルファ;IFNA1;IFNA2;IFNA4;IFNA5;IFNA6;IFNA7;IFNB1;IFN-ガンマ;IFNW1;IGBP1;IGF1;IGF1R;IGF2;IGFBP2;IGFBP3;IGFBP6;IL-1;IL1A;IL1B;IL10;IL10RA;IL10RB;IL11;IL11RA;IL-12;IL12A;IL12B;IL12RB1;IL12RB2;IL13;IL13RA1;IL13RA2;IL14;IL15;IL15RA;IL16;IL17;IL17B;IL17C;IL17R;IL18;IL18BP;IL18R1;IL18RAP;IL19;IL1A;IL1B;IL1F10;IL1F5;IL1F6;IL1F7;IL1F8;IL1F9;IL1HY1;IL1R1;IL1R2;IL1RAP;IL1RAPL1;IL1RAPL2;IL1RL1;IL1RL2;IL1RN;IL2;IL20;IL20RA;IL21R;IL22;IL22R;IL22RA2;IL23;IL24;IL25;IL26;IL27;IL28A;IL28B;IL29;IL2RA;IL2RB;IL2RG;IL3;IL30;IL3RA;IL4;IL4R;IL5;IL5RA;IL6;IL6R;IL6ST(糖タンパク質130);IL7;IL7R;IL8;IL8RA;IL8RB;IL8RB;IL9;IL9R;ILK;INHA;INHBA;INSL3;INSL4;IRAK1;IRAK2;ITGA1;ITGA2;ITGA3;ITGA6(a6インテグリン);ITGAV;ITGB3;ITGB4(b4インテグリン);JAG1;JAK1;JAK3;JUN;K6HF;KAI1;KDR;KITLG;KLF5(GC Box BP);KLF6;KLK10;KLK12;KLK13;KLK14;KLK15;KLK3;KLK4;KLK5;KLK6;KLK9;KRT1;KRT19(ケラチン19);KRT2A;KRTHB6(毛髪特異的タイプIIケラチン);L-セレクチン;LAMA5;LEP(レプチン);Lingo-p75;Lingo-Troy;LPS;LTA(TNF-b);LTB;LTB4R(GPR16);LTB4R2;LTBR;MACMARCKS;MAG又はOmgp;MAP2K7(c-Jun);MDK;MIB1;ミドカイン;MIF;MIP-2;MKI67(Ki-67);MMP2;MMP9;MS4A1;MSMB;MT3(メタロチオネクチン-III);MTSS1;MUC1(ムチン);MYC;MYD88;NCK2;ニューロカン;NKG2D;NFKB1;NFKB2;NGF;NGFB(NGF);NGFR;NgR-Lingo;NgR-Nogo66(Nogo);NgR-p75;NgR-Troy;NME1(NM23A);NOX5;NPPB;NR0B1;NR0B2;NR1D1;NR1D2;NR1H2;NR1H3;NR1H4;NRII2;NRII3;NR2C1;NR2C2;NR2E1;NR2E3;NR2F1;NR2F2;NR2F6;NR3C1;NR3C2;NR4A1;NR4A2;NR4A3;NR5A1;NR5A2;NR6A1;NRP1;NRP2;NT5E;NTN4;ODZ1;OPRD1;P2RX7;PAP;PARTI;PATE;PAWR;PCA3;PCNA;PDGFA;PDGFB;PECAM1;PF4(CXCL4);PGE2;PGF;PGR;ホスファカン;PIAS2;PIK3CG;プラスミノーゲンアクチベーター;PLAU(uPA);PLG;PLXDC1;PPBP(CXCL7);PPID;PR1;PRKCQ;PRKD1;PRL;PROC;プロテインC;PROK2;PSAP;PSCA;PTAFR;PTEN;PTGS2(COX-2);PTN;RAC2(p21Rac2);RAGE;RARB;RGS1;RGS13;RGS3;RNF110(ZNF144);ROB02;SI00A2;SCGB1D2(リポフィリンB);SCGB2A1(マンマグロビン2);SCGB2A2(マンマグロビン1);SCYE1(内皮性単球活性化サイトカイン);SDF2;SERPINA1;SERPINA3;SERPINB5(マスピン);SERPINE1(PAI-1);SERPINF1;SHBG;SLA2;SLC2A2;SLC33A1;SLC43A1;SLIT2;SPP1;SPRR1B(Spr1);ST6GAL1;STAB1;STAT6;STEAP;STEAP2;サブスタンスP;TB4R2;TBX21;TCP10;TDGF1;TEK;TGFA;TGFB1;TGFB111;TGFB2;TGFB3;TGFBI;TGFBR1;TGFBR2;TGFBR3;TH1L;THBS1(トロンボスポンジン-1);THBS2;THBS4;THPO;TIE(Tie-1);TIMP3;組織因子;TLR10;TLR2;TLR3;TLR4;TLR5;TLR6;TLR7;TLR8;TLR9;TNF-アルファ;TNFAIP2(B94);TNFAIP3;TNFRSF11A;TNFRSF1A;TNFRSF1B;TNFRSF21;TNFRSF5;TNFRSF6(Fas);TNFRSF7;TNFRSF8;TNFRSF9;TNFSF10(TRAIL);TNFSF11(TRANCE);TNFSF12(AP03L);TNFSF13(April);TNFSF13B;TNFSF14(HVEML);TNFSF15(VEGI);TNFSF18;TNFSF4(OX40リガンド);TNFSF5(CD40リガンド);TNFSF6(FasL);TNFSF7(CD27リガンド);TNFSF8(CD30リガンド);TNFSF9(4-1BBリガンド);TOLLIP;Toll様受容体;TOP2A(トポイソメラーゼIIa);TP53;TPM1;TPM2;TRADD;TRAF1;TRAF2;TRAF3;TRAF4;TRAF5;TRAF6;TREM1;TREM2;TRPC6;TSLP;TWEAK;トロンボモジュリン;トロンビン;VEGF;VEGFB;VEGFC;バーシカン;VHL C5;VLA-4;XCL1(リンホタクチン);XCL2(SCM-1b);XCR1(GPR5/CCXCR1);YY1;及びZFPM2から選択される
少なくとも1つの遺伝子によりコードされるタンパク質、タンパクの一部分、又はペプチドから選択される、請求項31に記載のaAb。 - 第1の抗原及び第2の抗原が、
同一の抗原である;
前記第1の抗原及び前記第2の抗原が異なる;又は
前記第1の抗原及び前記第2の抗原が同一の抗原であるが、第1の抗原結合部位及び第2の抗原結合部位が前記同一の抗原の異なるエピトープに結合する、
のうちの少なくとも1つに該当する、請求項32に記載のaAb。 - 第1の抗原結合部位又は第2の抗原結合部位が、腫瘍標的に結合する、請求項32に記載のaAb。
- 腫瘍標的が、腫瘍標的抗原、HER1、HER2、HER3、GD2、癌胎児抗原(CEA)、上皮増殖因子受容体活性ミュータント(EGFRVIII)、CD133、線維芽細胞活性化タンパク質アルファ(FAP)、上皮細胞接着分子(Epcam)、グリピカン3(GPC3)、EPH受容体A4(EphA)、チロシン-プロテインキナーゼMet(cMET)、IL-13Ra2、ミクロソームエポキシドヒドロラーゼ(mEH)、MAGE、メソテリン、MUC16、MUC1、前立腺幹細胞抗原(PSCA)、ウィルムス腫瘍-1(WT-1)、又はクローディンファミリーメンバーから選択される、請求項40に記載のaAb。
- 第1の抗原結合部位又は第2の抗原結合部位が、T細胞マーカーに結合する、請求項32に記載のaAb。
- T細胞マーカーが、CTLA4、PD-1、Lag3、S15、B7H3、B7H4、TCR-アルファ、TCR-ベータ、TIM-3から選択される、請求項42に記載のaAb。
- 第1の抗原結合部位又は第2の抗原結合部位が、T細胞アクチベーターに結合する、請求項32に記載のaAb。
- T細胞アクチベーターが、CD3、41BB、又はOX40から選択される、請求項44に記載のaAb。
- 切断可能リンカーが、プロテアーゼ切断可能リンカーである、請求項31に記載のaAb。
- 切断可能リンカーが、腫瘍関連プロテアーゼ:MMP1、MMP2、MMP3、MMP7、MMP9、MMP10、MMP11、MMP12、MMP13、MMP14、MMP15、MMP16、MMP17、MMP19、MMP20、MMP21、uPA、FAPa、又はカテプシンBにより切断される、請求項31に記載のaAb。
- 切断可能リンカーが、アポトーシス又は炎症関連応答期間中に上方制御されるプロテアーゼにより切断される、請求項31に記載のaAb。
- 切断可能リンカーが、カスパーゼにより切断される、請求項45に記載のaAb。
- カスパーゼが、カスパーゼ1、カスパーゼ2、カスパーゼ3、カスパーゼ4、カスパーゼ5、カスパーゼ6、カスパーゼ7、カスパーゼ8、カスパーゼ9、カスパーゼ10、カスパーゼ11、及びカスパーゼ12である、請求項49に記載のaAb。
- 切断可能リンカーが、抗原結合部位を遮蔽しない、請求項31に記載のaAb。
- aAbにコンジュゲートした薬剤をさらに含む、請求項31に記載のaAb。
- 薬剤が、毒素又はその毒性断片;微小管阻害剤;核酸ダメージング剤;検出可能部分;又は診断用薬剤のうちの少なくとも1つである、請求項52に記載のaAb。
- 配列番号1、2、又は3から選択される、請求項31に記載のaAb。
- 請求項1に記載のaAbをコードする核酸。
- 請求項31に記載のaAbをコードする核酸。
- 請求項1に記載のaAbをコードする核酸を含む細胞。
- 請求項31に記載のaAbをコードする核酸を含む細胞。
- 請求項1に記載の活性化可能なAbと、担体とを含む医薬組成物。
- 正常組織に対する抗体の結合活性を低下させ、及びがん細胞を標的とする方法であって、有効量の請求項1に記載の抗体を、それを必要としている対象に投与するステップを含む、前記方法。
- がんの症状を治療、緩和し、又はその進行を遅延させる方法であって、有効量の請求項1に記載の抗体を、それを必要としている対象に投与するステップを含む、前記方法。
- がんが、切断可能リンカーを切断する酵素を発現するがんである、請求項63に記載の方法。
- がんが、膀胱がん、骨がん、乳がん、癌様体、子宮頸がん、結腸がん、子宮内膜がん、神経膠腫、頭頸部がん、肝がん、肺がん、リンパ腫、黒色腫、卵巣がん、膵がん、前立腺がん、腎臓がん、肉腫、皮膚がん、胃がん、精巣がん、甲状腺がん、泌尿生殖器がん、又は尿路上皮がんから選択される、請求項63に記載の方法。
- がんが、急性骨髄性白血病、副腎皮質癌、B細胞リンパ腫、膀胱尿路上皮癌、乳房腺管癌、乳房小葉癌、食道の癌、去勢抵抗性前立腺がん(CRPC)、子宮頸癌、胆管癌、慢性骨髄性白血病、結腸直腸腺癌、結腸直腸がん(CRC)、食道癌、胃腺癌、多形膠芽細胞腫、頭頸部扁平上皮癌、ホジキンリンパ腫/原発性縦隔B細胞リンパ腫、肝細胞癌(HCC)、腎色素嫌性癌、腎明細胞癌、腎乳頭状細胞癌、低悪性度神経膠腫、肺腺癌、肺扁平上皮癌、黒色腫(MEL)、中皮腫、非扁平上皮NSCLC、卵巣漿液性腺癌、膵管腺癌、傍神経節腫及びクローム親和細胞腫、前立腺腺癌、腎細胞癌(RCC)、肉腫、皮膚黒色腫、頭頸部の扁平上皮癌、T細胞リンパ腫、胸腺腫、甲状腺乳頭状癌、子宮癌肉腫、子宮体類内膜癌、及びぶどう膜黒色腫からなる群から選択される、請求項63に記載の方法。
- 第1の可変軽鎖領域と、
切断可能リンカーと、
第1の可変重鎖領域と、
Fc領域と
を順に含む、活性化可能な抗体(aAb)であって、
前記切断可能リンカーが、前記第1の可変軽鎖領域及び前記第1の可変重鎖領域が第1の抗原に対して第1の抗原結合部位を形成することを防止し、
前記切断可能リンカーが、前記抗原結合部位を遮蔽せず、かつ
前記切断可能リンカーが切断されると、前記第1の可変重鎖領域が解放されて、第1の抗原に結合する前記第1の抗原結合部位の形成を可能にする、
前記aAb。 - 下記の構造:
第1の可変軽鎖領域を含む第1の軽鎖と、
切断可能リンカーと、
第1の可変重鎖領域を含む第1の重鎖と
を順に含む、活性化可能な抗体(aAb)を発現する細胞であって、
前記切断可能リンカーが、前記第1の軽鎖及び前記第1の重鎖が第1の抗原に対して第1の抗原結合部位を形成することを防止し又は低下させ、かつ
前記切断可能リンカーが切断されると、前記第1の重鎖が解放されて、第1の抗原に結合する前記第1の抗原結合部位の形成を可能にする、
前記細胞。 - T細胞又は間葉系幹細胞である、請求項68に記載の細胞。
- aAbが、前記aAbをT細胞の表面に係留してキメラ抗原受容体を形成する膜貫通配列をさらに含み、前記細胞が、CAR T細胞である、請求項68に記載の細胞。
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