JP2022126886A - Protac抗体コンジュゲート及び使用方法 - Google Patents
Protac抗体コンジュゲート及び使用方法 Download PDFInfo
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Abstract
Description
本出願は、2016年5月20日出願の米国仮特許出願第62/339,257号の優先権の利益を主張し、当該出願の内容はその内容が参照により本明細書に組み込まれる。
配列表の正式なコピーは、2016年5月20日作成の、SEQLIST.TXTと名付けた77キロバイトのサイズを有するファイルでASCII形式の配列表としてEFS-Webを介して電子的に提出され、本明細書と同時に提出されている。このASCII形式の文書に含まれる配列表は、本明細書の一部であり、その全体が参照により本明細書に組み込まれる。配列番号1~6は意図的に省略されている。
Ab-(L1-D)p
式中、Dは、構造E3LB-L2-PBを有するPROTACであり、E3LBは、L2に共有結合したE3リガーゼ結合基であり、L2は、E3LB及びPBに共有結合したリンカーであり、PBは、L2に共有結合したタンパク質結合基であり、Abは、L1に共有結合した抗体であり、L1は、Ab及びDに共有結合したリンカーであり、pは、約1~約8の値を有する。
特定の実施形態では、例えば、以下が提供される:
(項目1)
以下の化学構造を有するコンジュゲートであって、
Ab-(L1-D)p
式中、
Dは、構造E3LB-L2-PBを有するPROTACであり、
E3LBは、L2と共有結合したE3リガーゼ結合基であり、
L2は、E3LB及びPBと共有結合したリンカーであり、
PBは、L2と共有結合したタンパク質結合基であり、
Abは、L1と共有結合した抗体であり、
L1は、Ab及びDと共有結合したリンカーであり、
pは、約1~約8の値を有する、コンジュゲート。
(項目2)
E3LBが、E3リガーゼに結合する基であり、前記E3リガーゼが、表13~27に列挙されている、項目1に記載のコンジュゲート。
(項目3)
E3LBが、E3リガーゼに結合する基であり、前記E3リガーゼが、von Hippel-Lindau(VHL);セレブロン;XIAP;E3A;MDM2;後期促進複合体(APC);UBR5(EDD1);SOCS/BC-box/eloBC/CUL5/RING;LNXp80;CBX4;CBLL1;HACE1;HECTD1;HECTD2;HECTD3;HECW1;HECW2;HERC1;HERC2;HERC3;HERC4;HUWE1;ITCH;NEDD4;NEDD4L;PPIL2;PRPF19;PIAS1;PIAS2;PIAS3;PIAS4;RANBP2;RNF4;RBX1;SMURF1;SMURF2;STUB1;TOPORS;TRIP12;UBE3A;UBE3B;UBE3C;UBE4A;UBE4B;UBOX5;UBR5;WWP1;WWP2;Parkin;A20/TNFAIP3;AMFR/gp78;ARA54;ベータ-TrCP1/BTRC;BRCA1;CBL;CHIP/STUB1;E6;E6AP/UBE3A;F-boxタンパク質15/FBXO15;FBXW7/Cdc4;GRAIL/RNF128;HOIP/RNF31;cIAP-1/HIAP-2;cIAP-2/HIAP-1;cIAP(pan);ITCH/AIP4;KAP1;MARCH8;;Mind Bomb 1/MIB1;Mind Bomb 2/MIB2;MuRF1/TRIM63;NDFIP1;NEDD4;NleL;Parkin;RNF2;RNF4;RNF8;RNF168;RNF43;SART1;Skp2;SMURF2;TRAF-1;TRAF-2;TRAF-3;TRAF-4;TRAF-5;TRAF-6;TRIM5;TRIM21;TRIM32;UBR5;及びZNRF3からなる群から選択される、項目1に記載のコンジュゲート。
(項目4)
E3LBが、XIAP、VHL、セレブロン、及びMDM2からなる群から選択されるE3リガーゼに結合する基である、項目1に記載のコンジュゲート。
(項目5)
E3LBが、VHLに結合する化合物、VHLに結合するヒドロキシプロリン化合物、MDM2に結合する化合物、セレブロンに結合する化合物、テトラヒドロ-ベンゾジアゼピノン ナトリン、サリドマイド、レナリドマイド、及びポマリドマイドからなる群から選択される、項目1に記載のコンジュゲート。
(項目6)
E3LBが、以下の式を有するテトラヒドロ-ベンゾジアゼピノンであるXIAP阻害剤であり、
式中、R1、R2、R3、R4、及びR5が、WO/2015/071393に記載される通りである、項目1に記載のコンジュゲート。
(項目7)
PBが、FoxOl、HDAC、DP-1、E2F、ABL、AMPK、BRK、BRSK I、BRSK2、BTK、CAMKK1、CAMKKアルファ、CAMKKベータ、Rb、Suv39HI、SCF、p19INK4D、GSK-3、pi 8INK4、myc、サイクリンE、CDK2、CDK9、CDG4/6、サイクリンD、pl6 INK4A、cdc25A、BMI1、SCF、Akt、CHKl/2、C1デルタ、CK1ガンマ、C2、CLK2、CSK、DDR2、DYRK1A/2/3、EF2K、EPH-A2/A4/B1/B2/B3/B4、EIF2A 3、Smad2、Smad3、Smad4、Smad7、p53、p21 Cipl、PAX、Fyn、CAS、C3G、SOS、Tal、Raptor、RACK-1、CRK、Rapl、Rac、KRas、NRas、HRas、GRB2、FAK、PI3K、spred、Spry、mTOR、MPK、LKBl、PAK1/2/4/5/6、PDGFRA、PYK2、Src、SRPK1、PLC、PKC、PKA、PKBアルファ/ベータ、PKCアルファ/ガンマ/ゼータ、PKD、PLKl、PRAK、PRK2、RIPK2、WAVE-2、TSC2、DAPKl、BAD、IMP、C-TAK1、TAKl、TAOl、TBK1、TESK1、TGFBR1、TIE2、TLK1、TrkA、TSSK1、TTBK1/2、TTK、Tpl2/cotl、MEK1、MEK2、PLDL Erkl、Erk2、Erk5、Erk8、p90RSK、PEA-15、SRF、p27KIP1、TIF la、HMGN1、ER81、MKP-3、c-Fos、FGF-R1、GCK、GSK3ベータ、HER4、HIPK1/2/3/、IGF-1R、cdc25、UBF、LAMTOR2、Statl、StaO、CREB、JAK、Src、PTEN、NF-カッパB、HECTH9、Bax、HSP70、HSP90、Apaf-1、Cyto c、BCL-2、Bcl-xL、Smac、XIAP、カスパーゼ-9、カスパーゼ-3、カスパーゼ-6、カスパーゼ-7、CDC37、TAB、IKK、TRADD、TRAF2、R1P1、FLIP、TAKl、JNKl/2/3、Lck、A-Raf、B-Raf、C-Raf、MOS、MLKl/3、MN l/2、MSKl、MST2/3/4、MPSK1、MEKKl、ME K4、MEL、ASK1、MINK1、MKK1/2/3/4/6/7、NE2a/6/7、NUAK1、OSR1、SAP、STK33、Syk、Lyn、PDK1、PHK、PIM1/2/3、アタキシン-1、mTORCl、MDM2、p21Wafl、サイクリンDl、Lamln A、Tpl2、Myc、カテニン、Wnt、IKK-ベータ、IKK-ガンマ、IKK-アルファ、IKK-エプシロン、ELK、p65RelA、IRAKI、IRA2、IRAK4、IRR、FADD、TRAF6、TRAF3、MKK3、MKK6、ROCK2、RSK1/2、SGK1、SmMLCK、SIK2/3、ULK1/2、VEGFR1、WNKl、YES1、ZAP70、MAP4K3、MAP4K5、MAPKlb、MAPKAP-K2 K3、p38アルファ/ベータ/デルタ/ガンマMAPK、オーロラA、オーロラB、オーロラC、MCAK、Clip、MAPKAPK、FAK、MARK1/2/3/4、Mucl、SHC、CXCR4、Gap-1、Myc、ベータ-カテニン/TCF、Cbl、BRM、Mcl1、BRD2、BRD3、BRD4、AR、RAS、ErbB3、EGFR、IRE1、HPK1、RIPK2、及びERα(これらの全てのバリアント、変異、スプライスバリアント、インデル、及び融合体を含む)に結合する基である、項目1に記載のコンジュゲート。
(項目8)
PBが、熱ショックタンパク質90(HSP90)阻害剤、キナーゼ及びホスファターゼ阻害剤、MDM2阻害剤、HDAC阻害剤、ヒトリジンメチルトランスフェラーゼ阻害剤、血管新生阻害剤、免疫抑制化合物、ならびにヒトBETブロモドメイン含有タンパク質、アリール炭化水素受容体(AHR)、REF受容体キナーゼ、FKBP、アンドロゲン受容体(AR)、エストロゲン受容体(ER)、甲状腺ホルモン受容体、HIVプロテアーゼ、HIVインテグラーゼ、HCVプロテアーゼ、及びアシル-タンパク質チオエステラーゼ-1及び-2(APT1及びAPT2)を標的とする化合物からなる群から選択される、項目1に記載のコンジュゲート。
(項目9)
PBが、エストロゲン受容体アルファ(ERa)を標的とする基である、項目1に記載のコンジュゲート。
(項目10)
前記Abが、システイン操作された抗体またはそのバリアントである、項目1に記載のコンジュゲート。
(項目11)
Abが、DLL3、EDAR、CLL1;BMPR1B;E16;STEAP1;0772P;MPF;NaPi2b;Sema5b;PSCA hlg;ETBR;MSG783;STEAP2;TrpM4;CRIPTO;CD21;CD79b;FcRH2;B7-H4;HER2;NCA;MDP;IL20Rα;ブレビカン;EphB2R;ASLG659;PSCA;GEDA;BAFF-R;CD22;CD79a;CXCR5;HLA-DOB;P2X5;CD72;LY64;FcRH1;IRTA2;TENB2;PMEL17;TMEFF1;GDNF-Ra1;Ly6E;TMEM46;Ly6G6D;LGR5;RET;LY6K;GPR19;GPR54;ASPHD1;チロシナーゼ;TMEM118;GPR172A;MUC16及びCD33からなる群から選択されるポリペプチドのうちの1つ以上に結合する、項目1に記載のコンジュゲート。
(項目12)
Abが、CLL1、STEAP1、NaPi2b、STEAP2、TrpM4、CRIPTO、CD21、CD79b、FcRH2、B7-H4、HER2、CD22、CD79a、CD72、LY64、Ly6E、MUC16、及びCD33からなる群から選択されるポリペプチドのうちの1つ以上に結合する、項目10に記載のコンジュゲート。
(項目13)
Abが、B7-H4、HER2、CLL1、CD33、CD22、及びNaPi2bからなる群から選択されるポリペプチドのうちの1つ以上に結合する抗体である、項目12に記載のコンジュゲート。
(項目14)
前記抗体が、HER2またはB7-H4に結合する、項目12に記載のコンジュゲート。
(項目15)
前記抗体が、HER2に結合する、項目14に記載のコンジュゲート。
(項目16)
L1が、ペプチド模倣リンカーである、項目1に記載のコンジュゲート。
(項目17)
L1が、以下の式によって表されるペプチド模倣リンカーであり、
-Str-(PM)-Sp-
式中、
Strは、Abに共有結合したストレッチャー単位であり、
Abは、抗体であり、
Spは、PROTAC部分に共有結合した結合またはスペーサ単位であり、
PMは、以下からなる群から選択される非ペプチド化学部分であり、
Wは、-NH-ヘテロシクロアルキル-またはヘテロシクロアルキルであり、
Yは、ヘテロアリール、アリール、-C(O)C1-C6アルキレン、C1-C6アルキレン-NH2、C1-C6アルキレン-NH-CH3、C1-C6アルキレン-N-(CH3)2、C1-C6アルケニル、またはC1-C6アルキレニルであり、
各R1は独立して、C1-C10アルキル、C1-C10アルケニル、(C1-C6アルキル)NHC(NH)NH2、(C1-C6アルキル)NHC(O)NH2、(C1-C10アルキル)NHC(NH)NH2、または(C1-C10アルキル)NHC(O)NH2であり、
R3及びR2は各々独立して、H、C1-C10アルキル、C1-C10アルケニル、アリールアルキル、もしくはヘテロアリールアルキルであるか、またはR3及びR2は一緒になってC3-C7シクロアルキルを形成してもよく、
R4及びR5は各々独立して、C1-C10アルキル、C1-C10アルケニル、アリールアルキル、ヘテロアリールアルキル、(C1-C10アルキル)OCH2-であるか、またはR4及びR5は一緒になってC3-C7シクロアルキル環を形成してもよい、項目16に記載のコンジュゲート。
(項目18)
Yが、ヘテロアリールであり、R4及びR5が一緒になってシクロブチル環を形成する、項目17に記載のコンジュゲート。
(項目19)
Yが、以下からなる群から選択される部分である、項目17に記載のコンジュゲート。
(項目20)
Strは、以下の式によって表される化学部分であり、
式中、R6は、C1-C10アルキレン、C1-C10アルケニル、C3-C8シクロアルキル、(C1-C8アルキレン)O-、及びC1-C10アルキレン-C(O)N(Ra)-C2-C6アルキレンからなる群から選択され、各アルキレンは、ハロ、トリフルオロメチル、ジフルオロメチル、アミノ、アルキルアミノ、シアノ、スルホニル、スルホンアミド、スルホキシド、ヒドロキシ、アルコキシ、エステル、カルボン酸、アルキルチオ、C3-C8シクロアルキル、C4-C7ヘテロシクロアルキル、ヘテロアリールアルキル、アリールアリールアルキル、ヘテロアリールアルキル、及びヘテロアリールからなる群から選択される1~5個の置換基によって置換されてもよく、各Raは独立して、HまたはC1-C6アルキルであり、
Spは、-C1-C6アルキレン-C(O)NH-または-Ar-Rb-であり、Arは、アリールまたはヘテロアリールであり、Rbは、(C1-C10アルキレン)O-である、項目17に記載のコンジュゲート。
(項目21)
Strが、以下の式を有し、
式中、R7は、C1-C10アルキレン、C1-C10アルケニル、(C1-C10アルキレン)O-、N(Rc)-(C2-C6アルキレン)-N(Rc)、及びN(Rc)-(C2-C6アルキレン)から選択され、各Rcは独立して、HまたはC1-C6アルキルであり、
Spは、-C1-C6アルキレン-C(O)NH-または-Ar-Rb-であり、Arは、アリールまたはヘテロアリールであり、Rbは、(C1-C10アルキレン)O-である、項目17に記載のコンジュゲート。
(項目22)
L1が、以下の式を有し、
式中、R1は、C1-C6アルキル、C1-C6アルケニル、(C1-C6アルキル)NHC(NH)NH2または(C1-C6アルキル)NHC(O)NH2であり、
R3及びR2は各々独立して、H、C1-C10アルキルである、項目17に記載のコンジュゲート。
(項目23)
L1が、以下の式を有し、
R1は、C1-C6アルキル、(C1-C6アルキル)NHC(NH)NH2、または(C1-C6アルキル)NHC(O)NH2であり、
R4及びR5は一緒になってC3-C7シクロアルキル環を形成する、項目17に記載のコンジュゲート。
(項目24)
L1が、以下の式を有し、
R1は、C1-C6アルキル、(C1-C6アルキル)NHC(NH)NH2、または(C1-C6アルキル)NHC(O)NH2である、項目17に記載のコンジュゲート。
(項目25)
以下の式を有し、
式中、
Spは、PROTAC部分Dに共有結合した結合またはスペーサ単位であり、
Yは、ヘテロアリール、アリール、-C(O)C1-C6アルキレン、C1-C6アルキレン-NH2、C1-C6アルキレン-NH-CH3、C1-C6アルキレン-N-(CH3)2、C1-C6アルケニル、またはC1-C6アルキレニルであり、
R1は独立して、C1-C10アルキル、C1-C10アルケニル、(C1-C6アルキル)NHC(NH)NH2、(C1-C6アルキル)NHC(O)NH2、(C1-C10アルキル)NHC(NH)NH2、または(C1-C10アルキル)NHC(O)NH2であり、
R3及びR2は各々独立して、H、C1-C10アルキル、C1-C10アルケニル、アリールアルキル、もしくはヘテロアリールアルキルであるか、またはR3及びR2は一緒になってC3-C7シクロアルキルを形成してもよく、
Strは、以下の式によって表される化学部分であり、
R6は、C1-C10アルキレン及びC1-C10アルキレン-C(O)N(Ra)-C2-C6アルキレンからなる群から選択され、各アルキレンは、ハロ、トリフルオロメチル、ジフルオロメチル、アミノ、アルキルアミノ、シアノ、スルホニル、スルホンアミド、スルホキシド、ヒドロキシ、アルコキシ、エステル、カルボン酸、アルキルチオ、C3-C8シクロアルキル、C4-C7ヘテロシクロアルキル、ヘテロアリールアルキル、アリール、アリールアルキル、ヘテロアリールアルキル、及びヘテロアリールからなる群から選択される1~5個の置換基によって置換されてもよく、各Raは独立して、HまたはC1-C6アルキルであり、pは、1、2、3、または4である、項目1に記載のコンジュゲート。
(項目26)
以下を有し、
式中、
Spは、PROTAC部分Dに共有結合した結合またはスペーサ単位であり、
R4及びR5は各々独立して、C1-C10アルキル、C1-C10アルケニル、アリールアルキル、ヘテロアリールアルキル、(C1-C10アルキル)OCH2-であるか、またはR4及びR5は一緒になってC3-C7シクロアルキル環を形成してもよく、
R1は独立して、C1-C10アルキル、C1-C10アルケニル、(C1-C6アルキル)NHC(NH)NH2、(C1-C6アルキル)NHC(O)NH2、(C1-C10アルキル)NHC(NH)NH2、または(C1-C10アルキル)NHC(O)NH2であり、
Strは、以下の式によって表される化学部分であり、
R6は、C1-C10アルキレン及びC1-C10アルキレン-C(O)N(Ra)-C2-C6アルキレンからなる群から選択され、各アルキレンは、ハロ、トリフルオロメチル、ジフルオロメチル、アミノ、アルキルアミノ、シアノ、スルホニル、スルホンアミド、スルホキシド、ヒドロキシ、アルコキシ、エステル、カルボン酸、アルキルチオ、C3-C8シクロアルキル、C4-C7ヘテロシクロアルキル、アリール、アリールアルキル、ヘテロアリールアルキル、及びヘテロアリールからなる群から選択される1~5個の置換基によって置換されてもよく、各Raは独立して、HまたはC1-C6アルキルであり、pは、1、2、3、または4である、項目1に記載のコンジュゲート。
(項目27)
Yが、ヘテロアリール、アリール、またはアルケニルであり、R6が、C1-C10アルキレンである、項目25に記載のコンジュゲート。
(項目28)
Yが、以下である、項目25に記載のコンジュゲート。
(項目29)
Yが、以下である、項目25に記載のコンジュゲート。
(項目30)
Yが、以下である、項目25に記載のコンジュゲート。
(項目31)
Strは、以下の式によって表される化学部分であり、
R6は、C1-C6アルキレンであり、
Spは、-C1-C6アルキレン-C(O)NH-または-Ar-Rb-であり、Arは、アリールであり、Rbは、(C1-C3アルキレン)O-である、項目25に記載のコンジュゲート。
(項目32)
以下の式を有し、
式中、
Yは、ヘテロアリール、アリール、-C(O)C1-C6アルキレン、C1-C6アルキレン-NH2、C1-C6アルキレン-NH-CH3、C1-C6アルキレン-N-(CH3)2、C1-C6アルケニル、またはC1-C6アルキレニルであり、
R1は、C1-C6アルキル-NH2、(C1-C6アルキル)NHC(NH)NH2、または(C1-C6アルキル)NHC(O)NH2であり、
R3及びR2は各々独立して、H、C1-C10アルキル、C1-C10アルケニル、アリールアルキル、もしくはヘテロアリールアルキルであるか、またはR3及びR2は一緒になってC3-C7シクロアルキルを形成してもよく、
pは、1、2、3、または4である、項目1に記載のコンジュゲート。
(項目33)
以下の式を有し、
式中、
pは、1、2、3、または4であり、
R1は、C1-C6アルキル-NH2、(C1-C6アルキル)NHC(NH)NH2、または(C1-C6アルキル)NHC(O)NH2であり、
R4及びR5は各々独立して、C1-C6アルキルであり、前記アルキルは、非置換であるか、またはR4及びR5は、C3-C7シクロアルキル環を形成してもよい、項目1に記載のコンジュゲート。
(項目34)
L1が以下の式を有し、
式中、R1及びR2は独立して、H及びC1-C6アルキルから選択されるか、またはR1及びR2は、3、4、5、もしくは6員シクロアルキルもしくはヘテロシクリル基を形成する、項目1に記載のコンジュゲート。
(項目35)
PAC1、PAC2、PAC3、PAC4、及びPAC5からなる群から選択される、項目1に記載のコンジュゲート。
(項目36)
pが、約1.0~約3である、項目1に記載のコンジュゲート。
(項目37)
pが、約2である、項目1に記載のコンジュゲート。
(項目38)
項目1に記載のコンジュゲートと、1つ以上の薬学的に許容される賦形剤とを含む、薬学的組成物。
(項目39)
治療を必要とするヒトにおける疾患を治療する方法であって、有効量の項目1に記載のコンジュゲートまたは項目38に記載の組成物を前記ヒトに投与することを含む、方法。(項目40)
前記疾患が癌である、項目39に記載の方法。
(項目41)
前記癌が、癌腫、リンパ腫、芽細胞腫、肉腫、白血病、リンパ系腫瘍、扁平上皮癌、小細胞肺癌、非小細胞肺癌、肺の腺癌、及び肺の扁平上皮癌を含む肺癌、腹膜の癌、肝細胞癌、胃腸癌を含む胃癌(gastric cancer)または胃癌(stomach cancer)、膵臓癌、膠芽腫、子宮頸癌、卵巣癌、肝臓癌、膀胱癌、肝細胞腫、乳癌、結腸癌、直腸癌、結腸直腸癌、子宮内膜癌または子宮癌、唾液腺癌、腎臓癌(kidney cancer)または腎臓癌(renal cancer)、前立腺癌、外陰癌、甲状腺癌、肝癌、肛門癌、陰茎癌、ならびに頭頚部癌からなる群から選択される、項目40に記載の方法。
(項目42)
前記癌が、HER2陽性の癌である、項目41に記載の方法。
(項目43)
前記HER2陽性の癌が、乳癌または胃癌である、項目42に記載の方法。
(項目44)
前記疾患が、自己免疫疾患である、項目39に記載の方法。
(項目45)
前記自己免疫疾患が、リウマチ学的障害、骨関節炎、自己免疫胃腸障害及び肝臓障害、血管炎、自己免疫神経障害、腎障害、自己免疫皮膚障害、血液疾患、アテローム性動脈硬化、ブドウ膜炎、自己免疫聴覚疾患、ベーチェット病、レイノー症候群、臓器移植、自己免疫内分泌障害、アジソン病、ならびに自己免疫甲状腺疾患からなる群から選択される、項目44に記載の方法。
(項目46)
前記自己免疫疾患が、リウマチ性関節炎、潰瘍性大腸炎、ANCA関連血管炎、ループス、多発性硬化症、シェーグレン症候群、グレーブス病、IDDM、悪性貧血、甲状腺炎、及び糸球体腎炎からなる群から選択される、項目45に記載の方法。
「PROTAC」という用語は、概して3つの構成要素、E3ユビキチンリガーゼ結合基(E3LB)、リンカーL2、及びタンパク質結合基(PB)を有するタンパク質分解標的キメラ分子を指す。
al(1975)Nature,256:495によって最初に記載されたハイブリドーマ法によって作製され得るか、または組み換えDNA法(例えば、US4816567;US5807715を参照されたい)によって作製され得る。モノクローナル抗体はまた、例えば、Clackson et al(1991)Nature,352:624-628;Marks et al(1991)J.Mol.Biol.,222:581-597に記載される技術を使用して、ファージ抗体ライブラリから単離されてもよい。
100×分数X/Y
式中、Xは、配列アラインメントプログラムALIGN-2によってA及びBのそのプログラムの配列において同一の一致としてスコア化されたアミノ酸残基の数であり、Yは、Bにおけるアミノ酸残基の総数である。アミノ酸配列Aの長さがアミノ酸配列Bの長さと等しくない場合、A対Bのアミノ酸配列同一性%は、B対Aのアミノ酸配列同一性%と等しくならないことが理解されよう。別途明記されない限り、本明細書に使用される全てのアミノ酸配列同一性%値は、直前の段落にに際されるようにALIGN-2コンピュータプログラムを使用して得られる。
et al(1998)J.Immunol.161:4083-4090;Lund
et al(2000)Eur.J.Biochem.267:7246-7256;US2005/0048572;US2004/0229310)が含まれる。
Chemistry of Heterocyclic Compounds,A series of Monographs」(John Wiley&Sons,New
York,1950to present)、特に第13、14、16、19、及び28環;ならびにJ.Am.Chem.Soc.(1960)82:5566に記載されている。「ヘテロシクリル」はまた、複素環基が、飽和、部分不飽和環、または芳香族炭素環式環もしくは複素環式環に縮合されている基も含む。複素環式環の例としては、モルホリン-4-イル、ピペリジン-1-イル、ピペラジニル、ピペラジン-4-イル-2-オン、ピペラジン-4-イル-3-オン、ピロリジン-1-イル、チオモルホリン-4-イル、S-ジオキソチオモルホリン-4-イル、アゾカン-1-イル、アゼチジン-1-イル、オクタヒドロピリド[1,2-a]ピラジン-2-イル、[1,4]ジアゼパン-1-イル、ピロリジニル、テトラヒドロフラニル、ジヒドロフラニル、テトラヒドロチエニル、テトラヒドロピラニル、ジヒドロピラニル、テトラヒドロチオピラニル、ピペリジノ、モルホリノ、チオモルホリノ、チオキサニル、ピペラジニル、ホモピペラジニル、アゼチジニル、オキセタニル、チエタニル、ホモピペリジニル、オキセパニル、チエパニル、オキサゼピニル、ジアゼピニル、チアゼピニル、2-ピロリニル、3-ピロリニル、インドリニル、2H-ピラニル、4H-ピラニル、ジオキサニル、1,3-ジオキソラニル、ピラゾリニル、ジチアニル、ジチオラニル、ジヒドロピラニル、ジヒドロチエニル、ジヒドロフラニル、ピラゾリジニルイミダゾリニル、イミダゾリジニル、3-アザビシコ(azabicyco)[3.1.0]ヘキサニル、3-アザビシクロ[4.1.0]ヘプタニル、アザビシクロ[2.2.2]ヘキサニル、3H-インドリルキノリジニル、及びN-ピリジル尿素が挙げられるが、これらに限定されない。スピロ部分もまた、この定義の範囲内に含まれる。2個の環原子がオキソ(=O)部分で置換されている複素環基の例は、ピリミジノニル及び1,1-ジオキソ-チオモルホリニルである。本明細書の複素環基は、任意に、本明細書に記載される1つ以上の置換基で独立して置換される。
of Organic Compounds(1994)John Wiley & Sons,Inc.,New Yorkに従う。多くの有機化合物は、光学活性形態で存在し、すなわち、それらは、平面偏光の平面を回転させる能力を有する。光学活性化合物を説明する際、接頭辞D及びLまたはR及びSは、そのキラル中心(複数可)の周りでの分子の絶対配置を示すために使用される。接頭辞d及びlまたは(+)及び(-)は、化合物による平面偏光の回転の印を示すために用いられ、(-)または1は、化合物が左旋性であることを意味する。(+)またはdの接頭辞を有する化合物は、右旋性である。所与の化学構造について、これらの立体異性体は、それらが互いの鏡像であるということ以外、同一である。特定の立体異性体はまた、エナンチオマーと称される場合があり、かかる異性体の混合物はしばしば、エナンチオマー混合物と呼ばれる。エナンチオマーの50:50混合物は、ラセミ混合物またはラセミ体と称され、これは、化学反応またはプロセスにおいて立体選択または立体特異性がなかった場合に生じ得る。「ラセミ混合物」及び「ラセミ体」という用語は、光学活性を欠く2つのエナンチオマー種の等モル混合物を指す。
本明細書に記載されるPROTAC-抗体コンジュゲート(PAC)分子は、リンカー(L1)を介してPROTACにコンジュゲートされた抗体を含み、PROTACは、ユビキチンE3リガーゼ結合基(「E3LB」)、リンカー(「L2」)、及びタンパク質結合基(「PB」)を含む。PACの一般式は、以下であり、
Ab-(L1-D)p
式中、Dは、構造E3LB-L2-PBを有するPROTACであり、E3LBは、L2に共有結合したE3リガーゼ結合基であり、L2は、E3LB及びPBに共有結合したリンカーであり、PBは、L2に共有結合したタンパク質結合基であり、Abは、L1に共有結合した抗体であり、L1は、Ab及びDに共有結合したリンカーであり、pは、約1~約50の値を有する。変数pは、抗体が1つ以上のL1-D基と結合し得ることを反映する。一実施形態では、pは、約1~8である。別の実施形態では、pは、約2である。
本明細書に記載されるように、抗体、例えば、モノクローナル抗体(mAB)は、標的細胞、例えば、抗体によって標的とされる特異的タンパク質を発現する細胞へとPROTACを送達するために使用される。PACの抗体部分は、抗原を発現する細胞を標的とすることができ、それにより、抗原特異PACは、典型的にはエンドサイトーシスを通して標的細胞へと細胞内送達される。細胞表面上に見られない抗原に対する抗体を含むPACは、PROTAC部分の細胞内へのより少ない特異的細胞内送達をもたらし得る一方、PACはなおも飲作用を受けている場合がある。本明細書に記載されるPAC及びそれらの使用方法は、細胞表面の抗体認識及び/またはPACのエンドサイトーシスを有利に利用して、PROTAC部分を細胞の内部に送達する。
ある特定の実施形態では、本明細書に提供される抗体は、ヒト抗体である。ヒト抗体は、当該技術分野で既知の様々な技術を使用して産生され得る。ヒト抗体は、一般に、van Dijk and van de Winkel,Curr.Opin.Pharmacol.5 : 368-74(2001)及びLonberg,Curr.Opin
.Immunol.20:450-459(2008)に記載されている。
et al.,Proc.Natl.Acad.Sci.USA,103:3557-3562(2006)に記載されている。さらなる方法には、例えば、米国特許第7,189,826号(ハイブリドーマ細胞株からのヒトIgM抗体の産生について記載)及びNi,Xiandai Mianyixue,26(4):265-268(2006)(ヒト-ヒトハイブリドーマについて記載)に記載されるものが含まれる。ヒトハイブリドーマ技術(トリオーマ技術)はまた、Vollmers and Brandlein,Histology and Histopathology,20(3):927-937(2005)及びVollmers and Brandlein,Methods and Findings in Experimental and Clinical Pharmacology,27(3):185-91(2005)にも記載されている。
PACにおける使用のための抗体は、所望の活性(複数可)を有する抗体についてコンビナトリアルライブラリをスクリーニングすることによって単離され得る。例えば、ファージディスプレイライブラリを生成し、所望の結合特性を保有する抗体についてかかるライブラリをスクリーニングするための多様な方法が当該技術分野で既知である。かかる方法は、例えば、Hoogenboom et al.Methods in Molecular Biology178:1-37(O’Brien et al.,ed.,Human Press,Totowa,NJ,2001)に概説され、例えば、McCafferty et al.,Nature348:552-554;Clackson et al.,Nature352:624-628(1991);Marks et al.,J.Mol.Biol.222:581-597(1992);Marks
and Bradbury,Methods in Molecular Biology248:161-175(Lo,ed.,Human Press,Totowa,NJ,2003);Sidhu et al.,J.Mol.Biol.338(2):299-310(2004);Lee et al.,J.Mol.Biol.340(5):1073-1093(2004);Fellouse,Proc.Natl.Acad.Sci.USA101(34):12467-12472(2004);及びLee et al.,J.Immunol.Methods284(1-2):119-132(2004)にさらに記載されている。
ある特定の実施形態では、本明細書に提供される抗体は、キメラ抗体である。ある特定のキメラ抗体は、例えば、米国特許第4,816,567号、及びMorrison et al.,Proc.Natl.Acad.Sci.USA,81:6851-6855(1984))に記載されている。一例において、キメラ抗体は、非ヒト可変領域(例えば、マウス、ラット、ハムスター、ウサギ、またはサルなどの非ヒト霊長類に由来する可変領域)及びヒト定常領域を含む。さらなる例において、キメラ抗体は、親抗体からクラスまたはサブクラスが変わった抗体である、「クラススイッチ」抗体である。キメラ抗体には、その抗原結合断片が含まれる。
ある特定の実施形態では、本明細書に提供される抗体は、多重特異性抗体、例えば、二重特異性抗体である。「多重特異性抗体」という用語は、本明細書で使用される場合、ポリエピトープ特異性を有する(すなわち、1つの分子上の2つ以上の異なるエピトープに結合することができるか、または2つ以上の異なる分子上のエピトープに結合することができる)抗原結合ドメインを含む抗体を指す。
et al.,EMBO J.10:3655(1991)を参照されたい)、ならびに「ノブ・イン・ホール」操作(例えば、米国特許第5,731,168号、WO2009/089004、US2009/0182127、US2011/0287009、Marvin and Zhu,Acta Pharmacol.Sin.(2005)26(6):649-658、及びKontermann(2005)Acta Pharmacol.Sin.,26:1-9を参照されたい)が含まれるが、これらに限定されない。「ノブ・イン・ホール」または「KnH」技術という用語は、本明細書で使用される場合、それらが相互作用する界面において隆起(ノブ)を一方のポリペプチド内に、及び空洞(ホール)を他方のポリペプチド内に導入することによって、2つのポリペプチドのインビトロまたはインビボを共に対形成することを指示する技術を指す。例えば、KnHは、抗体のFc:Fc結合面、CL:CH1結合面、またはVH/VL界面において導入されている(例えば、US2011/0287009、US2007/0178552、WO96/027011、WO98/050431、Zhu et al.,1997,Protein Science6:781-788、及びWO2012/106587を参照されたい)。いくつかの実施形態では、KnHは、多重特異性抗体の製造中に、2つの異なる重鎖を共に対形成することを駆動する。例えば、それらのFc領域中にKnHを有する多重特異性抗体は、各Fc領域に結合した単一の可変ドメインをさらに含み得るか、または類似のまたは異なる軽鎖可変ドメインと対形成する異なる重鎖可変ドメインをさらに含み得る。KnH技術はまた、2つの異なる受容体細胞外ドメインを共に、または異なる標的認識配列を含む任意の他のポリペプチド配列(例えば、アフィボディ、ペプチボディ、及び他のFc融合)を対形成するために使用され得る。
ある特定の実施形態では、本明細書に提供される抗体は、抗体断片である。抗体断片には、Fab、Fab’、Fab’-SH、F(ab’)2、Fv、及びscFv断片、ならびに以下に記載される他の断片が含まれるが、これらに限定されない。ある特定の抗体断片の概説については、Hudson et al.Nat.Med.9:129-134(2003)を参照されたい。scFv断片の概説については、例えば、Pluckthuen,The Pharmacology of Monoclonal抗体,vol.113、Rosenburg and Moore eds.,(Springer-Verlag,New York),pp.269-315(1994)を参照されたい。WO93/16185、ならびに米国特許第5,571,894号及び同第5,587,458号も参照されたい。サルベージ受容体結合エピトープ残基を含み、増加したインビボ半減期を有するFab及びF(ab’)2断片の考察については、米国特許第5,869,046号を参照されたい。
ある特定の実施形態では、本明細書に提供される抗体のアミノ酸配列バリアントが企図される。例えば、抗体の結合親和性及び/または他の生物学的特性を改善することが望ましい場合がある。抗体のアミノ酸配列バリアントは、抗体をコードするヌクレオチド配列中に適切な修飾を導入することによって、またはペプチド合成によって調製され得る。かかる修飾には、例えば、抗体のアミノ酸配列からの欠失、及び/またはそこへの挿入、及び/またはその中での残基の置換が含まれる。欠失、挿入、及び置換を任意に組み合わせて最終構築物に到達することができるが、但し、最終構築物が所望の特性、例えば抗原結合を保有することを条件とする。
ある特定の実施形態では、1つ以上のアミノ酸置換を有する抗体バリアントが提供される。置換型辺誘発のための目的の部位には、HVR及びFRが含まれる。保存的置換は、「好ましい置換」という見出しの下で表1に示される。より多くの置換型変化が「例示的な置換」という見出しの下で表1に提供され、アミノ酸側鎖クラスに関連して以下にさらに記載される。アミノ酸置換が目的の抗体中に導入され得、生成物は、所望の活性、例えば、保持/改善された抗原結合、低下した免疫原性、または改善された抗体依存性細胞傷害(ADCC)もしくは保体依存性細胞傷害(CDC)についてスクリーニングされ得る。
アミノ酸は、一般的な側鎖特性に従って群分けされ得る:
(1)疎水性:ノルロイシン、Met、Ala、Val、Leu、Ile;
(2)中性親水性:Cys、Ser、Thr、Asn、Gln;
(3)酸性:Asp、Glu;
(4)塩基性:His、Lys、Arg;
(5)鎖の配向に影響を及ぼす残基:Gly、Pro;
(6)芳香族:Trp、Tyr、Phe。
ある特定の実施形態では、システイン操作された抗体、例えば、抗体の1つ以上の残基がシステイン残基で置換されている「THIOMAB(商標)抗体」を作製することが望ましい場合がある。特定の実施形態では、置換された残基は、抗体の利用可能な部位で生じる。これらの残基をシステインで置換することによって、反応性チオール基がそれにより抗体の利用可能な部位に位置付けられ、抗体をL1-PROTAC基などの他の部分にコンジュゲートするために使用して、本明細書にさらに記載されるようにPACを作製することができる。ある特定の実施形態では、以下の残基のうちの1つ以上がシステインで置換され得る:軽鎖のV205(Kabat付番);重鎖のA140(EU付番);重鎖のL174(EU付番);重鎖のY373(EU付番);軽鎖のK149(Kabat付番);重鎖のA118(EU付番);及び重鎖Fc領域のS400(EU付番)。特定の実施形態では、本明細書に記載される抗体は、HC-A140C(EU付番)システイン置換を含む。特定の実施形態では、本明細書に記載される抗体は、LC-K149C(Kabat付番)システイン置換を含む。特定の実施形態では、本明細書に記載される抗体は、HC-A118C(EU付番)システイン置換を含む。
ある特定の実施形態では、本明細書に提供される抗体は、抗体が糖鎖付加される程度を増加または減少させるために改変されている。抗体への糖鎖付加部位の付加または欠失は、1つ以上の糖鎖付加部位が作製または除去されるようにアミノ酸を改変することによって好都合に達成され得る。
ある特定の実施形態では、1つ以上のアミノ酸修飾は、本明細書に提供される抗体のFc領域内に導入され、それによってFc領域バリアントを生成し得る。Fc領域バリアントは、1つ以上のアミノ酸位置におけるアミノ酸修飾(例えば、置換)を含むヒトFc領域配列(例えば、ヒトIgG1、IgG2、IgG3、またはIgG4Fc領域)を含んでもよい。
Acad.Sci.USA82:1499-1502(1985);5,821,337(Bruggemann,M.et al.,J.Exp.「Med.」166:1351-1361(1987)を参照されたい)に記載されている。代替的には、非放射性アッセイ法を用いてもよい(例えば、フローサイトメトリーのためのACTI(商標)非放射性細胞傷害性アッセイ(CellTechnology,Inc.(Mountain View,CA)及びCytoTox96(登録商標)非放射性細胞傷害性アッセイ(Promega(Madison,WI))を参照されたい。かかるアッセイのために有用なエフェクター細胞には、末梢血単核球(PBMC)及びナチュラルキラー(NK)細胞が含まれる。代替的には、または追加的には、目的の分子のADCC活性は、例えば、Clynes et al.Proc.Nat’l Acad.Sci.USA95:652-656(1998)に開示されるものなどの動物モデルにおいて、インビボで評価され得る。抗体がC1qに結合することができず、ゆえにCDC活性を欠くことを確認するために、C1q結合アッセイも実施され得る。例えば、WO2006/029879及びWO2005/100402におけるC1q及びC3c結合ELISAを参照されたい。補体活性を評価するために、CDCアッセイを行ってもよい(例えば、Gazzano-Santoro et al.,J.Immunol.Methods 202:163(1996)、Cragg,M.S.et al.,Blood101:1045-1052(2003)、及びCragg,M.S.and M.J.Glennie,Blood103:2738-2743(2004)を参照されたい)。FcRn結合及びインビボクリアランス/半減期判定はまた、当該技術分野で既知の方法を使用して行うことができる(例えば、Petkova,S.B.et al.,Int’l.Immunol.18(12):1759-1769(2006)を参照されたい)。
ある特定の実施形態では、本明細書に提供される抗体は、当該技術分野で既知であり、容易に入手可能なさらなる非タンパク質性部分を含有するようにさらに修飾されてもよい。抗体の誘導体かに好適な部分には、水溶性ポリマーが含まれるが、これに限定されない。水溶性ポリマーの非限定的な例としては、ポリエチレングリコール(PEG)、エチレングリコール/プロピレングリコールのコポリマー、カルボキシメチルセルロース、デキストラン、ポリビニルアルコール、ポリビニルピロリドン、ポリ-1,3-ジオキソラン、ポリ-1,3,6-トリオキサン、エチレン/無水マレイン酸コポリマー、ポリアミノ酸(ホモポリマーまたはランダムコポリマーのいずれか)、及びデキストランまたはポリ(n-ビニルピロリドン)ポリエチレングリコール、プロピレングリコールホモポリマー、ポリプロピレンオキシド/エチレンオキシドコポリマー、ポリオキシエチル化ポリオール(例えば、グリセロール)、ポリビニルアルコール、ならびにこれらの混合物が挙げられるが、これらに限定されない。ポリエチレングリコールプロピオンアルデヒドは、水中でのその安定性により、製造における利点を有し得る。ポリマーは、任意の分子量であってもよく、分岐であっても非分岐であってもよい。抗体に結合したポリマーの数は異なり得、2個以上のポリマーが結合している場合、それらは同じ分子であっても異なる分子であってもよい。一般に、誘導体化に使用されるポリマーの数及び/または種類は、改善される抗体の特定の特性または機能、抗体誘導体が規定の条件下で療法に使用されることになるかどうかなどを含むがこれらに限定されない検討事項に基づいて決定され得る。
癌の治療において本明細書に提供されるPACに有用であり得る、システイン操作された抗体を含むがこれに限定されない抗体には、細胞表面受容体及び腫瘍関連抗原(TAA)に対する抗体が含まれるが、これらに限定されない。ある特定の腫瘍関連抗原は当該技術分野で既知であり、当該技術分野で既知の方法及び情報を使用した抗体の生成における使用のために調製することができる。癌の診断及び療法のための有効な細胞標的をは発見する試みにおいて、研究者らは、1つ以上の正常な非癌性細胞(複数可)と比較して、1つ以上の特定の種類(複数可)の癌細胞の表面上に特異的に発現される膜貫通ポリペプチドまたは別様の腫瘍関連ポリペプチドを同定するように努めてきた。しばしば、かかる腫瘍関連ポリペプチドは、非癌性細胞の表面上と比較して、癌細胞の表面上により豊富に発現される。かかる腫瘍関連細胞表面抗原ポリペプチドの同定は、抗体に基づく療法を介して破壊のための癌細胞をより特異的に標的とする能力をもたらした。
抗体は、例えば、米国特許第4,816,567号に記載されるように、組み換え法及び組成物を使用して産生され得る。一実施形態では、本明細書に記載される抗体をコードする単離された抗体が提供される。かかる核酸は、抗体のVLを含むアミノ酸配列及び/またVHを含むアミノ酸配列(例えば、抗体の軽鎖及び/または重鎖)をコードし得る。さらなる実施形態では、かかる核酸を含む1つ以上のベクター(例えば、発現ベクター)が提供される。さらなる実施形態では、かかる核酸を含む宿主細胞が提供される。1つのかかる実施形態では、宿主細胞は、以下を含む(例えば、これらにより形質転換される):(1)抗体のVLを含むアミノ酸配列及び抗体のVHを含むアミノ酸配列をコードする核酸を含むベクター、または(2)抗体のVLを含むアミノ酸配列をコードする核酸を含む第1のベクター及び抗体のVHを含むアミノ酸配列をコードする核酸を含む第2のベクター。一実施形態では、宿主細胞は、真核性であり、例えば、チャイニーズハムスター卵巣(CHO)細胞またはリンパ球細胞(例えば、Y0、NS0、Sp20細胞)である。一実施形態では、抗体を作製する方法が提供され、該方法は、上記のように、抗体の発現に好適な条件下で抗体をコードする核酸を含む宿主細胞を培養することと、任意に宿主細胞(または宿主細胞培養培地)から抗体を回収することと、を含む。
(1)BMPR1B(骨形成タンパク質受容体IB型、Genbank受託
番号NM_001203)
ten Dijke,P.,et al Science264(5155):101-104(1994),Oncogene14(11):1377-1382(1997));WO2004063362(請求項2);WO2003042661(請求項12);US2003134790-A1(38~39頁);WO2002102235(請求項13;296頁);WO2003055443(91~92頁);WO200299122(実施例2;528~530頁);WO2003029421(請求項6);WO2003024392(請求項2;図112);WO200298358(請求項1;183頁);WO200254940(100~101頁);WO200259377(349~350頁);WO200230268(請求項27;376頁);WO200148204(実施例;図4)NP_001194骨形成タンパク質受容体、IB型/pid=NP_001194.1-相互参照:MIM:603248;NP_001194.1;AY065994
(2)E16(LAT1、SLC7A5、Genbank受託番号NM_003486)Biochem.Biophys.Res.Commun.255(2),283-288(1999),Nature395(6699):288-291(1998),Gaugitsch,H.W.,et al(1992)J.Biol.Chem.267(16):11267-11273);WO2004048938(実施例2);WO2004032842(実施例IV);WO2003042661(請求項12);WO2003016475(請求項1);WO200278524(実施例2);WO200299074(請求項19;127~129頁);WO200286443(請求項27;222、393頁);WO2003003906(請求項10;293頁);WO200264798(請求項33;93~95頁);WO200014228(請求項5;133~136頁);US2003224454(図3);WO2003025138(請求項12;150頁);NP_003477溶質輸送体ファミリー7(カチオン性アミノ酸輸送体、y+系)、メンバー5/pid=NP_003477.3-ホモサピエンス相互参照:MIM:600182;NP_003477.3;NM_015923;NM_003486_1
(3)STEAP1(前立腺の6膜貫通上皮抗原、Genbank受託番号NM_012449)Cancer Res.61(15),5857-5860(2001),Hubert,R.S.,et al(1999)Proc.Natl.Acad.Sci.U.S.A.96(25):14523-14528);WO2004065577(請求項6);WO2004027049(図1L);EP1394274(実施例11);WO2004016225(請求項2);WO2003042661(請求項12);US2003157089(実施例5);US2003185830(実施例5);US2003064397(図2);WO200289747(実施例5;618~619頁);WO2003022995(実施例9;図13A、実施例53;173頁、実施例2;図2A);NP_036581前立腺の6膜貫通上皮抗原相互参照:MIM:604415;NP_036581.1;NM_012449_1
(4)0772P(CA125、MUC16、Genbank受託番号AF361486)J.Biol.Chem.276(29):27371-27375(2001));WO2004045553(請求項14);WO200292836(請求項6;図12);WO200283866(請求項15;116~121頁);US2003124140(実施例16);US798959。相互参照:GI:34501467;AAK74120.3;AF361486_1
(5)MPF(MPF、MSLN、SMR、巨核球増強因子、メソテリン、Genbank受託番号NM_005823)Yamaguchi,N.,et al Biol.Chem.269(2),805-808(1994),Proc.Natl.Acad.Sci.U.S.A.96(20):11531-11536(1999),Proc.Natl.Acad.Sci.U.S.A.93(1):136-140(1996),J.Biol.Chem.270(37):21984-21990(1995));WO2003101283(請求項14);(WO2002102235(請求項13;287~288頁);WO2002101075(請求項4;308~309頁);WO200271928(320~321頁);WO9410312(52~57頁);相互参照:MIM:601051;NP_005814.2;NM_005823_1
(6)Napi2b(Napi3b、NAPI-3B、NPTIIb、SLC34A2、溶質輸送体ファミリー34(リン酸ナトリウム)、メンバー2、II型ナトリウム依存性リン酸輸送体3b、Genbank受託番号NM_006424)J.Biol.Chem.277(22):19665-19672(2002),Genomics62(2):281-284(1999),Feild,J.A.,et al(1999)Biochem.Biophys.Res.Commun.258(3):578-582);WO2004022778(請求項2);EP1394274(実施例11);WO2002102235(請求項13;326頁);EP875569(請求項1;17~19頁);WO200157188(請求項20;329頁);WO2004032842(実施例IV);WO200175177(請求項24;139 140頁);相互参照:MIM:604217;NP_006415.1;NM_006424_1
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、セマフォリン5b Hlog、セマドメイン、7トロンボスポンジン反復(1型及び1型様)、膜貫通ドメイン(TM)及び短い細胞質ドメイン、(セマフォリン)5B、Genbank受託番号AB040878)Nagase T.,et
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(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA2700050C12、RIKEN cDNA2700050C12遺伝子、Genbank受託番号AY358628);Ross et al(2002)Cancer Res.62:2546-2553;US2003129192(請求項2);US2004044180(請求項12);US2004044179(請求項11);US2003096961(請求項11);US2003232056(実施例5);WO2003105758(請求項12);US2003206918(実施例5);EP1347046(請求項1);WO2003025148(請求項20);相互参照:GI:37182378;AAQ88991.1;AY358628_1
(9)ETBR(エンドセリン受容体タイプB、Genbank受託番号AY275463);Nakamuta M.,et al Biochem.Biophys.Res.Commun.177,34-39,1991;Ogawa Y.,et al Biochem.Biophys.Res.Commun.178,248-255,1991;Arai H.,et al Jpn.Circ.J.56,1303-1307,1992;Arai H.,et alJ.Biol.Chem.268,3463-3470,1993;Sakamoto A.,Yanagisawa M.,et al
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T.,et al,Hum.Mol.Genet.4,2407-2409,1995;Auricchio A.,et al Hum.Mol.Genet.5:351-354,1996;Amiel J.,et al Hum.Mol.Genet.5,355-357,1996;Hofstra R.M.W.,et al Nat.Genet.12,445-447,1996;Svensson P.J.,et al Hum.Genet.103,145-148,1998;Fuchs S.,et al Mol.Med.7,115-124,2001;Pingault V et al(2002)Hum Genet 111 198 206;WO2004045516(請求項1);WO2004048938(実施例2);WO2004040000(請求項151);WO2003087768(請求項1);WO2003016475(請求項1);WO2003016475(請求項1);WO200261087(図1);WO2003016494(図6);WO2003025138(請求項12;144頁);WO200198351(請求項1;124~125頁);EP522868(請求項8;図2);WO200177172(請求項1;297~299頁);US2003109676;US6518404(図3);US5773223(請求項1a;欄31~34);WO2004001004;
(10)MSG783(RNF124、仮想タンパク質FLJ20315、Genbank受託番号NM_017763);WO2003104275(請求項1);WO2004046342(実施例2);WO2003042661(請求項12);WO2003083074(請求項14;61頁);WO2003018621(請求項1);WO2003024392(請求項2;図93);WO200166689(実施例6);相互参照:LocusID:54894;NP_060233.2;NM_017763_1(11)STEAP2(HGNC_8639、IPCA-1、PCANAP1、STAMP1、STEAP2、STMP、前立腺癌関連遺伝子1、前立腺癌関連タンパク質1、前立腺の6膜貫通上皮抗原2、6膜貫通前立腺タンパク質、Genbank受託番号AF455138)Lab.Invest.82(11):1573-1582(2002));WO2003087306;US2003064397(請求項1;図1);WO200272596(請求項13;54~55頁);WO200172962(請求項1;図4B);WO2003104270(請求項11);WO2003104270(請求項16);US2004005598(請求項22);WO2003042661(請求項12);US2003060612(請求項12;図10);WO200226822(請求項23;図2);WO200216429(請求項12;図10);相互参照:GI:22655488;AAN04080.1;AF455138_1
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、一過性受容器電位チャネル、サブファミリーM、メンバー4、Genbank受託番号NM_017636)Xu,X.Z.,et al Proc.Natl.Acad.Sci.U.S.A.98(19):10692-10697(2001),Cell109(3):397-407(2002),J.Biol.Chem.278(33):30813-30820(2003));US2003143557(請求項4);WO200040614(請求項14;100~103頁);WO200210382(請求項1;図9A);WO2003042661(請求項12);WO200230268(請求項27;391頁);US2003219806(請求項4);WO200162794(請求項14;図1A~D);相互参照:MIM:606936;NP_060106.2;NM_017636_1
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1、奇形癌腫由来成長因子、Genbank受託番号NP_003203またはNM_003212)Ciccodicola,A.,et al EMBO J.8(7):1987-1991(1989),Am.J.Hum.Genet.49(3):555-565(1991));US2003224411(請求項1);WO2003083041(実施例1);WO2003034984(請求項12);WO200288170(請求項2;52~53頁);WO2003024392(請求項2;図58);WO200216413(請求項1;94~95頁、105頁);WO200222808(請求項2;図1);US5854399(実施例2;欄17~18);US5792616(図2);相互参照:MIM:187395;NP_003203.1;NM_003212_1
(14)CD21(CR2(補体受容体2)またはC3DR(C3d/エプスタイン・バーウイルス受容体)またはHs.73792Genbank受託番号M26004)Fujisaku et al(1989)J.Biol.Chem.264(4):2118-2125);Weis J.J.,et alJ.Exp.Med.167,1047-1066,1988;Moore M.,et al Proc.Natl.Acad.Sci.U.S.A.84,9194-9198,1987;Barel M.,et al Mol.Immunol.35,1025-1031,1998;Weis J.J.,et al Proc.Natl.Acad.Sci.U.S.A.83,5639-5643,1986;Sinha S.K.,et al(1993)J.Immunol.150,5311-5320;WO2004045520(実施例4);US2004005538(実施例1);WO2003062401(請求項9);WO2004045520(実施例4);WO9102536(図9.1~9.9);WO2004020595(請求項1);受託:P20023;Q13866;Q14212;EMBL;M26004;AAA35786.1.
(15)CD79b(CD79B、CD79β、IGb(免疫グロブリン関連ベータ)、B29、Genbank受託番号NM_000626または11038674)Proc.Natl.Acad.Sci.U.S.A.(2003)100(7):4126-4131,Blood(2002)100(9):3068-3076,Muller et al(1992)Eur.J.Immunol.22(6):1621-1625);WO2004016225(請求項2、図140);WO2003087768、US2004101874(請求項1、102頁);WO2003062401(請求項9);WO200278524(実施例2);US2002150573(請求項5、15頁);US5644033;WO2003048202(請求項1、306及び309頁);WO99/558658、US6534482(請求項13、図17A/B);WO200055351(請求項11、1145~1146頁);相互参照:MIM:147245;NP_000617.1;NM_000626_1
(16)FcRH2(IFGP4、IRTA4、SPAP1A(ホスファターゼアンカータンパク質1aを含有するSH2ドメイン)、SPAP1B、SPAP1C、Genbank受託番号NM_030764、AY358130)Genome Res.13(10):2265-2270(2003),Immunogenetics54(2):87-95(2002),Blood99(8):2662-2669(2002),Proc.Natl.Acad.Sci.U.S.A.98(17):9772-9777(2001),Xu,M.J.,et al(2001)Biochem.Biophys.Res.Commun.280(3):768-775;WO2004016225(請求項2);WO2003077836;WO200138490(請求項5;図18D-1~18D-2);WO2003097803(請求項12);WO2003089624(請求項25);相互参照:MIM:606509;NP_110391.2;NM_030764_1
(17)HER2(ErbB2、Genbank受託番号M11730)Coussens L.,et al Science(1985)230(4730):1132-1139);Yamamoto T.,et al Nature319,230-234,1986;Semba K.,et al Proc.Natl.Acad.Sci.U.S.A.82,6497-6501,1985;Swiercz J.M.,et alJ.Cell Biol.165,869-880,2004;Kuhns J.J.,et alJ.Biol.Chem.274,36422-36427,1999;Cho H.-S.,et al Nature421,756-760,2003;Ehsani A.,et al(1993)Genomics15,426-429;WO2004048938(実施例2);WO2004027049(図1I);WO2004009622;WO2003081210;WO2003089904(請求項9);WO2003016475(請求項1);US2003118592;WO2003008537(請求項1);WO2003055439(請求項29;図1A~B);WO2003025228(請求項37;図5C);WO200222636(実施例13;95~107頁);WO200212341(請求項68;図7);WO200213847(71~74頁);WO200214503(114~117頁);WO200153463(請求項2;41~46頁);WO200141787(15頁);WO200044899(請求項52;図7);WO200020579(請求項3;図2);US5869445(請求項3;欄31~38);WO9630514(請求項2;56~61頁);EP1439393(請求項7);WO2004043361(請求項7);WO2004022709;WO200100244(実施例3;図4);受託:P04626;EMBL;M11767;AAA35808.1.EMBL;M11761;AAA35808.1.
(18)NCA(CEACAM6、Genbank受託番号M18728);Barnett T.,et al Genomics3,59-66,1988;Tawaragi Y.,et al Biochem.Biophys.Res.Commun.150,89-96,1988;Strausberg R.L.,et al Proc.Natl.Acad.Sci.U.S.A.99:16899-16903,2002;WO2004063709;EP1439393(請求項7);WO2004044178(実施例4);WO2004031238;WO2003042661(請求項12);WO200278524(実施例2);WO200286443(請求項27;427頁);WO200260317(請求項2);受託:P40199;Q14920;EMBL;M29541;AAA59915.1.EMBL;M18728;
(19)MDP(DPEP1Genbank受託番号BC017023)Proc.Natl.Acad.Sci.U.S.A.99(26):16899-16903(2002));WO2003016475(請求項1);WO200264798(請求項33;85~87頁);JP05003790(図6~8);WO9946284(図9);相互参照:MIM:179780;AAH17023.1;BC017023_1
(20)IL20Rα(IL20Ra、ZCYTOR7、Genbank受託番号AF184971);Clark H.F.,et al Genome Res.13,2265-2270,2003;Mungall A.J.,et al Nature425,805-811,2003;Blumberg H.,et al Cell 104,9-19,2001;Dumoutier L.,et alJ.Immunol.167,3545-3549,2001;Parrish-Novak J.,et alJ.Biol.Chem.277,47517-47523,2002;Pletnev S.,et al(2003)Biochemistry42:12617-12624;Sheikh F.,et al(2004)J.Immunol.172,2006-2010;EP1394274(実施例11);US2004005320(実施例5);WO2003029262(74~75頁);WO2003002717(請求項2;63頁);WO200222153(45~47頁);US2002042366(20~21頁);WO200146261(57~59頁);WO200146232(63~65頁);WO9837193(請求項1;55~59頁);受託:Q9UHF4;Q6UWA9;Q96SH8;EMBL;AF184971;AAF01320.1.
(21)ブレビカン(BCAN、BEHAB、Genbank受託番号AF229053)Gary S.C.,et al Gene256,139-147,2000;Clark H.F.,et al Genome Res.13,2265-2270,2003;Strausberg R.L.,et al Proc.Natl.Acad.Sci.U.S.A.99,16899-16903,2002;US2003186372(請求項11);US2003186373(請求項11);US2003119131(請求項1;図52);US2003119122(請求項1;図52);US2003119126(請求項1);US2003119121(請求項1;図52);US2003119129(請求項1);US2003119130(請求項1);US2003119128(請求項1;図52);US2003119125(請求項1);WO2003016475(請求項1);WO200202634(請求項1);
(22)EphB2R(DRT、ERK、Hek5、EPHT3、Tyro5、Genbank受託番号NM_004442)Chan,J.and Watt,V.M.,Oncogene6(6),1057-1061(1991)Oncogene10(5):897-905(1995),Annu.Rev.Neurosci.21:309-345(1998),Int.Rev.Cytol.196:177-244(2000));WO2003042661(請求項12);WO200053216(請求項1;41頁);WO2004065576(請求項1);WO2004020583(請求項9);WO2003004529(128~132頁);WO200053216(請求項1;42頁);相互参照:MIM:600997;NP_004433.2;NM_004442_1
(23)ASLG659(B7h、Genbank受託番号AX092328)US20040101899(請求項2);WO2003104399(請求項11);WO2004000221(図3);US2003165504(請求項1);US2003124140(実施例2);US2003065143(図60);WO2002102235(請求項13;299頁);US2003091580(実施例2);WO200210187(請求項6;図10);WO200194641(請求項12;図7b);WO200202624(請求項13;図1A~1B);US2002034749(請求項54;45~46頁);WO200206317(実施例2;320~321頁、請求項34;321~322頁);WO200271928(468~469頁);WO200202587(実施例1;図1);WO200140269(実施例3;190~192頁);WO200036107(実施例2;205~207頁);WO2004053079(請求項12);WO2003004989(請求項1);WO200271928(233~234、452~453頁);WO0116318;
(24)PSCA(前立腺幹細胞抗原前駆体、Genbank受託番号AJ297436)Reiter R.E.,et al Proc.Natl.Acad.Sci.U.S.A.95,1735-1740,1998;Gu Z.,et al Oncogene19,1288-1296,2000;Biochem.Biophys.Res.Commun.(2000)275(3):783-788;WO2004022709;EP1394274(実施例11);US2004018553(請求項17);WO2003008537(請求項1);WO200281646(請求項1;164頁);WO2003003906(請求項10;288頁);WO200140309(実施例1;図17);US2001055751(実施例1;図1b);WO200032752(請求項18;図1);WO9851805(請求項17;97頁);WO9851824(請求項10;94頁);WO9840403(請求項2;図1B);受託:O43653;EMBL;AF043498;AAC39607.1.
(25)GEDA(Genbank受託番号AY260763);AAP14954脂肪腫HMGIC融合パートナー様タンパク質/pid=AAP14954.1-ホモサピエンス種:ホモサピエンス(ヒト)WO2003054152(請求項20);WO2003000842(請求項1);WO2003023013(実施例3、請求項20);US2003194704(請求項45);相互参照:GI:30102449;AAP14954.1;AY260763_1
(26)BAFF-R(B細胞活性化因子受容体、BLyS受容体3、BR3、Genbank受託番号AF116456);BAFF受容体/pid=NP_443177.1-ホモサピエンスThompson,J.S.,et al Science293(5537),2108-2111(2001);WO2004058309;WO2004011611;WO2003045422(実施例;32~33頁);WO2003014294(請求項35;図6B);WO2003035846(請求項70;615~616頁);WO200294852(欄136~137);WO200238766(請求項3;133頁);WO200224909(実施例3;図3);相互参照:MIM:606269;NP_443177.1;NM_052945_1;AF132600
(27)CD22(B細胞受容体CD22-Bアイソフォーム、BL-CAM、Lyb-8、Lyb8、SIGLEC-2、FLJ22814、Genbank受託番号AK026467);Wilson et al(1991)J.Exp.Med.173:137-146;WO2003072036(請求項1;図1);相互参照:MIM:107266;NP_001762.1;NM_001771_1
(28)CD79a(CD79A、CD79α、免疫グロブリン関連アルファ、Igベータ(CD79B)と共有結合的に相互作用し、Ig M分子と共に表面上に複合体を形成するB細胞特異タンパク質、B細胞分化に関与するシグナルを伝達する)、pI:4.84,MW:25028 TM:2[P]遺伝子染色体:19q13.2、Genbank受託番号NP_001774.10)WO2003088808、US20030228319;WO2003062401(請求項9);US2002150573(請求項4、13~14頁);WO9958658(請求項13、図16);WO9207574(図1);US5644033;Ha et al(1992)J.Immunol.148(5):1526-1531;Mueller et al(1992)Eur.J.Biochem.22:1621-1625;Hashimoto et al(1994)Immunogenetics40(4):287-295;Preud’homme et al(1992)Clin.Exp.Immunol.90(1):141-146;Yu et al(1992)J.Immunol.148(2)633-637;Sakaguchi et al(1988)EMBO J.7(11):3457-3464;
(29)CXCR5(バーキットリンパ腫受容体1、CXCL13ケモカインによって活性化されたGタンパク質結合受容体、リンパ球遊走及び液性防御において機能する、HIV-2感染ならびにことによるとAIDS、リンパ腫、骨髄腫、及び白血病の発症において役割を担う);372aa,pI:8.54MW:41959TM:7[P]遺伝子染色体:11q23.3、Genbank受託番号NP_001707.1)WO2004040000;WO2004015426;US2003105292(実施例2);US6555339(実施例2);WO200261087(図1);WO200157188(請求項20、269頁);WO200172830(12~13頁);WO200022129(実施例1、152~153頁、実施例2、254~256頁);WO9928468(請求項1、38頁);US5440021(実施例2、欄49~52);WO9428931(56~58頁);WO9217497(請求項7、図5);Dobner et al(1992)Eur.J.Immunol.22:2795-2799;Barella et al(1995)Biochem.J.309:773-779;
(30)HLA-DOB(ペプチドに結合し、それらをCD4+Tリンパ球に提示するMHCクラスII分子(Ia抗原)のベータサブユニット);273aa、pI:6.56MW:30820TM:1[P]遺伝子染色体:6p21.3、Genbank受託番号NP_002111.1)Tonnelle et al(1985)EMBO J.4(11):2839-2847;Jonsson et al(1989)Immunogenetics29(6):411-413;Beck et al(1992)J.Mol.Biol.228:433-441;Strausberg et al(2002)Proc.Natl.Acad.Sci USA99:16899-16903;Servenius et al(1987)J.Biol.Chem.262:8759-8766;Beck et al(1996)J.Mol.Biol.255:1-13;Naruse et al(2002)Tissue Antigens59:512-519;WO9958658(請求項13、図15);US6153408(欄35~38);US5976551(欄168~170);US6011146(欄145~146);Kasahara et al(1989)Immunogenetics30(1):66-68;Larhammar et al(1985)J.Biol.Chem.260(26):14111-14119;
(31)P2X5(プリン受容体P2Xリガンド開口型イオンチャネル5、細胞外ATPによって開口されたイオンチャネル、シナプス伝達及び神経発生に関与する場合がある、欠乏は特発性排尿筋不安定の病態生理学に寄与する場合がある);422aa)、pI:7.63,MW:47206TM:1[P]遺伝子染色体:17p13.3、Genbank受託番号NP_002552.2)Le et al(1997)FEBS Lett.418(1-2):195-199;WO2004047749;WO2003072035(請求項10);Touchman et al(2000)Genome Res.10:165-173;WO200222660(請求項20);WO2003093444(請求項1);WO2003087768(請求項1);WO2003029277(82頁);
(32)CD72(B細胞分化抗原CD72、Lyb-2)タンパク質配列完全maeaity...tafrfpd(1..359;359aa)、pI:8.66,MW:40225TM:1[P]遺伝子染色体:9p13.3、Genbank受託番号NP_001773.1)WO2004042346(請求項65);WO2003026493(51~52、57~58頁);WO200075655(105~106頁);Von
Hoegen et al(1990)J.Immunol.144(12):4870-4877;Strausberg et al(2002)Proc.Natl.Acad.Sci USA99:16899-16903;
(33)LY64(リンパ球抗原64(RP105)、ロイシンリッチリピート(LRR)ファミリの-I型膜タンパク質、B細胞活性化及びアポトーシスを調節する、機能の喪失は全身性紅斑性狼瘡を有する患者における疾患活性の増加に関連する);661aa、pI:6.20,MW:74147TM:1[P]遺伝子染色体:5q12、Genbank受託番号NP_005573.1)US2002193567;WO9707198(請求項11、39~42頁);Miura et al(1996)Genomics38(3):299-304;Miura et al(1998)Blood92:2815-2822;WO2003083047;WO9744452(請求項8 57~61頁);WO200012130(24~26頁);
(34)FcRH1(Fc受容体様タンパク質1、C2型Ig様及びITAMドメインを含有する免疫グロブリンFcドメインの推定受容体、Bリンパ球分化において役割を担う場合がある);429aa、pI:5.28,MW:46925TM:1[P]遺伝子染色体:1q21-1q22、Genbank受託番号NP_443170.1)WO2003077836;WO200138490(請求項6、図18E-1~18-E-2);Davis et al(2001)Proc.Natl.Acad.Sci USA98(17):9772-9777;WO2003089624(請求項8);EP1347046(請求項1);
WO2003089624(請求項7);
(35)FCRH5(IRTA2、免疫グロブリンスーパーファミリー受容体転座関連2、B細胞発生及びリンパ腫形成の役割を有する可能性がある推定免疫受容体;いくつかのB細胞悪性腫瘍において転座による遺伝子の調節解除が生じる);977aa、pI:6.88MW:106468TM:1[P]遺伝子染色体:1q21、Genbank受託番号ヒト:AF343662、AF343663、AF343664、AF343665、AF369794、AF397453、AK090423、AK090475、AL834187、AY358085;マウス:AK089756、AY158090、AY506558;NP_112571.1WO2003024392(請求項2、図97);Nakayama et al(2000)Biochem.Biophys.Res.Commun.277(1):124-127;WO2003077836;WO200138490(請求項3、図18B-1~18B-2);
(36)TENB2(TMEFF2、トモレグリン、TPEF、HPP1、TR、推定膜貫通プロテオグリカン、成長因子及びフォリスタチンのEGF/ヘレグリンファミリーに関連する);374aa、NCBI受託:AAD55776、AAF91397、AAG49451、NCBI RefSeq:NP_057276;NCBI遺伝子:23671;OMIM:605734;SwissProt Q9UIK5;Genbank受託番号AF179274;AY358907、CAF85723、CQ782436
WO2004074320(配列番号810);JP2004113151(配列番号2、4、8);WO2003042661(配列番号580);WO2003009814(配列番号411);EP1295944(69~70頁);WO200230268(329頁);WO200190304(配列番号2706);US2004249130;US2004022727;WO2004063355;US2004197325;US2003232350;US2004005563;US2003124579;Horie et al(2000)Genomics67:146-152;Uchida et al(1999)Biochem.Biophys.Res.Commun.266:593-602;Liang et al(2000)Cancer Res.60:4907-12;Glynne-Jones et al(2001)Int J
Cancer.Oct15;94(2):178-84;
(37)PMEL17(銀ホモログ;SILV;D12S53E;PMEL17;SI;SIL);ME20;gp100)BC001414;BT007202;M32295;M77348;NM006928;McGlinchey R P et al(2009)Proc Natl.Acad.Sci.U.S.A.106(33),13731-13736;Kummer,M.P.et al(2009)J.Biol.Chem.284(4),2296-2306;
(38)TMEFF1(EGF様ドメイン及び2つのフォリスタチン様ドメイン1を有する膜貫通タンパク質;トモレグリン-1);H7365;C9orf2;C9ORF2;U19878;X83961;NM_080655;NM_003692;Harms,P.W.(2003)Genes Dev.17(21),2624-2629;Gery,S.et al(2003)Oncogene22(18):2723-2727;(39)GDNF-Ra1(GDNFファミリー受容体アルファ1;GFRA1;GDNFR;GDNFRA;RETL1;TRNR1;RET1L;GDNFR-アルファ1;GFR-ALPHA-1);U95847;BC014962;NM_145793NM_005264;Kim,M.H.et al(2009)Mol.Cell.Biol.29(8),2264-2277;Treanor,J.J.et al(1996)Nature382(6586):80-83;
(40)Ly6E(lリンパ球抗原6複合体、遺伝子座E;Ly67、RIG-E、SCA-2、TSA-1);NP_002337.1;NM_002346.2;de Nooij-van Dalen,A.G.et al(2003)Int.J.Cancer103(6),768-774;Zammit,D.J.et al(2002)Mol.Cell.Biol.22(3):946-952;WO2013/17705;
(41)TMEM46(shisaホモログ2(Xenopus laevis);SHISA2);NP_001007539.1;NM_001007538.1;Furushima,K.et al(2007)Dev.Biol.306(2),480-492;Clark,H.F.et al(2003)Genome Res.13(10):2265-2270;
(42)Ly6G6D(リンパ球抗原6複合体、遺伝子座G6D;Ly6-D、MEGT1);NP_067079.2;NM_021246.2;Mallya,M.et al(2002)Genomics80(1):113-123;Ribas,G.et al(1999)J.Immunol.163(1):278-287;
(43)LGR5(ロイシンリッチリピート含有Gタンパク質結合受容体5;GPR49、GPR67);NP_003658.1;NM_003667.2;Salanti,G.et al(2009)Am.J.Epidemiol.170(5):537-545;Yamamoto,Y.et al(2003)Hepatology37(3):528-533;
(44)RET(ret癌原遺伝子;MEN2A;HSCR1;MEN2B;MTC1;PTC;CDHF12;Hs.168114;RET51;RET-ELE1);NP_066124.1;NM_020975.4;Tsukamoto,H.et al(2009)Cancer Sci.100(10):1895-1901;Narita,N.et al(2009)Oncogene28(34):3058-3068;
(45)LY6K(リンパ球抗原6複合体、遺伝子座K;LY6K;HSJ001348;FLJ35226);NP_059997.3;NM_017527.3;Ishikawa,N.et al(2007)Cancer Res.67(24):11601-11611;de Nooij-van Dalen,A.G.et al(2003)Int.J.Cancer103(6):768-774;
(46)GPR19(Gタンパク質結合受容体19;Mm.4787);NP_006134.1;NM_006143.2;Montpetit,A.and Sinnett,D.(1999)Hum.Genet.105(1-2):162-164;O’Dowd,B.F.et al(1996)FEBS Lett.394(3):325-329;
(47)GPR54(KISS1受容体;KISS1R;GPR54;HOT7T175;AXOR12);NP_115940.2;NM_032551.4;Navenot,J.M.et al(2009)Mol.Pharmacol.75(6):1300-1306;Hata,K.et al(2009)Anticancer Res.29(2):617-623;
(48)ASPHD1(アスパラギン酸ベータ-ヒドロキシラーゼドメイン含有1;LOC253982);NP_859069.2;NM_181718.3;Gerhard,D.S.et al(2004)Genome Res.14(10B):2121-2127;
(49)チロシナーゼ(TYR;OCAIA;OCA1A;チロシナーゼ;SHEP3);NP_000363.1;NM_000372.4;Bishop,D.T.et al(2009)Nat.Genet.41(8):920-925;Nan,H.et al(2009)Int.J.Cancer125(4):909-917;(50)TMEM118(ringフィンガータンパク質、膜貫通2;RNFT2;FLJ14627);NP_001103373.1;NM_001109903.1;Clark,H.F.et al(2003)Genome Res.13(10):2265-2270;Scherer,S.E.et al(2006)Nature440(7082):346-351
(51)GPR172A(Gタンパク質結合受容体172A;GPCR41;FLJ11856;D15Ertd747e);NP_078807.1;NM_024531.3;Ericsson,T.A.et al(2003)Proc.Natl.Acad.Sci.U.S.A.100(11):6759-6764;Takeda,S.et al(2002)FEBS Lett.520(1-3):97-101.
(52)CD33、シアル酸結合免疫グロブリン様レクチンファミリのメンバー、67kDaの糖鎖付加された膜貫通タンパク質である。CD33は、前駆骨髄単球性及び赤血球全区細胞に加え、ほとんどの骨髄性及び単球性白血病細胞上で発現される。これは、最初期の多能性幹細胞、成熟顆粒球、リンパ球細胞、または非造血性細胞上では見られない(Sabbath et al.,(1985)J.Clin.Invest.75:756-56;Andrews et al.,(1986)Blood68:1030-5)。CD33は、その細胞質側末端上に2つのチロシン残基を含有し、その各々に、多くの抑制性受容体において見られる免疫受容抑制性チロシンモチーフ(ITIM)に類似する疎水性残基が続いている。
(53)CLL-1(CLEC12A、MICL、及びDCAL2)、C型レクチン/C型レクチン様ドメイン(CTL/CTLD)スーパーファミリー。このファミリーのメンバーは、共通のタンパク質フォールドを共有し、細胞接着、細胞間シグナル伝達、糖タンパク質代謝回転、ならびに炎症及び免疫応答における役割などの多様な機能を有する。この遺伝子によってコードされたタンパク質は、顆粒球及び単球機能の負の調節因子である。この遺伝子の、いくつかの代替的なスプライシングされた転写バリアントが記載されてきたが、これらのバリアントのうちのいくつかの全長の性質は判定されていない。この遺伝子は、染色体12p13上のナチュラルキラー遺伝子複合体領域において他のCTL/CTLDスーパーファミリーメンバーと密接に連結している(Drickamer K(1999)Curr.Opin.Struct.Biol.9(5):585-90;van Rhenen A,et al.,(2007)Blood110(7):2659-66;Chen CH,et al.(2006)Blood107(4):1459-67;Marshall AS,et al.(2006)Eur.J.Immunol.36(8):2159-69;Bakker AB,et al(2005)Cancer Res.64(22):8443-50;Marshall AS,et al(2004)J.Biol.Chem.279(15):14792-802)。CLL-1は、単一のC型レクチン様ドメイン(カルシウムまたは糖のいずれにも結合することが予測されない)、柄領域、膜貫通ドメイン、及びITIMモチーフを含有する短い細胞質側末端を含むII型膜貫通受容体であることが示されてきた。
ある特定の実施形態では、PACは、抗Ly6E抗体を含み得る。レチノイン酸誘発遺伝子E(RIG-E)及び幹細胞抗原2(SCA-2)としても知られる、リンパ球抗原6複合体、遺伝子座E(Ly6E)。これは、GPI結合した131アミノ酸長の、結合パートナーが知られていない未知の機能の約8.4kDaのタンパク質である。これは最初に、マウスにおける未成熟胸腺細胞、胸腺髄質上皮細胞中で発現された転写として同定された(Mao,et al.(1996)Proc.Natl.Acad.Sci.U.S.A.93:5910-5914)。いくつかの実施形態では、本明細書に記載される主題は、PCT公開第WO2013/177055号に記載される抗Ly6E抗体を含むPACを提供する。
ある特定の実施形態では、PACは、抗HER2抗体を含む。一実施形態では、PACの抗HER2抗体は、US5821337の表3に記載されるように、ヒト化抗HER2抗体、例えば、huMAb4D5-1、huMAb4D5-2、huMAb4D5-3、huMAb4D5-4、huMAb4D5-5、huMAb4D5-6、huMAb4D5-7、及びhuMAb4D5-8を含む。これらの抗体は、HER2に結合するマウス抗体(4D5)の相補性決定領域を有するヒトフレームワーク領域を含有する。ヒト化抗体huMAb4D5-8はまた、トラスツズマブとも称され、商標名HERCEPTIN^の下で市販されている。別の実施形態では、PACの抗HER2抗体は、US7862817に記載されるように、ヒト化抗HER2抗体、例えば、ヒト化2C4を含む。例示的なヒト化2C4抗体は、商標名PERJETA(登録商標)の下で市販されているペルツズマブである。
ある特定の実施形態では、PACは、抗MUC16抗体を含む。
ある特定の実施形態では、PACは、抗STEAP 1抗体を含む。
ある特定の実施形態では、PACは、抗NaPi2b抗体を含む。
ある特定の実施形態では、PACは、抗CD79b抗体を含む。
ある特定の実施形態では、PACは、3つの軽鎖超可変領域(HVR-L1、HVR-L2、及びHVR-L3)と3つの重鎖超可変領域(HVR-H1、HVR-H2、及びHVR-H3)とを含む抗CD22抗体を含み得る。一実施形態では、PACの抗CD22抗体は、3つの軽鎖超可変領域と3つの重鎖超可変領域(配列番号66~71)とを含み、それらの配列は以下に示される。一実施形態では、PACの抗CD22抗体は、配列番号72の可変軽鎖配列と配列番号73の可変重鎖配列とを含む。一実施形態では、本発明のPACの抗CD22抗体は、配列番号74の軽鎖配列と配列番号75の重鎖配列とを含む。
ある特定の実施形態では、PACは、3つの軽鎖超可変領域と3つの重鎖超可変領域とを含む抗CD33抗体を含み得、それらの配列(配列番号76~81)は以下に示される。一実施形態では、PACの抗CD33抗体は、配列番号82の可変軽鎖配列と配列番号83の可変重鎖配列とを含む。
ある特定の実施形態では、本明細書に提供される抗体は、≦1μM、≦100nM、≦50nM、≦10nM、≦5nM、≦1nM、≦0.1nM、≦0.01nM、または≦0.001nMの解離定数(Kd)を有し、かつ任意に、≧10-13M(例えば、10-8M未満、例えば、10-8M~10-13M、例えば、10-9M~10-13M)である。
et al.,J.Mol.Biol.293:865-881(1999)を参照されたい)。このアッセイのための条件を確立するために、MICROTITER(登録商標)マルチウェルプレート(Thermo Scientific)を、50mMの炭酸ナトリウム(pH9.6)中5μg/mlの捕捉用抗Fab抗体(Cappel Labs)で一晩コーティングし、その後、PBS中2%(w/v)ウシ血清アルブミンで2~5時間、室温(約23℃)でブロックする。非吸着プレート(Nunc#269620)中で、100pMまたは26pMの[125I]抗原を、目的のFabの段階希釈と混合する(例えば、Presta et al.,Cancer Res.57:4593-4599(1997)における抗VEGF抗体、Fab-12の評価と一致する)。その後、目的のFabを一晩インキュベートするが、インキュベーションは、平衡が達成されることを確実にするためにより長い時間(例えば、約65時間)にわたって継続されてもよい。その後、室温でのインキュベーションのために混合物を捕捉プレートに移す(例えば、1時間かけて)。次いで、溶液を除去し、プレートをPBS中0.1%ポリソルベート20(TWEEN-20(登録商標)で8回洗浄した。プレートが乾燥すると、150μl/ウェルのシンチラント(MICROSCINT-20(商標)、Packard)を添加し、プレートをTOPCOUNT(商標)ガンマ計数器(Packard)上で10分間計数する。最大結合の20%以下の各Fabの濃度を、競合結合アッセイにおける使用のために選択する。
本明細書に記載される場合、「リンカー」(L1)は、1つ以上のPROTAC部分(D)を抗体(Ab)に結合させてPACを形成するために使用することができる二感応性または多感応性部分である。いくつかの実施形態では、PACは、PROTAC及び抗体に共有結合するための反応性の官能性を有するL1を使用して調製することができる。例えば、いくつかの実施形態では、抗体(Ab)のシステインチオールは、リンカーの反応性官能基またはリンカーL1-PROTAC基と結合を形成してPACを作製することができる。特に、リンカーの化学構造は、PACの有効性及び安全性の両方に大きな影響を及ぼし得る(Ducry&Stump,Bioconjugate Chem,2010,21,5-13)。正しいリンカーを選択することは、標的細胞の意図する細胞区画への適切な薬物送達に影響を及ぼす。
リソソーム酵素によって切断可能なPACのための異なる種類の非ペプチドのペプチド模倣リンカーが本明細書に提供される。例えば、ジペプチド(例えば、Val-Cit)の中間にあるアミド結合がアミド模倣物で置換され、かつ/またはアミノ酸(例えば、Val-Citジペプチド中のバリンアミノ酸)全体が非アミノ酸部分(例えば、シクロアルキルジカルボニル構造(例えば、環サイズ=4もしくは5))で置換された。
-Str-(PM)-Sp-
式中、
Strは、Abに共有結合したストレッチャー単位であり、
Spは、PROTAC部分に共有結合した結合またはスペーサ単位であり、
PMは、以下からなる群から選択される非ペプチド化学部分であり、
Wは、-NH-ヘテロシクロアルキル-またはヘテロシクロアルキルであり、
Yは、ヘテロアリール、アリール、-C(O)C1-C6アルキレン、C1-C6アルキレン-NH2、C1-C6アルキレン-NH-CH3、C1-C6アルキレン-N-(CH3)2、C1-C6アルケニル、またはC1-C6アルキレニルであり、
各R1は独立して、C1-C10アルキル、C1-C10アルケニル、(C1-C10アルキル)NHC(NH)NH2、または(C1-C10アルキル)NHC(O)NH2であり、
R3及びR2は各々独立して、H、C1-C10アルキル、C1-C10アルケニル、アリールアルキル、もしくはヘテロアリールアルキルであるか、またはR3及びR2は一緒になってC3-C7シクロアルキルを形成してもよく、
R4及びR5は各々独立して、C1-C10アルキル、C1-C10アルケニル、アリールアルキル、ヘテロアリールアルキル、(C1-C10アルキル)OCH2-であるか、またはR4及びR5は一緒になってC3-C7シクロアルキル環を形成してもよい。
式中、R6は、C1-C10アルキレン、C1-C10アルケニル、C3-C8シクロアルキル、(C1-C8アルキレン)O-、及びC1-C10アルキレン-C(O)N(Ra)-C2-C6アルキレンからなる群から選択され、各アルキレンは、ハロ、トリフルオロメチル、ジフルオロメチル、アミノ、アルキルアミノ、シアノ、スルホニル、スルホンアミド、スルホキシド、ヒドロキシ、アルコキシ、エステル、カルボン酸、アルキルチオ、C3-C8シクロアルキル、C4-C7ヘテロシクロアルキル、アリール、アリールアルキル、ヘテロアリールアルキル、及びヘテロアリールからなる群から選択される1~5個の置換基によって置換されてもよく、各Raは独立して、HまたはC1-C6アルキルであり、Spは、-Ar-Rb-であり、式中、Arは、アリールまたはヘテロアリールであり、Rbは、(C1-C10アルキレン)O-である。
式中、R7は、C1-C10アルキレン、C1-C10アルケニル、(C1-C10アルキレン)O-、N(Rc)-(C2-C6アルキレン)-N(Rc)、及びN(Rc)-(C2-C6アルキレン)から選択され、各Rcは独立して、HまたはC1-C6アルキルであり、Spは、-Ar-Rb-であり、式中、Arは、アリールまたはヘテロアリールであり、Rbは、(C1-C10アルキレン)O-またはSp-C1-C6アルキレン-C(O)NH-である。
R1は、C1-C6アルキル、C1-C6アルケニル、(C1-C6アルキル)NHC(NH)NH2、または(C1-C6アルキル)NHC(O)NH2であり、
R3及びR2は各々独立して、HまたはC1-C10アルキルである。.
R1は、C1-C6アルキル、(C1-C6アルキル)NHC(NH)NH2または(C1-C6アルキル)NHC(O)NH2であり、
R4及びR5は一緒になってC3-C7シクロアルキル環を形成する。
R1は、C1-C6アルキル、(C1-C6アルキル)NHC(NH)NH2、または(C1-C6アルキル)NHC(O)NH2であり、Wは、上で定義した通りである。
態様において、リンカーL1は、抗体とジスルフィド結合を形成する。態様において、リンカーは、以下の構造を有し、
式中、R1及びR2は独立して、H及びC1-C6アルキルから選択されるか、またはR1及びR2は、3、4、5、もしくは6員のシクロアルキルもしくはヘテロシクリル基を形成する。リンカーは、以下のように抗体及びPROTACに共有結合される。
式中、Aは、「ストレッチャー単位」であり、0~1の整数であり、Wは、「アミノ酸単位」であり、wは、0~12であり、Yは、「スペーサ単位」であり、yは、0、1、または2である。かかるリンカーの例示的な実施形態は、米国特許第7,498,298号に記載されている。
有用なPROTACは、上記の一般式を有する。特定のPROTACは、US7,208,157、WO2013/106643、WO2013/106646、及びWO2015/160845に記載されている。PROTACには、以下の成分を有するものが含まれる。
E3ユビキチンリガーゼ(そのうち600個超がヒトにおいて知られている)は、ユビキチン化のための基質特異性を与える。これらのリガーゼに結合する既知のリガンドが存在する。本明細書に記載されるように、E3ユビキチンリガーゼ結合基は、E3ユビキチンリガーゼに結合することができるペプチドまたは小分子である。
WO2014/038606;WO2010/082612;WO2014/044401;WO2009/151069;WO2008/072655;W02014/100065;W02014/100071;W02014/123882;W02014/120748;W02013/096150;W02015/161032;W02012/155066;W02012/065022;W02011/060049;W02008/036168;W02006/091646;W02012/155066;W02012/065022;W02011/153509;W02013/049250;W02014/151863;W02014/130470;W02014/134207;W02014/200937;W02015/070224;W02015/158648;W02014/082889;W02013/178570;W02013/135648;W02012/116989;W02012/076513;W02012/038307;W02012/034954;W02012/022707;W02012/007409;W02011/134925;W02011/098398;W02011/101297;W02011/067185;W02011/061139;W02011/045257;W02010/121995;W02010/091979;W02010/094622;W02010/084097;W02009/115425;W02009/080488;W02009/077357;W02009/047161A1、W02008/141975A1、W02008/141917A1、W02008/125487A1、W02008/034736A2、W02008/055812A1;W02007/104714A1;W02007/104664A1;W02007/082805A1;W02007/063013A1、W02006/136606A2、W02006/097261A1、W02005/123691A1、W02005/110996A1、W02005/003097A1、W02005/002575A1;W02004/080460A1、W02003/051360A1、W02003/051359A1、W01998/001467;W02011/023677;W02011/076786;W02012/066095;W02012/175487;W02012/175520;W02012/176123;W02013/080141;W02013/111105;W02013/175417;W02014/115080;W02014/115077;W02014/191896;W02014/198266;W02016/028391A9;W02016/028391A2;W02016/026937;W02016/001376;W02015/189799;W02015/155332A1;W02015/004610A8;W02013/105037A1;W02012/155066A3;W02012/155066A2;W02012/033525A3;W02012/047587A2;W02012/033525A2;W02011/106650A3、W02011/106650A2、W02011/005219A1、W02010/058819A1;W02010/028862A1;W02009/037343A1、W02009/037308A1、W02008/130614A3、W02009/019274A1、W02008/130614A2;W02008/106507A3;W02008/106507A2;W02007/107545A1;W02007/107543A1;W02006032631A1、W02000/015657A1;W01998/001467A2;W01997/009343A3;W01997/009343A2;W01996/002642A1;US2007/0129416;Med.Chem.Lett,2013,4,466-469;J.Med.Chem.,2015,58,1038-1052;Bioorg.Med.Chem.Lett.25(2015)3621-3625;Bioorg.Med.Chem.Lett.16(2006)3310-3314に記載されるものも含まれる。PACでの使用のために企図されるMDM2に対する小分子結合化合物のさらなる具体的な例としては、RG7112、RG7388、MI773/SAR405838、AMG232、DS-3032b、RO6839921、RO5045337、RO5503781、Idasanutlin、CGM-097、MK-8242が挙げられる。
XIAPに対する他の小分子結合化合物には、AEG35156、エンベリン、TWX006、及びTWX024が含まれる。XIAP結合部分がPROTACの一部として使用される場合、XIAP結合部分は、XIAPのBIR2もしくはBIR3ドメイン、またはその両方に結合することができる。
PB成分は、分解を意図する標的タンパク質に結合する基である。「タンパク質」という用語には、それらがPB基に結合することができるのに十分な長さのオリゴペプチド及び参照ポリペプチド配列が含まれる。本明細書に別様に記載されるウイルス、細菌、または真菌を含む、真核生物系または微生物系における任意のタンパク質は、本明細書に記載される化合物によって媒介されるユビキチン化の標的である。
3、Smad2、Smad3、Smad4、Smad7、p53、p21 Cipl、PAX、Fyn、CAS、C3G、SOS、Tal、Raptor、RACK-1、CRK、Rapl、Rac、KRas、NRas、HRas、GRB2、FAK、PI3K、spred、Spry、mTOR、MPK、LKBl、PAK1/2/4/5/6、PDGFRA、PYK2、Src、SRPK1、PLC、PKC、PKA、PKBアルファ/ベータ、PKCアルファ/ガンマ/ゼータ、PKD、PLKl、PRAK、PRK2、WAVE-2、TSC2、DAPKl、BAD、IMP、C-TAK1、TAKl、TAOl、TBK1、TESK1、TGFBR1、TIE2、TLK1、TrkA、TSSK1、TTBK1/2、TTK、Tpl2/cotl、MEK1、MEK2、PLDL Erkl、Erk2、Erk5、Erk8、p90RSK、PEA-15、SRF、p27 KIP1、TIF la、HMGN1、ER81、MKP-3、c-Fos、FGF-R1、GCK、GSK3ベータ、HER4、HIPK1/2/3/、IGF-1R、cdc25、UBF、LAMTOR2、Statl、StaO、CREB、JAK、Src、PTEN、NF-カッパB、HECTH9、Bax、HSP70、HSP90、Apaf-1、Cyto c、BCL-2、Bcl-xL、Smac、XIAP、カスパーゼ-9、カスパーゼ-3、カスパーゼ-6、カスパーゼ-7、CDC37、TAB、IKK、TRADD、TRAF2、R1P1、FLIP、TAKl、JNKl/2/3、Lck、A-Raf、B-Raf、C-Raf、MOS、MLKl/3、MN l/2、MSKl、MST2/3/4、MPSK1、MEKKl、ME K4、MEL、ASK1、MINK1、MKK 1/2/3/4/6/7、NE 2a/6/7、NUAK1、OSR1、SAP、STK33、Syk、Lyn、PDK1、PHK、PIM 1/2/3、アタキシン-1、mTORCl、MDM2、p21 Wafl、サイクリンDl、Lamln A、Tpl2、Myc、カテニン、Wnt、IKK-ベータ、IKK-ガンマ、IKK-アルファ、IKK-エプシロン、ELK、p65RelA、IRAKI、IRA 2、IRAK4、IRR、FADD、TRAF6、TRAF3、MKK3、MKK6、ROCK2、RSK1/2、SGK 1、SmMLCK、SIK2/3、ULK1/2、VEGFR1、WNK l、YES1、ZAP70、MAP4K3、MAP4K5、MAPKlb、MAPKAP-K2 K3、p38アルファ/ベータ/デルタ/ガンマMAPK、オーロラA、オーロラB、オーロラC、MCAK、Clip、MAPKAPK、FAK、MARK
1 /2/3/4、Mucl、SHC、CXCR4、Gap-1、Myc、ベータ-カテニン/TCF、Cbl、BRM、Mcl-1、BRD2、BRD3、BRD4、AR、RAS、ErbB3、EGFR、IRE1、HPK1、RIPK2、及びERα(列挙されるこれらのタンパク質の全てのバリアント、変異、スプライスバリアント、インデル、及び融合体を含む)などの標的タンパク質に結合する任意のペプチドまたは小分子である。
本明細書に記載されるPROTACのE3LB及びPB基は、リンカー(L2)と接続されることができる。ある特定の実施形態では、リンカー基L2は、Aの1つ以上の共有結合した構造単位(例えば、-A1...Aq-)を含む基であり、式中、A1は、E3LB、PB、またはこれらの組み合わせのうちの少なくとも1つに結合した基である。ある特定の実施形態では、A1は、E3LB、PB、またはこれらの組み合わせを、別のE3LB、PB、またはこれらの組み合わせに直接結合させる。他の実施形態では、A1は、Aqを通して、EL3B、PB、またはこれらの組み合わせを、別のE3LB、PB、またはこれらの組み合わせと間接的に結合させる。
式中、各Rは、H、またはC1-C3アルキル、アルカノール基、または複素環(リンカー基の水溶性を促進するための水溶性複素環、好ましくはモルホリノ、ピペリジン、もしくはピペラジン基を含む)であり、各Yは独立して、結合、O、S、またはN-Rであり、各iは独立して、0~100、1~75、1~60、1~55、1~50、1~45、1~40、2~35、3~30、1~15、1~10、1~8、1~6、1、2、3、4、または5である。
(式中、各Vは独立して、結合(不在)である)、
jは、1~100、1~75、1~60、1~55、1~50、1~45、1~40、
2~35、3~30、1~15、1~10、1~8、1~6、1、2、3、4、または5であり、
kは、1~100、1~75、1~60、1~55、1~50、1~45、1~40、2~35、3~30、1~15、1~10、1~8、1~6、1、2、3、4、または5であり、好ましくはkは、1、2、3、4、または5であり、
m’は、1~100、1~75、1~60、1~55、1~50、1~45、1~40、2~35、3~30、1~15、1~10、1~8、1~6、1、2、3、4、または5であり、
nは、1~100、1~75、1~60、1~55、1~50、1~45、1~40、2~35、3~30、1~15、1~10、1~8、1~6、1、2、3、4、または5であり、
X1は、O、S、またはN-R、好ましくはOであり、
Yは、上記と同じであり、
CONは、リンカー基中に存在する場合、ZをXに結合させるコネクター基(結合であり得る)である。
(式中、X2は、O、S、NR4、S(O)、S(O)2、-S(O)2O、-OS(O)2、またはOS(O)2Oであり、
X3は、O、S、CHR4、NR4であり、
Rは、H、または1つまたは2つのヒドロキシル基で任意に置換されたC1-C3アルキル基、またはその薬学的に許容される塩、エナンチオマー、もしくは立体異性体である)である。
本明細書に記載されるPROTACは、リンカーL1と共有結合して、L1-PROTAC基を調製することができる。これらの化合物は、以下の一般式を有し、
L1-D
式中、Dは、構造E3LB-L2-PBを有するPROTACであり、E3LBは、L2と共有結合したE3リガーゼ結合基であり、L2は、E3LB及びPBと共有結合したリンカーであり、PBは、L2と共有結合したタンパク質結合基であり、L1は、Dと共有結合したリンカーである。これらの成分に有用な基は、上記の通りである。
式中、
Strは、ストレッチャー単位であり、
Spは、D、すなわち、PROTAC部分と共有結合した結合またはスペーサ単位であり、
R1は、C1-C10アルキル、(C1-C10アルキル)NHC(NH)NH2、または(C1-C10アルキル)NHC(O)NH2であり、
R4及びR5は各々独立して、C1-C10アルキル、アリールアルキル、ヘテロアリールアルキル、(C1-C10アルキル)OCH2-であるか、またはR4及びR5はC3-C7シクロアルキル環を形成してもよく、
Dは、PROTAC部分である。
式中、
Strは、ストレッチャー単位であり、
Spは、D、すなわち、PROTAC部分と共有結合した任意のスペーサ単位であり、
Yは、ヘテロアリール、アリール、-C(O)C1-C6アルキレン、C1-C6アルキレン-NH2、C1-C6アルキレン-NH-CH3、C1-C6アルキレン-N-(CH3)2、C1-C6アルケニル、またはC1-C6アルキレニルであり、R1は、C1-C10アルキル、(C1-C10アルキル)NHC(NH)NH2、または(C1-C10アルキル)NHC(O)NH2であり、
R3及びR2は各々独立して、H、C1-C10アルキル、アリールアルキル、もしくはヘテロアリールアルキルであるか、またはR3及びR2は一緒にC3-C7シクロアルキルを形成してもよく、
Dは、PROTAC部分である。
式中、R6は、C1-C10アルキレンであり、R1、R2、及びR3は本明細書の他の箇所に記載される通りであり、Dは、PROTAC部分である。
式中、R6は、C1-C10アルキレン、C3-C8シクロアルキル、O-(C1-C8アルキレン)、及びC1-C10アルキレン-C(O)N(Ra)-C2-C6アルキレンからなる群から選択され、各アルキレンは、ハロ、トリフルオロメチル、ジフルオロメチル、アミノ、アルキルアミノ、シアノ、スルホニル、スルホンアミド、スルホキシド、ヒドロキシ、アルコキシ、エステル、カルボン酸、アルキルチオ、C3-C8シクロアルキル、C4-C7ヘテロシクロアルキルアリール、アリールアルキル、ヘテロアリールアルキル、及びヘテロアリールからなる群から選択される1~5個の置換基によって置換されてもよく、各Raは各々独立して、HまたはC1-C6アルキルであり、Spは、-Ar-Rb-であり、Arは、アリールまたはヘテロアリールであり、Rbは、(C1-C10アルキレン)O-である。
式中、
は、抗体にコンジュゲートすることができる部分を示し、R7は、C1-C10アルキレン、C1-C10アルキレン-O、N(Rc)-(C2-C6アルキレン)-N(Rc)、及びN(Rc)-(C2-C6アルキレン)から選択され、各Rcは独立して、HまたはC1-C6アルキルであり、
Spは、-Ar-Rb-であり、式中、Arは、アリールもしくはヘテロアリールであり、Rbは、(C1-C10アルキレン)O-であるか、またはR6は、C1-C10アルキレンであり、Spは、-Ar-Rb-であり、Arは、アリールであり、Rbは、(C1-C6アルキレン)O-である。
1.以下の化学構造を有するコンジュゲートであって、
Ab-(L1-D)p
式中、
Dは、構造E3LB-L2-PBを有するPROTACであり、
E3LBは、L2と共有結合したE3リガーゼ結合基であり、
L2は、E3LB及びPBと共有結合したリンカーであり、
PBは、L2と共有結合したタンパク質結合基であり、
Abは、L1と共有結合した抗体であり、
L1は、Ab及びDと共有結合したリンカーであり、
pは、約1~約8の値を有する、コンジュゲート。
式中、R1、R2、R3、R4、及びR5が、WO/2015/071393に記載される通りであり、その中に全ての化合物を含む、任意の上記の実施形態に記載のコンジュゲート。
-Str-(PM)-Sp-
式中、
Strは、Abに共有結合したストレッチャー単位であり、
Spは、PROTAC部分に共有結合した結合またはスペーサ単位であり、
PMは、以下からなる群から選択される非ペプチド化学部分であり、
Wは、-NH-ヘテロシクロアルキル-またはヘテロシクロアルキルであり、
Yは、ヘテロアリール、アリール、-C(O)C1-C6アルキレン、C1-C6アルキレン-NH2、C1-C6アルキレン-NH-CH3、C1-C6アルキレン-N-(CH3)2、C1-C6アルケニル、またはC1-C6アルキレニルであり、
各R1は独立して、C1-C10アルキル、C1-C10アルケニル、(C1-C10アルキル)NHC(NH)NH2、または(C1-C10アルキル)NHC(O)NH2であり、
R3及びR2は各々独立して、H、C1-C10アルキル、C1-C10アルケニル、アリールアルキル、もしくはヘテロアリールアルキルであるか、またはR3及びR2は一緒になってC3-C7シクロアルキルを形成してもよく、
R4及びR5は各々独立して、C1-C10アルキル、C1-C10アルケニル、アリールアルキル、ヘテロアリールアルキル、(C1-C10アルキル)OCH2-であるか、またはR4及びR5は一緒になってC3-C7シクロアルキル環を形成してもよい、任意の上記の実施形態に記載のコンジュゲート。
式中、R6は、C1-C10アルキレン、C1-C10アルケニル、C3-C8シクロアルキル、(C1-C8アルキレン)O-、及びC1-C10アルキレン-C(O)N(Ra)-C2-C6アルキレンからなる群から選択され、各アルキレンは、ハロ、トリフルオロメチル、ジフルオロメチル、アミノ、アルキルアミノ、シアノ、スルホニル、スルホンアミド、スルホキシド、ヒドロキシ、アルコキシ、エステル、カルボン酸、アルキルチオ、C3-C8シクロアルキル、C4-C7ヘテロシクロアルキル、ヘテロアリールアルキル、アリールアリールアルキル、ヘテロアリールアルキル、及びヘテロアリールからなる群から選択される1~5個の置換基で置換されてもよく、各Raは独立して、HまたはC1-C6アルキルであり、Spは、-C1-C6アルキレン-C(O)NH-または-Ar-Rb-であり、Arは、アリールまたはヘテロアリールであり、Rbは、(C1-C10アルキレン)O-である、任意の上記の実施形態に記載のコンジュゲート。
式中、R7は、C1-C10アルキレン、C1-C10アルケニル、(C1-C10アルキレン)O-、N(Rc)-(C2-C6アルキレン)-N(Rc)、及びN(Rc)-(C2-C6アルキレン)から選択され、各Rcは独立して、HまたはC1-C6アルキルであり、
Spは、-C1-C6アルキレン-C(O)NH-または-Ar-Rb-であり、Arは、アリールまたはヘテロアリールであり、Rbは、(C1-C10アルキレン)O-である、任意の上記の実施形態に記載のコンジュゲート。
R1は、C1-C6アルキル、C1-C6アルケニル、(C1-C6アルキル)NHC(NH)NH2、または(C1-C6アルキル)NHC(O)NH2であり、
R3及びR2は各々独立して、H、C1-C10アルキルであり、Str及びSpは、本明細書に定義される通りである、任意の上記の実施形態に記載のコンジュゲート。
R1は、C1-C6アルキル、(C1-C6アルキル)NHC(NH)NH2、または(C1-C6アルキル)NHC(O)NH2であり、Str及びSpは、本明細書に定義される通りであり、
R4及びR5は一緒になってC3-C7シクロアルキル環を形成する、任意の上記の実施形態に記載のコンジュゲート。
Str及びSpは、本明細書に定義される通りであり、
R1は、C1-C6アルキル、(C1-C6アルキル)NHC(NH)NH2、または(C1-C6アルキル)NHC(O)NH2である、任意の上記の実施形態に記載のコンジュゲート。
式中、
Strは、以下の式によって表される化学構造であり、
R6は、C1-C10アルキレン及びC1-C10アルキレン-C(O)N(Ra)-C2-C6アルキレンからなる群から選択され、各アルキレンは、ハロ、トリフルオロメチル、ジフルオロメチル、アミノ、アルキルアミノ、シアノ、スルホニル、スルホンアミド、スルホキシド、ヒドロキシ、アルコキシ、エステル、カルボン酸、アルキルチオ、C3-C8シクロアルキル、C4-C7ヘテロシクロアルキル、ヘテロアリールアルキル、アリール、アリールアルキル、ヘテロアリールアルキル、及びヘテロアリールからなる群から選択される1~5個の置換基によって置換されてもよく、各Raは独立して、HまたはC1-C6アルキルであり、
Ab及びSpは、本明細書に定義される通りであり、
pは、1、2、3、または4である、任意の上記の実施形態に記載のコンジュゲート。
式中、
Strは、以下の式によって表される化学構造であり、
R6は、C1-C10アルキレン及びC1-C10アルキレン-C(O)N(Ra)-C2-C6アルキレンからなる群から選択され、各アルキレンは、ハロ、トリフルオロメチル、ジフルオロメチル、アミノ、アルキルアミノ、シアノ、スルホニル、スルホンアミド、スルホキシド、ヒドロキシ、アルコキシ、エステル、カルボン酸、アルキルチオ、C3-C8シクロアルキル、C4-C7ヘテロシクロアルキル、アリール、アリールアルキル、ヘテロアリールアルキル、及びヘテロアリールからなる群から選択される1~5個の置換基によって置換されてもよく、各Raは独立して、HまたはC1-C6アルキルであり、
R1、R4、R5、Ab、D、及びSpは、本明細書に定義される通りであり、
pは、1、2、3、または4である、任意の上記の実施形態に記載のコンジュゲート。
R6は、C1-C6アルキレンであり、
Spは、-C1-C6アルキレン-C(O)NH-または-Ar-Rb-であり、Arは、アリールであり、Rbは、(C1-C3アルキレン)O-である、任意の上記の実施形態に記載のコンジュゲート。
式中、
Ab、D、R2、及びR3は、本明細書に定義される通りであり、
R1は、C1-C6アルキル-NH2、(C1-C6アルキル)NHC(NH)NH2、または(C1-C6アルキル)NHC(O)NH2であり、
pは、1、2、3、または4である、任意の上記の実施形態に記載のコンジュゲート。
式中、
Ab及びDは、本明細書に定義される通りであり、
pは、1、2、3、または4であり、
R1は、C1-C6アルキル-NH2、(C1-C6アルキル)NHC(NH)NH2、または(C1-C6アルキル)NHC(O)NH2であり、
R4及びR5は各々独立して、C1-C6アルキルであり、アルキルは、非置換であるか、またはR4及びR5は、それが結合する炭素と一緒になってシクロブチルなどのC3-C7シクロアルキル環を形成することができる、任意の上記の実施形態に記載のコンジュゲート。
式中、R1及びR2は独立して、H及びC1-C6アルキルから選択されるか、またはR1及びR2は、3、4、5、もしくは6員のシクロアルキルもしくはヘテロシクリル基を形成する、任意の上記の実施形態に記載のコンジュゲート。
本明細書に記載されるPAC及び化合物は、特に、本明細書に含まれる説明を考慮して、化学分野で周知であるもの、及びComprehensive Heterocyclic Chemistry II,Editors Katritzky and Rees,Elsevier,1997、例えば第3巻;Liebigs Annalen der Chemie,(9):1910-16,(1985);Helvetica Chimica Acta,41:1052-60,(1958);Arzneimittel-Forschung,40(12):1328-31,(1990)に記載される他の複素環のためのものと類似のプロセスを含む合成経路によって合成することができる。開始材料は、一般に、Aldrich Chemicals(Milwaukee,WI)などの商業的な供給源から入手可能であるか、または当業者に周知である方法を使用して容易に調製される(例えば、Louis F.Fieser and Mary Fieser,Reagents for Organic Synthesis,v.1-23,Wiley,N.Y.(1967-2006ed.)、またはその付録も(これもまたBeilsteinオンラインデータベースを介して入手可能である)を含む、Beilsteins Handbuch der organischen Chemie,4,Aufl.ed.Springer-Verlag,Berlinに一般に記載される方法によって調製される)。
York,1991を参照されたい。
リンカーL1に関して、スキーム1~4は、抗体Abへのジスルフィド結合のための例示的なリンカーL1への合成経路を描写する。Abは、ジスルフィド結合を通してL1と接続し、PROTACは、PROTAC上の任意の利用可能な結合を通してL1と接続している。
還元及び再酸化によるコンジュゲーションのためのシステイン操作された抗体に関して、それらは一般に以下のように調製することができる。軽鎖アミノ酸は、Kabat(Kabat et al.,Sequences of proteins of immunological interest,(1991)5th Ed.,US Dept of Health and Human Service,National Institutes of Health,Bethesda,MD)に従って付番される。重鎖アミノ酸は、Kabatシステムとして示されている場合を除いて、EU付番システム(Edelman et al(1969)Proc.Natl.Acad.of
Sci.63(1):78-85)に従って付番される。一文字のアミノ酸の略語が使用される。
リンカーL1-PROTAC化合物を抗体にコンジュゲートする1つの方法では、上記の還元及び再酸化手順の後に、10mMコハク酸塩(pH5)、150mM NaCl、2mM EDTA中のシステイン操作された抗体(THIOMAB(商標)抗体)を、1M TrisでpH7.5~8.5になるようにpH調節する。チオール反応性(例えば、マレイミドまたは4-ニトロピリジジスルフィド)を有する、過剰量の約3モル~20当量のリンカー-PROTAC中間体をDMF、DMA、またはプロピレングリコール中に溶解し、還元、再酸化、及びpH調節された抗体に添加する。反応を室温または37℃でインキュベートし、反応混合物のLC-MS分析によって判定される完了まで監視する(1~約24時間)。反応が完了すると、コンジュゲートを、残りの未反応リンカー-PROTAC中間体及び凝集タンパク質(有意なレベルで存在する場合)を除去することを目的として、いくつかの方法のうちの1つまたは任意の組み合わせによって精製する。例えば、最終pHがおよそ5.5になるまでコンジュゲートを10mM酢酸ヒスチジン(pH5.5)で希釈し、Akta精製システムに接続したHiTrap Sカラム(GE Healthcare)またはSマキシスピンカラム(Pierce)のいずれかを使用してSカチオン交換クロマトグラフィーによって精製してもよい。代替的には、コンジュゲートを、Akta精製システムに接続したS200カラムまたはZebaスピンカラムを使用してゲル濾過クロマトグラフィーによって精製してもよい。代替的には、透析を使用してもよい。THIOMAB(商標)抗体PROTACコンジュゲートを、ゲル濾過または透析のいずれかを使用して、240mMのスクロースで20mM His/酢酸(pH5)内に製剤化した。精製されたコンジュゲートを遠心分離限外濾過によって濃縮し、滅菌状態下で0.2μmのフィルターを通して濾過し、保管のために冷凍する。タンパク質濃度を判定するためのBCAアッセイ、凝集分析のための分析的SEC(サイズ排除クロマトグラフィー)、及びPARを計算するためのリジンCエンドペプチダーゼ(LysC)での処理後のLC-MSによってPACを特性評価した。
本明細書に記載される治療用PROTAC-抗体コンジュゲート(PAC)の製剤は、薬学的に許容される非経口ビヒクルと共に、非経口投与、例えば、ボーラス、静脈内、腫瘍内注射のために、かつ単位用量注射可能な形態で調製することができる。所望の純度を有するPACは、再構成のための凍結乾燥製剤または水溶液の形態で、1つ以上の薬学的に許容される賦形剤と任意に混合される(Remington’s Pharmaceutical Sciences(1980)16th edition,Osol,A.Ed.)。
本明細書に開示されるPROTAC-抗体コンジュゲート(PAC)は、様々な疾患または障害を治療するための使用され得ることが企図される。例示的な過剰増殖性障害には、良性または悪性の固形腫瘍、ならびに白血病及びリンパ系腫瘍など血液疾患が含まれる。他には、神経、膠細胞、星細胞、視床下部、腺、マクロファージ、上皮、間質、胞胚腔、炎症、血管新生、自己免疫を含む免疫の疾患が含まれる。
別の態様において、製品が本明細書に記載され、例えば、上記の疾患及び障害の治療のために有用な材料を含有する「キット」が提供される。キットは、PACを含む容器を含む。キットは、容器上に、または容器と関連付けられたラベルまたは添付文書をさらに含んでもよい。「添付文書」という用語は、治療剤製品の適応症、使用法、投薬量、投与、禁忌症、及び/またはその使用に関する警告についての情報を含む、かかる治療剤製品のパッケージに通例含まれる指示書を指すように使用される。
PACの合成
A.PROTACの化学合成:
i.E3リガーゼ結合基(E3LB)へのリンカー(L2)の結合
4-[[(2S,3S)-3-[(2S)-2-[[(tert-ブトキシ)カルボニル](メチル)アミノ]プロパンアミド]-8-シアノ-5-[(2-メトキシナフタレン-1-イル)メチル]-2-メチル-4-オキソ-2,3,4,5-テトラヒドロ-1H-1,5-ベンゾジアゼピン-1-イル]カルボニル]安息香酸メチル1,2-ジクロロエタン(50mL)中のN-[(1S)-1-[[(3S,4S)-7-シアノ-1-[(2-メトキシナフタレン-1-イル)メチル]-4-メチル-2-オキソ-2,3,4,5-テトラヒドロ-1H-1,5-ベンゾジアゼピン-3-イル]カルバモイル]エチル]-N-メチルカルバミン酸tert-ブチル(3.00g、5.25mmol)の溶液に、トリエチルアミン(2.6g、25.7mmol)及び4-(カルボノクロリドイル)安息香酸メチル(3.10g、15.61mmol)を窒素下で添加した。得られた溶液を、80℃で5時間撹拌し、室温まで冷却した。水(100mL)を添加した。得られた溶液を3×100mLのジクロロメタンで抽出し、有機層を合わせ、無水硫酸ナトリウム上で乾燥させ、真空下で濃縮した。酢酸エチル/石油エーテル(1:1)で溶出するシリカゲル上のフラッシュクロマトグラフィーによって残渣を精製した。これは、3.10g(81%)の4-[[(2S,3S)-3-[(2S)-2-[[(tert-ブトキシ)カルボニル](メチル)アミノ]プロパンアミド]-8-シアノ-5-[(2-メトキシナフタレン-1-イル)メチル]-2-メチル-4-オキソ-2,3,4,5-テトラヒドロ-1H-1,5-ベンゾジアゼピン-1-イル]カルボニル]安息香酸メチルを茶色の固体としてもたらした。MS(ESI):[M+H]+=734.4。
2,2-ジメトキシプロパン(5mL、40.327mmol)中の2-[2-(2-アミノエトキシ)エトキシ]酢酸塩酸塩(500mg、2.505mmol)の溶液に、濃縮HCl(0.2mL)を室温で滴下した。反応混合物を25℃で15時間撹拌し、真空下で濃縮した。さらなる精製を伴わずに残渣を直接使用した。
4-((2S,3S)-8-シアノ-5-((2-メトキシナフタレン-1-イル)メチル)-2-メチル-3-((S)-2-(メチルアミノ)プロパンアミド)-4-オキソ-2,3,4,5-テトラヒドロ-1H-ベンゾ[b][1,4]ジアゼピン-1-カルボニル)-N-(2-(2-(2-((2-(4-(1-(4-ヒドロキシフェニル)-2-フェニルブト-1-エン-1-イル)フェノキシ)エチル)(メチル)アミノ)-2-オキソエトキシ)エトキシ)エチル)ベンズアミド(「化合物P1」)2-メチルテトラヒドロフラン(0.855mL)中の2-[2-[2-[[4-[(3S,4S)-3-[[(2S)-2-[tert-ブトキシカルボニル(メチル)アミノ]プロパノイル]アミノ]-7-シアノ-1-[(2-メトキシ-1-ナフチル)メチル]-4-メチル-2-オキソ-3,4-ジヒドロ-1,5-ベンゾジアゼピン-5-カルボニル]ベンゾイル]アミノ]エトキシ]エトキシ]酢酸(74mg、0.0855mmol)の溶液に、HATU(1.1当量、36.5mg、0.0941mmol)及びN,N-ジイソプロピルエチルアミン(3.0当量、0.045mL、0.257mmol)を添加した。混合物を室温で30分間撹拌し、その後、2-メチルテトラヒドロフラン(60、0.5mL、400mg、5mmol)中の4-[1-[4-[2-(メチルアミノ)エトキシ]フェニル]-2-フェニル-ブト-1-エニル]フェノール(1.05当量、33.5mg、0.0898mmol)の溶液、続いて0.2mL DMFを添加した。混合物を室温で22時間撹拌した。水を添加し、溶液をiPrOAcで3回抽出した。有機層を合わせ、その後、硫酸ナトリウムで乾燥させ、真空中で濃縮した。
iii.PROTACへのリンカーL1の結合
N-[(1S)-1-[[(1S)-4-(カルバモイルアミノ)-1-[(4-[4-[(1Z)-1-(4-[2-[2-(2-[2-[(4-[[(2S,3S)-8-シアノ-5-[(2-メトキシナフタレン-1-イル)メチル]-2-メチル-3-[(2S)-2-(メチルアミノ)プロパンアミド]-4-オキソ-2,3,4,5-テトラヒドロ-1H-1,5-ベンゾジアゼピン-1-イル]カルボニル]フェニル)ホルムアミド]エトキシ]エトキシ)-N-メチルアセトアミド]エトキシ]フェニル)-2-フェニルブト-1-エン-1-イル]フェノキシメチル]フェニル)カルバモイル]ブチル]カルバモイル]-2-メチルプロピル]-6-(2,5-ジオキソ-2,5-ジヒドロ-1H-ピロール-1-イル)ヘキサンアミド(「化合物LP2」)DMF(0.9mL)中の(2S)-N-[(3S,4S)-7-シアノ-5-[(4-[[2-(2-[[(2-[4-[(1Z)-1-(4-ヒドロキシフェニル)-2-フェニルブト-1-エン-1-イル]フェノキシ]エチル)(メチル)カルバモイル]メトキシ]エトキシ)エチル]カルバモイル]フェニル)カルボニル]-1-[(2-メトキシナフタレン-1-イル)メチル]-4-メチル-2-オキソ-2,3,4,5-テトラヒドロ-1H-1,5-ベンゾジアゼピン-3-イル]-2-(メチルアミノ)プロパンアミド(化合物P1、48mg、0.043mmol)及びN-[(1S)-1-{[(1S)-4-(カルバモイルアミノ)-1-{[4-(クロロメチル)フェニル]カルバモイル}ブチル]カルバモイル}-2-メチルプロピル]-6-(2,5-ジオキソ-2,5-ジヒドロ-1H-ピロール-1-イル)ヘキサンアミド(90mg、0.152mmol)の溶液に、K2CO3(60mg、0.43mmol)を0℃で添加した。反応混合物を0℃で4時間撹拌し、予冷されたDMF(0.9mL)で希釈した。固体を濾過して除去した。濾液を以下の条件(カラム、SunFire Prep C18OBDカラム、19*150mm5um、10nm;移動相、水(0.1%TFA)及びCH3CN(5%CH3CNから10分間で最大48%);検出器、UV254/220nm)で分取HPLCによって精製して、22mg(31%)のN-[(1S)-1-[[(1S)-4-(カルバモイルアミノ)-1-[(4-[4-[(1Z)-1-(4-[2-[2-(2-[2-[(4-[[(2S,3S)-8-シアノ-5-[(2-メトキシナフタレン-1-イル)メチル]-2-メチル-3-[(2S)-2-(メチルアミノ)プロパンアミド]-4-オキソ-2,3,4,5-テトラヒドロ-1H-1,5-ベンゾジアゼピン-1-イル]カルボニル]フェニル)ホルムアミド]エトキシ]エトキシ)-N-メチルアセトアミド]エトキシ]フェニル)-2-フェニルブト-1-エン-1-イル]フェノキシメチル]フェニル)カルバモイル]ブチル]カルバモイル]-2-メチルプロピル]-6-(2,5-ジオキソ-2,5-ジヒドロ-1H-ピロール-1-イル)ヘキサンアミドを白色の固体として得た。MS(ESI):[M+H]+=1675.1;1H-NMR(400Mhz、DMSO-d6):δ(ppm)10.15(s、1H)、9.95-9.72(m、1H)、9.52-9.41(m、1H)、9.31-9.14(m、1H)、8.43(brs、1H)、8.20-8.18(m、1H)、8.17-8.07(m、2H)、7.93(m、2H)、7.70(d、J=8Hz、1H)、7.70-7.65(m、3H)、7.48-7.42(m、2H)、7.41-7.36(m、1H)、7.33-7.28(m、1H)、7.23(m、1H)、7.18-7.07(m、7H)、7.02-7.01(m、1H)、6.99(s、3H)、6.96-6.92(m、2H)、6.76-6.67(m、2H)、6.60-6.58(m、2H)、6.40(d、J=8.4Hz、1H)、6.13-6.08(m、1H)、5.99(s、1H)、5.80(d、J=7.6Hz、2H)、5.55(d、J=15.2Hz、1H)、5.44(brs、1H)、5.02-4.93(m、1H)、7.43-4.36(m、3H)、4.26-4.02(m、6H)、3.95-3.88(m、4H)、3.66-3.63(m、3H)、3.57-3.53(m、4H)、3.39-3.36(m、4H)、3.05-2.81(m、5H)、2.68(s、2H)、2.42-2.39(m、3H)、2.22-2.07(m、2H)、2.03-1.91(m、1H)、1.71(brs、2H)、1.62(brs、3H)、1.50-1.36(m、6H)、1.21-1.17(m、5H)、0.87-0.82(m、10H)。
iv.リンカーL1を介したPROTACへの抗体(Ab)の結合
PROTAC-抗体コンジュゲート(PAC)を得るためのHER2及びB7H4抗体へのPROTACのコンジュゲーションを以下のように達成した。
PACの特性評価
PACを特性評価して、タンパク質濃度(例えば、BCAアッセイによって)、凝集レベル(分析的SECによって)、PAR(例えば、LC-MSによって)を判定した。
MC-VC-PABは、(6-マレイミドカプロイル)-(バリン-シトルリン)-(p-アミノベンジル)を指す。
Thioは、THIOMAB(商標)抗体を意味する。
LC K149Cは、軽鎖において149位のKがCに変わったことを示すHuは、ヒトを意味する
抗HER2及び抗B7-H4は、それぞれHER2及びB7-H4に結合する抗体を意味する。
HER-2含有PACのエストロゲン受容体α密度への効果の検出
以下の実験は、PROTAC及びPROTAC-抗体コンジュゲートによる治療後の、ウェスタンブロット法によるMCF7-neo/HER2細胞株中のエストロゲン受容体α(ER-α)の検出について記載する。
NaCl、2.5mM MgCl2、0.1% Triton X-100、プロテアーゼ阻害剤カクテル(Roche))中に溶解した。全タンパク質濃度をBCA(ThermoFisher)によって判定した。各試料について、10ugの全細胞タンパク質を4~12% Bis-Trisゲル上で分離し、Invitrolon PVDF膜(Thermofisher)に移した。10%脱脂粉乳を含有するPBS-0.1% Tween-20中で膜をブロックし、1:1000希釈にてエストロゲン受容体α(Santa Cruz、SC-8002)及びGAPDH(Santa Cruz、SC25778 HRP)に対する一次抗体で、続いて1:5000希釈にてマウスIgG(GE
Healthcare)に対する二次抗体で探索した。
HER-2含有PACのエストロゲン受容体α密度への効果の検出
以下の実験は、PROTAC及びPROTAC-抗体コンジュゲートでの治療後のMCF7-neo/HER2細胞中のERαの定量化について記載する。
Molecular Biology,2nd Ed.,J.Wiley&Sons,New York,NY;及びJaneway,C.,Travers,P.,Walport,M.,Shlomchik(2001)Immunobiology,5th Ed.,Garland Publishing,New Yorkと一致する。
SEQUENCE LISTING
<110> Genentech, Inc.
<120> PROTAC ANTIBODY CONJUGATES AND METHODS OF USE
<140> PCT/US2017/033611
<141> 2017-05-19
<150> US 62/339,257
<151> 2016-05-20
<160> 92
<170> PatentIn version 3.5
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Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 17
<211> 112
<212> PRT
<213> homo sapiens
<400> 17
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Gln Ser Val Ser Gly Ser
20 25 30
Arg Phe Thr Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Ile Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 18
<211> 118
<212> PRT
<213> homo sapiens
<400> 18
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Leu Asp Ala Glu Ile Arg Ala Asn Gln Lys Phe
50 55 60
Arg Asp Arg Val Thr Ile Thr Val Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Tyr Asp Gly Gly Phe Glu Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser
115
<210> 19
<211> 15
<212> PRT
<213> homo sapiens
<400> 19
Arg Ala Ser Gln Ser Val Ser Gly Ser Arg Phe Thr Tyr Met His
1 5 10 15
<210> 20
<211> 7
<212> PRT
<213> homo sapiens
<400> 20
Tyr Ala Ser Ile Leu Glu Ser
1 5
<210> 21
<211> 10
<212> PRT
<213> homo sapiens
<400> 21
Gln His Ser Trp Glu Ile Pro Pro Trp Thr
1 5 10
<210> 22
<211> 5
<212> PRT
<213> homo sapiens
<400> 22
Gly Tyr Trp Met Asn
1 5
<210> 23
<211> 17
<212> PRT
<213> homo sapiens
<400> 23
Met Ile His Pro Leu Asp Ala Glu Ile Arg Ala Asn Gln Lys Phe Arg
1 5 10 15
Asp
<210> 24
<211> 9
<212> PRT
<213> homo sapiens
<400> 24
Gly Thr Tyr Asp Gly Gly Phe Glu Tyr
1 5
<210> 25
<211> 219
<212> PRT
<213> homo sapiens
<400> 25
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Gln Ser Val Ser Gly Ser
20 25 30
Arg Phe Thr Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Ile Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 26
<211> 448
<212> PRT
<213> homo sapiens
<400> 26
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Leu Asp Ala Glu Ile Arg Ala Asn Gln Lys Phe
50 55 60
Arg Asp Arg Val Thr Ile Thr Val Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Tyr Asp Gly Gly Phe Glu Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 27
<211> 17
<212> PRT
<213> homo sapiens
<400> 27
Met Ile His Pro Met Asp Ser Glu Ile Arg Ala Asn Gln Lys Phe Arg
1 5 10 15
Asp
<210> 28
<211> 17
<212> PRT
<213> homo sapiens
<400> 28
Met Ile His Pro Leu Asp Ser Glu Ile Arg Ala Asn Gln Lys Phe Arg
1 5 10 15
Asp
<210> 29
<211> 9
<212> PRT
<213> homo sapiens
<400> 29
Gly Thr Tyr Asp Gly Gly Phe Lys Tyr
1 5
<210> 30
<211> 219
<212> PRT
<213> homo sapiens
<400> 30
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly
1 5 10 15
Glu Arg Ala Thr Ile Asn Cys Arg Ala Ser Gln Ser Val Ser Gly Ser
20 25 30
Arg Phe Thr Tyr Met His Trp Tyr Gln Gln Lys Pro Gly Gln Pro Pro
35 40 45
Lys Leu Leu Ile Lys Tyr Ala Ser Ile Leu Glu Ser Gly Val Pro Asp
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln His Ser Trp
85 90 95
Glu Ile Pro Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Cys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 31
<211> 448
<212> PRT
<213> homo sapiens
<400> 31
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Leu Asp Ala Glu Ile Arg Ala Asn Gln Lys Phe
50 55 60
Arg Asp Arg Val Thr Ile Thr Val Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Tyr Asp Gly Gly Phe Glu Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Cys Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 32
<211> 448
<212> PRT
<213> homo sapiens
<400> 32
Glu Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Ser Phe Thr Gly Tyr
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Ile
35 40 45
Gly Met Ile His Pro Leu Asp Ala Glu Ile Arg Ala Asn Gln Lys Phe
50 55 60
Arg Asp Arg Val Thr Ile Thr Val Asp Thr Ser Thr Ser Thr Ala Tyr
65 70 75 80
Leu Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Gly Thr Tyr Asp Gly Gly Phe Glu Tyr Trp Gly Gln Gly Thr
100 105 110
Leu Val Thr Val Ser Ser Cys Ser Thr Lys Gly Pro Ser Val Phe Pro
115 120 125
Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly
130 135 140
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn
145 150 155 160
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
165 170 175
Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
180 185 190
Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys Pro Ser
195 200 205
Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp Lys Thr
210 215 220
His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly Pro Ser
225 230 235 240
Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
245 250 255
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
260 265 270
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
275 280 285
Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val
290 295 300
Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
305 310 315 320
Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu Lys Thr
325 330 335
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu
340 345 350
Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
355 360 365
Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
370 375 380
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
385 390 395 400
Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
405 410 415
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
420 425 430
Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
435 440 445
<210> 33
<211> 8
<212> PRT
<213> homo sapiens
<400> 33
Tyr Gly Ala Thr Ser Leu Glu Thr
1 5
<210> 34
<211> 9
<212> PRT
<213> homo sapiens
<400> 34
Gln Gln Tyr Trp Thr Thr Pro Phe Thr
1 5
<210> 35
<211> 11
<212> PRT
<213> homo sapiens
<400> 35
Gly Tyr Ser Ile Thr Asn Asp Tyr Ala Trp Asn
1 5 10
<210> 36
<211> 17
<212> PRT
<213> homo sapiens
<400> 36
Gly Tyr Ile Ser Tyr Ser Gly Tyr Thr Thr Tyr Asn Pro Ser Leu Lys
1 5 10 15
Ser
<210> 37
<211> 9
<212> PRT
<213> homo sapiens
<400> 37
Ala Arg Trp Ala Ser Gly Leu Asp Tyr
1 5
<210> 38
<211> 108
<212> PRT
<213> homo sapiens
<400> 38
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Asp Leu Ile His Asn Trp
20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile
35 40 45
Tyr Gly Ala Thr Ser Leu Glu Thr Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Tyr Trp Thr Thr Pro Phe
85 90 95
Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105
<210> 39
<211> 116
<212> PRT
<213> homo sapiens
<400> 39
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Ser Ile Thr Asn Asp
20 25 30
Tyr Ala Trp Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Tyr Ile Ser Tyr Ser Gly Tyr Thr Thr Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Trp Ala Ser Gly Leu Asp Tyr Trp Gly Gln Gly Thr Leu Val
100 105 110
Thr Val Ser Ser
115
<210> 40
<211> 11
<212> PRT
<213> homo sapiens
<400> 40
Gly Tyr Ser Ile Thr Ser Asp Tyr Ala Trp Asn
1 5 10
<210> 41
<211> 17
<212> PRT
<213> homo sapiens
<400> 41
Gly Tyr Ile Ser Asn Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu Lys
1 5 10 15
Ser
<210> 42
<211> 15
<212> PRT
<213> homo sapiens
<400> 42
Glu Arg Asn Tyr Asp Tyr Asp Asp Tyr Tyr Tyr Ala Met Asp Tyr
1 5 10 15
<210> 43
<211> 17
<212> PRT
<213> homo sapiens
<400> 43
Lys Ser Ser Gln Ser Leu Leu Tyr Arg Ser Asn Gln Lys Asn Tyr Leu
1 5 10 15
Ala
<210> 44
<211> 7
<212> PRT
<213> homo sapiens
<400> 44
Trp Ala Ser Thr Arg Glu Ser
1 5
<210> 45
<211> 9
<212> PRT
<213> homo sapiens
<400> 45
Gln Gln Tyr Tyr Asn Tyr Pro Arg Thr
1 5
<210> 46
<211> 124
<212> PRT
<213> homo sapiens
<400> 46
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Val Ser Gly Tyr Ser Ile Thr Ser Asp
20 25 30
Tyr Ala Trp Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
35 40 45
Val Gly Tyr Ile Ser Asn Ser Gly Ser Thr Ser Tyr Asn Pro Ser Leu
50 55 60
Lys Ser Arg Phe Thr Ile Ser Arg Asp Thr Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Arg Asn Tyr Asp Tyr Asp Asp Tyr Tyr Tyr Ala Met Asp
100 105 110
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 47
<211> 113
<212> PRT
<213> homo sapiens
<400> 47
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ser Ser Gln Ser Leu Leu Tyr Arg
20 25 30
Ser Asn Gln Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys
35 40 45
Ala Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val
50 55 60
Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
65 70 75 80
Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln
85 90 95
Tyr Tyr Asn Tyr Pro Arg Thr Phe Gly Gln Gly Thr Lys Val Glu Ile
100 105 110
Lys
<210> 48
<211> 10
<212> PRT
<213> homo sapiens
<400> 48
Gly Phe Ser Phe Ser Asp Phe Ala Met Ser
1 5 10
<210> 49
<211> 18
<212> PRT
<213> homo sapiens
<400> 49
Ala Thr Ile Gly Arg Val Ala Phe His Thr Tyr Tyr Pro Asp Ser Met
1 5 10 15
Lys Gly
<210> 50
<211> 13
<212> PRT
<213> homo sapiens
<400> 50
Ala Arg His Arg Gly Phe Asp Val Gly His Phe Asp Phe
1 5 10
<210> 51
<211> 16
<212> PRT
<213> homo sapiens
<400> 51
Arg Ser Ser Glu Thr Leu Val His Ser Ser Gly Asn Thr Tyr Leu Glu
1 5 10 15
<210> 52
<211> 7
<212> PRT
<213> homo sapiens
<400> 52
Arg Val Ser Asn Arg Phe Ser
1 5
<210> 53
<211> 9
<212> PRT
<213> homo sapiens
<400> 53
Phe Gln Gly Ser Phe Asn Pro Leu Thr
1 5
<210> 54
<211> 120
<212> PRT
<213> homo sapiens
<400> 54
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Asp Phe
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Gly Arg Val Ala Phe His Thr Tyr Tyr Pro Asp Ser Met
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Arg Gly Phe Asp Val Gly His Phe Asp Phe Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 55
<211> 113
<212> PRT
<213> homo sapiens
<400> 55
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Glu Thr Leu Val His Ser
20 25 30
Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Arg Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Phe Asn Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 56
<211> 117
<212> PRT
<213> homo sapiens
<400> 56
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Thr Phe Ser Ser Tyr
20 25 30
Trp Ile Glu Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Ile
35 40 45
Gly Glu Ile Leu Pro Gly Gly Gly Asp Thr Asn Tyr Asn Glu Ile Phe
50 55 60
Lys Gly Arg Ala Thr Phe Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Thr Arg Arg Val Pro Ile Arg Leu Asp Tyr Trp Gly Gln Gly Thr Leu
100 105 110
Val Thr Val Ser Ser
115
<210> 57
<211> 112
<212> PRT
<213> homo sapiens
<400> 57
Asp Ile Gln Leu Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Lys Ala Ser Gln Ser Val Asp Tyr Glu
20 25 30
Gly Asp Ser Phe Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
35 40 45
Lys Leu Leu Ile Tyr Ala Ala Ser Asn Leu Glu Ser Gly Val Pro Ser
50 55 60
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
65 70 75 80
Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Asn
85 90 95
Glu Asp Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys Arg
100 105 110
<210> 58
<211> 10
<212> PRT
<213> homo sapiens
<400> 58
Gly Tyr Thr Phe Ser Ser Tyr Trp Ile Glu
1 5 10
<210> 59
<211> 18
<212> PRT
<213> homo sapiens
<400> 59
Gly Glu Ile Leu Pro Gly Gly Gly Asp Thr Asn Tyr Asn Glu Ile Phe
1 5 10 15
Lys Gly
<210> 60
<211> 10
<212> PRT
<213> homo sapiens
<400> 60
Thr Arg Arg Val Pro Ile Arg Leu Asp Tyr
1 5 10
<210> 61
<211> 15
<212> PRT
<213> homo sapiens
<400> 61
Lys Ala Ser Gln Ser Val Asp Tyr Glu Gly Asp Ser Phe Leu Asn
1 5 10 15
<210> 62
<211> 7
<212> PRT
<213> homo sapiens
<400> 62
Ala Ala Ser Asn Leu Glu Ser
1 5
<210> 63
<211> 9
<212> PRT
<213> homo sapiens
<400> 63
Gln Gln Ser Asn Glu Asp Pro Leu Thr
1 5
<210> 64
<211> 219
<212> PRT
<213> homo sapiens
<400> 64
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Glu Thr Leu Val His Ser
20 25 30
Ser Gly Asn Thr Tyr Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Arg Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Phe Asn Pro Leu Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 65
<211> 450
<212> PRT
<213> homo sapiens
<400> 65
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Ser Phe Ser Asp Phe
20 25 30
Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ala Thr Ile Gly Arg Val Ala Phe His Thr Tyr Tyr Pro Asp Ser Met
50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg His Arg Gly Phe Asp Val Gly His Phe Asp Phe Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Cys Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 66
<211> 16
<212> PRT
<213> homo sapiens
<400> 66
Arg Ser Ser Gln Ser Ile Val His Ser Val Gly Asn Thr Phe Leu Glu
1 5 10 15
<210> 67
<211> 7
<212> PRT
<213> homo sapiens
<400> 67
Lys Val Ser Asn Arg Phe Ser
1 5
<210> 68
<211> 9
<212> PRT
<213> homo sapiens
<400> 68
Phe Gln Gly Ser Gln Phe Pro Tyr Thr
1 5
<210> 69
<211> 10
<212> PRT
<213> homo sapiens
<400> 69
Gly Tyr Glu Phe Ser Arg Ser Trp Met Asn
1 5 10
<210> 70
<211> 17
<212> PRT
<213> homo sapiens
<400> 70
Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Ser Gly Lys Phe Lys
1 5 10 15
Gly
<210> 71
<211> 11
<212> PRT
<213> homo sapiens
<400> 71
Asp Gly Ser Ser Trp Asp Trp Tyr Phe Asp Val
1 5 10
<210> 72
<211> 113
<212> PRT
<213> homo sapiens
<400> 72
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Val Gly Asn Thr Phe Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Gln Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg
<210> 73
<211> 120
<212> PRT
<213> homo sapiens
<400> 73
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Glu Phe Ser Arg Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Ser Gly Lys Phe
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Ser Ser Trp Asp Trp Tyr Phe Asp Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser
115 120
<210> 74
<211> 219
<212> PRT
<213> homo sapiens
<400> 74
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ser Ser Gln Ser Ile Val His Ser
20 25 30
Val Gly Asn Thr Phe Leu Glu Trp Tyr Gln Gln Lys Pro Gly Lys Ala
35 40 45
Pro Lys Leu Leu Ile Tyr Lys Val Ser Asn Arg Phe Ser Gly Val Pro
50 55 60
Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile
65 70 75 80
Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Phe Gln Gly
85 90 95
Ser Gln Phe Pro Tyr Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu
115 120 125
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe
130 135 140
Tyr Pro Arg Glu Ala Lys Val Gln Trp Cys Val Asp Asn Ala Leu Gln
145 150 155 160
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser
165 170 175
Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
180 185 190
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser
195 200 205
Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
210 215
<210> 75
<211> 450
<212> PRT
<213> homo sapiens
<400> 75
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Tyr Glu Phe Ser Arg Ser
20 25 30
Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Gly Arg Ile Tyr Pro Gly Asp Gly Asp Thr Asn Tyr Ser Gly Lys Phe
50 55 60
Lys Gly Arg Phe Thr Ile Ser Ala Asp Thr Ser Lys Asn Thr Ala Tyr
65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Asp Gly Ser Ser Trp Asp Trp Tyr Phe Asp Val Trp Gly Gln
100 105 110
Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val
115 120 125
Phe Pro Leu Ala Pro Ser Ser Lys Ser Thr Ser Gly Gly Thr Ala Ala
130 135 140
Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser
145 150 155 160
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val
165 170 175
Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
180 185 190
Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
195 200 205
Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser Cys Asp
210 215 220
Lys Thr His Thr Cys Pro Pro Cys Pro Ala Pro Glu Leu Leu Gly Gly
225 230 235 240
Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
245 250 255
Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
260 265 270
Asp Pro Glu Val Lys Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
275 280 285
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg
290 295 300
Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys
305 310 315 320
Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile Glu
325 330 335
Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
340 345 350
Thr Leu Pro Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu
355 360 365
Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
370 375 380
Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val
385 390 395 400
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
405 410 415
Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His
420 425 430
Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
435 440 445
Gly Lys
450
<210> 76
<211> 16
<212> PRT
<213> homo sapiens
<400> 76
Arg Ser Ser Gln Ser Leu Leu His Ser Asn Gly Tyr Asn Tyr Leu Asp
1 5 10 15
<210> 77
<211> 7
<212> PRT
<213> homo sapiens
<400> 77
Leu Gly Val Asn Ser Val Ser
1 5
<210> 78
<211> 5
<212> PRT
<213> homo sapiens
<400> 78
Asn His Ala Ile Ser
1 5
<210> 79
<211> 17
<212> PRT
<213> homo sapiens
<400> 79
Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe Gln
1 5 10 15
Gly
<210> 80
<211> 8
<212> PRT
<213> homo sapiens
<400> 80
Glu Trp Ala Asp Val Phe Asp Ile
1 5
<210> 81
<211> 8
<212> PRT
<213> homo sapiens
<400> 81
Glu Trp Ala Asp Val Phe Asp Ile
1 5
<210> 82
<211> 112
<212> PRT
<213> homo sapiens
<400> 82
Glu Ile Val Leu Thr Gln Ser Pro Leu Ser Leu Pro Val Thr Pro Gly
1 5 10 15
Glu Pro Ala Ser Ile Ser Cys Arg Ser Ser Gln Ser Leu Leu His Ser
20 25 30
Asn Gly Tyr Asn Tyr Leu Asp Trp Tyr Leu Gln Lys Pro Gly Gln Ser
35 40 45
Pro Gln Leu Leu Ile Tyr Leu Gly Val Asn Ser Val Ser Gly Val Pro
50 55 60
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Lys Ile
65 70 75 80
Ser Arg Val Glu Ala Glu Asp Val Gly Val Tyr Tyr Cys Met Gln Ala
85 90 95
Leu Gln Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile Lys
100 105 110
<210> 83
<211> 117
<212> PRT
<213> homo sapiens
<400> 83
Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ser
1 5 10 15
Ser Val Lys Val Ser Cys Lys Ala Ser Gly Gly Ile Phe Ser Asn His
20 25 30
Ala Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met
35 40 45
Gly Gly Ile Ile Pro Ile Phe Gly Thr Ala Asn Tyr Ala Gln Lys Phe
50 55 60
Gln Gly Arg Val Thr Ile Thr Ala Asp Glu Ser Thr Ser Thr Ala Phe
65 70 75 80
Met Glu Leu Ser Ser Leu Arg Ser Glu Asp Thr Ala Val Tyr Tyr Cys
85 90 95
Ala Arg Glu Trp Ala Asp Val Phe Asp Ile Trp Gly Gln Gly Thr Met
100 105 110
Val Thr Val Ser Ser
115
<210> 84
<211> 11
<212> PRT
<213> homo sapiens
<400> 84
Arg Ala Ser Gln Gly Ile Arg Asn Asp Leu Gly
1 5 10
<210> 85
<211> 7
<212> PRT
<213> homo sapiens
<400> 85
Ala Ala Ser Ser Leu Gln Ser
1 5
<210> 86
<211> 5
<212> PRT
<213> homo sapiens
<400> 86
Gly Asn Tyr Met Ser
1 5
<210> 87
<211> 5
<212> PRT
<213> homo sapiens
<400> 87
Gly Asn Tyr Met Ser
1 5
<210> 88
<211> 16
<212> PRT
<213> homo sapiens
<400> 88
Leu Ile Tyr Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys Gly
1 5 10 15
<210> 89
<211> 10
<212> PRT
<213> homo sapiens
<400> 89
Asp Gly Tyr Tyr Val Ser Asp Met Val Val
1 5 10
<210> 90
<211> 107
<212> PRT
<213> homo sapiens
<400> 90
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 91
<211> 118
<212> PRT
<213> homo sapiens
<400> 91
Glu Val Gln Leu Val Glu Ser Gly Gly Ala Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Ile Ser Gly Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Tyr Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Asn Ile Ser Arg Asp Ile Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys Val
85 90 95
Arg Asp Gly Tyr Tyr Val Ser Asp Met Val Val Trp Gly Lys Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 92
<211> 107
<212> PRT
<213> homo sapiens
<400> 92
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 93
<211> 118
<212> PRT
<213> homo sapiens
<400> 93
Glu Val Gln Leu Val Glu Ser Gly Gly Ala Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Ile Ser Gly Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Tyr Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Thr Ile Ser Arg Asp Ile Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys Val
85 90 95
Arg Asp Gly Tyr Tyr Val Ser Asp Met Val Val Trp Gly Lys Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 94
<211> 107
<212> PRT
<213> homo sapiens
<400> 94
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 95
<211> 118
<212> PRT
<213> homo sapiens
<400> 95
Glu Val Gln Leu Val Glu Ser Gly Gly Ala Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Ile Ser Gly Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Tyr Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Ser Ile Ser Arg Asp Ile Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys Val
85 90 95
Arg Asp Gly Tyr Tyr Val Ser Asp Met Val Val Trp Gly Lys Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 96
<211> 107
<212> PRT
<213> homo sapiens
<400> 96
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser Ala Ser Val Gly
1 5 10 15
Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Arg Asn Asp
20 25 30
Leu Gly Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Arg Leu Ile
35 40 45
Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly
50 55 60
Ser Gly Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro
65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Leu Gln His Asn Ser Tyr Pro Trp
85 90 95
Thr Phe Gly Gln Gly Thr Lys Leu Glu Ile Lys
100 105
<210> 97
<211> 118
<212> PRT
<213> homo sapiens
<400> 97
Glu Val Gln Leu Val Glu Ser Gly Gly Ala Leu Ile Gln Pro Gly Gly
1 5 10 15
Ser Leu Arg Leu Ser Cys Val Ala Ser Gly Phe Thr Ile Ser Gly Asn
20 25 30
Tyr Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45
Ser Leu Ile Tyr Ser Gly Asp Ser Thr Tyr Tyr Ala Asp Ser Val Lys
50 55 60
Gly Arg Phe Ala Ile Ser Arg Asp Ile Ser Lys Asn Thr Val Tyr Leu
65 70 75 80
Gln Met Asn Ser Leu Arg Val Glu Asp Thr Ala Val Tyr Tyr Cys Val
85 90 95
Arg Asp Gly Tyr Tyr Val Ser Asp Met Val Val Trp Gly Lys Gly Thr
100 105 110
Thr Val Thr Val Ser Ser
115
<210> 98
<211> 1255
<212> PRT
<213> homo sapiens
<400> 98
Met Glu Leu Ala Ala Leu Cys Arg Trp Gly Leu Leu Leu Ala Leu Leu
1 5 10 15
Pro Pro Gly Ala Ala Ser Thr Gln Val Cys Thr Gly Thr Asp Met Lys
20 25 30
Leu Arg Leu Pro Ala Ser Pro Glu Thr His Leu Asp Met Leu Arg His
35 40 45
Leu Tyr Gln Gly Cys Gln Val Val Gln Gly Asn Leu Glu Leu Thr Tyr
50 55 60
Leu Pro Thr Asn Ala Ser Leu Ser Phe Leu Gln Asp Ile Gln Glu Val
65 70 75 80
Gln Gly Tyr Val Leu Ile Ala His Asn Gln Val Arg Gln Val Pro Leu
85 90 95
Gln Arg Leu Arg Ile Val Arg Gly Thr Gln Leu Phe Glu Asp Asn Tyr
100 105 110
Ala Leu Ala Val Leu Asp Asn Gly Asp Pro Leu Asn Asn Thr Thr Pro
115 120 125
Val Thr Gly Ala Ser Pro Gly Gly Leu Arg Glu Leu Gln Leu Arg Ser
130 135 140
Leu Thr Glu Ile Leu Lys Gly Gly Val Leu Ile Gln Arg Asn Pro Gln
145 150 155 160
Leu Cys Tyr Gln Asp Thr Ile Leu Trp Lys Asp Ile Phe His Lys Asn
165 170 175
Asn Gln Leu Ala Leu Thr Leu Ile Asp Thr Asn Arg Ser Arg Ala Cys
180 185 190
His Pro Cys Ser Pro Met Cys Lys Gly Ser Arg Cys Trp Gly Glu Ser
195 200 205
Ser Glu Asp Cys Gln Ser Leu Thr Arg Thr Val Cys Ala Gly Gly Cys
210 215 220
Ala Arg Cys Lys Gly Pro Leu Pro Thr Asp Cys Cys His Glu Gln Cys
225 230 235 240
Ala Ala Gly Cys Thr Gly Pro Lys His Ser Asp Cys Leu Ala Cys Leu
245 250 255
His Phe Asn His Ser Gly Ile Cys Glu Leu His Cys Pro Ala Leu Val
260 265 270
Thr Tyr Asn Thr Asp Thr Phe Glu Ser Met Pro Asn Pro Glu Gly Arg
275 280 285
Tyr Thr Phe Gly Ala Ser Cys Val Thr Ala Cys Pro Tyr Asn Tyr Leu
290 295 300
Ser Thr Asp Val Gly Ser Cys Thr Leu Val Cys Pro Leu His Asn Gln
305 310 315 320
Glu Val Thr Ala Glu Asp Gly Thr Gln Arg Cys Glu Lys Cys Ser Lys
325 330 335
Pro Cys Ala Arg Val Cys Tyr Gly Leu Gly Met Glu His Leu Arg Glu
340 345 350
Val Arg Ala Val Thr Ser Ala Asn Ile Gln Glu Phe Ala Gly Cys Lys
355 360 365
Lys Ile Phe Gly Ser Leu Ala Phe Leu Pro Glu Ser Phe Asp Gly Asp
370 375 380
Pro Ala Ser Asn Thr Ala Pro Leu Gln Pro Glu Gln Leu Gln Val Phe
385 390 395 400
Glu Thr Leu Glu Glu Ile Thr Gly Tyr Leu Tyr Ile Ser Ala Trp Pro
405 410 415
Asp Ser Leu Pro Asp Leu Ser Val Phe Gln Asn Leu Gln Val Ile Arg
420 425 430
Gly Arg Ile Leu His Asn Gly Ala Tyr Ser Leu Thr Leu Gln Gly Leu
435 440 445
Gly Ile Ser Trp Leu Gly Leu Arg Ser Leu Arg Glu Leu Gly Ser Gly
450 455 460
Leu Ala Leu Ile His His Asn Thr His Leu Cys Phe Val His Thr Val
465 470 475 480
Pro Trp Asp Gln Leu Phe Arg Asn Pro His Gln Ala Leu Leu His Thr
485 490 495
Ala Asn Arg Pro Glu Asp Glu Cys Val Gly Glu Gly Leu Ala Cys His
500 505 510
Gln Leu Cys Ala Arg Gly His Cys Trp Gly Pro Gly Pro Thr Gln Cys
515 520 525
Val Asn Cys Ser Gln Phe Leu Arg Gly Gln Glu Cys Val Glu Glu Cys
530 535 540
Arg Val Leu Gln Gly Leu Pro Arg Glu Tyr Val Asn Ala Arg His Cys
545 550 555 560
Leu Pro Cys His Pro Glu Cys Gln Pro Gln Asn Gly Ser Val Thr Cys
565 570 575
Phe Gly Pro Glu Ala Asp Gln Cys Val Ala Cys Ala His Tyr Lys Asp
580 585 590
Pro Pro Phe Cys Val Ala Arg Cys Pro Ser Gly Val Lys Pro Asp Leu
595 600 605
Ser Tyr Met Pro Ile Trp Lys Phe Pro Asp Glu Glu Gly Ala Cys Gln
610 615 620
Pro Cys Pro Ile Asn Cys Thr His Ser Cys Val Asp Leu Asp Asp Lys
625 630 635 640
Gly Cys Pro Ala Glu Gln Arg Ala Ser Pro Leu Thr Ser Ile Ile Ser
645 650 655
Ala Val Val Gly Ile Leu Leu Val Val Val Leu Gly Val Val Phe Gly
660 665 670
Ile Leu Ile Lys Arg Arg Gln Gln Lys Ile Arg Lys Tyr Thr Met Arg
675 680 685
Arg Leu Leu Gln Glu Thr Glu Leu Val Glu Pro Leu Thr Pro Ser Gly
690 695 700
Ala Met Pro Asn Gln Ala Gln Met Arg Ile Leu Lys Glu Thr Glu Leu
705 710 715 720
Arg Lys Val Lys Val Leu Gly Ser Gly Ala Phe Gly Thr Val Tyr Lys
725 730 735
Gly Ile Trp Ile Pro Asp Gly Glu Asn Val Lys Ile Pro Val Ala Ile
740 745 750
Lys Val Leu Arg Glu Asn Thr Ser Pro Lys Ala Asn Lys Glu Ile Leu
755 760 765
Asp Glu Ala Tyr Val Met Ala Gly Val Gly Ser Pro Tyr Val Ser Arg
770 775 780
Leu Leu Gly Ile Cys Leu Thr Ser Thr Val Gln Leu Val Thr Gln Leu
785 790 795 800
Met Pro Tyr Gly Cys Leu Leu Asp His Val Arg Glu Asn Arg Gly Arg
805 810 815
Leu Gly Ser Gln Asp Leu Leu Asn Trp Cys Met Gln Ile Ala Lys Gly
820 825 830
Met Ser Tyr Leu Glu Asp Val Arg Leu Val His Arg Asp Leu Ala Ala
835 840 845
Arg Asn Val Leu Val Lys Ser Pro Asn His Val Lys Ile Thr Asp Phe
850 855 860
Gly Leu Ala Arg Leu Leu Asp Ile Asp Glu Thr Glu Tyr His Ala Asp
865 870 875 880
Gly Gly Lys Val Pro Ile Lys Trp Met Ala Leu Glu Ser Ile Leu Arg
885 890 895
Arg Arg Phe Thr His Gln Ser Asp Val Trp Ser Tyr Gly Val Thr Val
900 905 910
Trp Glu Leu Met Thr Phe Gly Ala Lys Pro Tyr Asp Gly Ile Pro Ala
915 920 925
Arg Glu Ile Pro Asp Leu Leu Glu Lys Gly Glu Arg Leu Pro Gln Pro
930 935 940
Pro Ile Cys Thr Ile Asp Val Tyr Met Ile Met Val Lys Cys Trp Met
945 950 955 960
Ile Asp Ser Glu Cys Arg Pro Arg Phe Arg Glu Leu Val Ser Glu Phe
965 970 975
Ser Arg Met Ala Arg Asp Pro Gln Arg Phe Val Val Ile Gln Asn Glu
980 985 990
Asp Leu Gly Pro Ala Ser Pro Leu Asp Ser Thr Phe Tyr Arg Ser Leu
995 1000 1005
Leu Glu Asp Asp Asp Met Gly Asp Leu Val Asp Ala Glu Glu Tyr
1010 1015 1020
Leu Val Pro Gln Gln Gly Phe Phe Cys Pro Asp Pro Ala Pro Gly
1025 1030 1035
Ala Gly Gly Met Val His His Arg His Arg Ser Ser Ser Thr Arg
1040 1045 1050
Ser Gly Gly Gly Asp Leu Thr Leu Gly Leu Glu Pro Ser Glu Glu
1055 1060 1065
Glu Ala Pro Arg Ser Pro Leu Ala Pro Ser Glu Gly Ala Gly Ser
1070 1075 1080
Asp Val Phe Asp Gly Asp Leu Gly Met Gly Ala Ala Lys Gly Leu
1085 1090 1095
Gln Ser Leu Pro Thr His Asp Pro Ser Pro Leu Gln Arg Tyr Ser
1100 1105 1110
Glu Asp Pro Thr Val Pro Leu Pro Ser Glu Thr Asp Gly Tyr Val
1115 1120 1125
Ala Pro Leu Thr Cys Ser Pro Gln Pro Glu Tyr Val Asn Gln Pro
1130 1135 1140
Asp Val Arg Pro Gln Pro Pro Ser Pro Arg Glu Gly Pro Leu Pro
1145 1150 1155
Ala Ala Arg Pro Ala Gly Ala Thr Leu Glu Arg Pro Lys Thr Leu
1160 1165 1170
Ser Pro Gly Lys Asn Gly Val Val Lys Asp Val Phe Ala Phe Gly
1175 1180 1185
Gly Ala Val Glu Asn Pro Glu Tyr Leu Thr Pro Gln Gly Gly Ala
1190 1195 1200
Ala Pro Gln Pro His Pro Pro Pro Ala Phe Ser Pro Ala Phe Asp
1205 1210 1215
Asn Leu Tyr Tyr Trp Asp Gln Asp Pro Pro Glu Arg Gly Ala Pro
1220 1225 1230
Pro Ser Thr Phe Lys Gly Thr Pro Thr Ala Glu Asn Pro Glu Tyr
1235 1240 1245
Leu Gly Leu Asp Val Pro Val
1250 1255
Claims (1)
- 本明細書に記載の発明。
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201662339257P | 2016-05-20 | 2016-05-20 | |
US62/339,257 | 2016-05-20 | ||
JP2018560504A JP2019522633A (ja) | 2016-05-20 | 2017-05-19 | Protac抗体コンジュゲート及び使用方法 |
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