JP2022137034A - システイン操作抗体及びコンジュゲート - Google Patents
システイン操作抗体及びコンジュゲート Download PDFInfo
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Abstract
Description
表1.例示的な軽鎖システイン変異
表2.例示的な重鎖システイン変異
(i)システイン操作抗体をコードするように、1つ以上のアミノ酸残基をシステインで置き換えることによって親抗体の核酸配列に変異生成を行うことと、
(ii)前記システイン操作抗体を発現させることと、
(iii)システイン操作抗体を単離することと、を含むプロセスによって調製される。
a)CDKTHTGGGSQRLMEDICLPRWGCLWEDDF(配列番号144)、
b)QRLMEDICLPRWGCLWEDDF(配列番号145)、
c)QRLIEDICLPRWGCLWEDDF(配列番号146)、
d)RLIEDICLPRWGCLWEDD(配列番号147)、または
e)DICLPRWGCLW(配列番号148)から選択される配列を含む。
(1)BMPR1B(骨形成タンパク質受容体IB型)、
(2)E16(LAT1、SLC7A5)、
(3)STEAP1(前立腺の6回膜貫通上皮抗原)、
(4)0772P(CA125、MUC16)、
(5)MPF(MPF、MSLN、SMR、巨核球増強因子、メソテリン)、
(6)Napi3b(NaPi2bとしても知られる)(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)、
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、セマフォリン5b Hlog、セマドメイン、7回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)、
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA 2700050C12、RIKEN cDNA 2700050C12遺伝子)、
(9)ETBR(エンドセリンB型受容体)、
(10)MSG783(RNF124、仮説上のタンパク質FLJ20315)、
(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回膜貫通上皮抗原2、6回膜貫通前立腺タンパク質)、
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、一過性受容器電位カチオンチャネル、サブファミリーM、メンバー4)、
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1、奇形癌由来の成長因子)、
(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.73792)、
(15)CD79b(CD79B、CD79β、IGb(免疫グロブリン関連ベータ)、B29)、
(16)FcRH2(IFGP4、IRTA4、SPAP1A(SH2ドメイン含有ホスファターゼアンカータンパク質1a)、SPAP1B、SPAP1C)、
(17)HER2、
(18)NCA、
(19)MDP、
(20)IL20Rα、
(21)ブレビカン、
(22)EphB2R、
(23)ASLG659、
(24)PSCA、
(25)GEDA、
(26)BAFF-R(B細胞活性化因子受容体、BLyS受容体3、BR3、
(27)CD22(B細胞受容体CD22-Bアイソフォーム)、
(28)CD79a(CD79A、CD79α、免疫グロブリン関連アルファ、B細胞特異的タンパク質)、
(29)CXCR5(バーキットリンパ腫受容体1、Gタンパク質結合型受容体)、
(30)HLA-DOB(MHCクラスII分子のベータサブユニット(Ia抗原)、
(31)P2X5(プリン受容体P2Xリガンド開口型イオンチャネル5)、
(32)CD72(B細胞分化抗原CD72、Lyb-2)、
(33)LY64(リンパ球抗原64(RP105)、ロイシンリッチ反復(LRR)ファミリーのI型膜タンパク質)、
(34)FcRH1(Fc受容体様タンパク質1)、
(35)IRTA2(免疫グロブリンスーパーファミリー受容体転位関連2)、
(36)TENB2(推定上の膜貫通プロテオグリカン)、
(37)PMEL17(silver相同体、SILV、D12S53E、PMEL17、SI、SIL)、
(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を有する膜貫通タンパク質1、トモレグリン(Tomoregulin)1)、
(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-アルファ-1)、
(40)Ly6E(リンパ球抗原6複合体、遺伝子座E、Ly67、RIG-E、SCA-2、TSA-1)、
(41)TMEM46(shisa相同体2)、
(42)Ly6G6D(リンパ球抗原6複合体、遺伝子座G6D、Ly6-D、MEGT1)、
(43)LGR5(ロイシンリッチ反復含有Gタンパク質結合型受容体5、GPR49、GPR67)、
(44)RET(ret癌原遺伝子、MEN2A、HSCR1、MEN2B、MTC1、PTC、CDHF12、Hs.168114、RET51、RET-ELE1)、
(45)LY6K(リンパ球抗原6複合体、遺伝子座K、LY6K、HSJ001348、FLJ35226)、
(46)GPR19(Gタンパク質結合型受容体19、Mm.4787)、
(47)GPR54(KISS1受容体、KISS1R、GPR54、HOT7T175、AXOR12)、
(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)、
(49)チロシナーゼ(TYR、OCAIA、OCA1A、チロシナーゼ、SHEP3)、
(50)TMEM118(ringフィンガータンパク質、膜貫通2、RNFT2、FLJ14627)、
(51)GPR172A(Gタンパク質結合型受容体172A、GPCR41、FLJ11856、D15Ertd747e)、
(52)CD33、ならびに
(53)CLL-1(CLEC12A、MICL、及びDCAL2)。
のうちの1つを有し、式中、Valはバリンであり、Citはシトルリンであり、pは、1、2、3、または4である。本発明のある特定の実施形態では、本明細書に記載されるシステイン操作抗体は、以下の構造を有する。
(i)システイン操作抗体をコードするように、1つ以上のアミノ酸残基をシステインで置き換えることによって親抗体の核酸配列に変異生成を行うことと、
(ii)前記システイン操作抗体を発現させることと、
(iii)システイン操作抗体を単離することと、を含むプロセスによって調製される。
a)CDKTHTGGGSQRLMEDICLPRWGCLWEDDF(配列番号144)、
b)QRLMEDICLPRWGCLWEDDF(配列番号145)、
c)QRLIEDICLPRWGCLWEDDF(配列番号146)、
d)RLIEDICLPRWGCLWEDD(配列番号147)、または
e)DICLPRWGCLW(配列番号148)から選択される配列を含む。
(1)BMPR1B(骨形成タンパク質受容体IB型)、
(2)E16(LAT1、SLC7A5)、
(3)STEAP1(前立腺の6回膜貫通上皮抗原)、
(4)0772P(CA125、MUC16)、
(5)MPF(MPF、MSLN、SMR、巨核球増強因子、メソテリン)、
(6)Napi3b(NaPi2bとしても知られる)(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)、
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、セマフォリン5b Hlog、セマドメイン、7回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)、
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA 2700050C12、RIKEN cDNA 2700050C12遺伝子)、
(9)ETBR(エンドセリンB型受容体)、
(10)MSG783(RNF124、仮説上のタンパク質FLJ20315)、
(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回膜貫通上皮抗原2、6回膜貫通前立腺タンパク質)、
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、一過性受容器電位カチオンチャネル、サブファミリーM、メンバー4)、
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1、奇形癌由来の成長因子)、
(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.73792)、
(15)CD79b(CD79B、CD79β、IGb(免疫グロブリン関連ベータ)、B29)、
(16)FcRH2(IFGP4、IRTA4、SPAP1A(SH2ドメイン含有ホスファターゼアンカータンパク質1a)、SPAP1B、SPAP1C)、
(17)HER2、
(18)NCA、
(19)MDP、
(20)IL20Rα、
(21)ブレビカン、
(22)EphB2R、
(23)ASLG659、
(24)PSCA、
(25)GEDA、
(26)BAFF-R(B細胞活性化因子受容体、BLyS受容体3、BR3、
(27)CD22(B細胞受容体CD22-Bアイソフォーム)、
(28)CD79a(CD79A、CD79α、免疫グロブリン関連アルファ、B細胞特異的タンパク質)、
(29)CXCR5(バーキットリンパ腫受容体1、Gタンパク質結合型受容体)、
(30)HLA-DOB(MHCクラスII分子のベータサブユニット(Ia抗原)、
(31)P2X5(プリン受容体P2Xリガンド開口型イオンチャネル5)、
(32)CD72(B細胞分化抗原CD72、Lyb-2)、
(33)LY64(リンパ球抗原64(RP105)、ロイシンリッチ反復(LRR)ファミリーのI型膜タンパク質)、
(34)FcRH1(Fc受容体様タンパク質1)、
(35)IRTA2(免疫グロブリンスーパーファミリー受容体転位関連2)、
(36)TENB2(推定上の膜貫通プロテオグリカン)、
(37)PMEL17(silver相同体、SILV、D12S53E、PMEL17、SI、SIL)、
(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を有する膜貫通タンパク質1、トモレグリン(Tomoregulin)1)、
(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-アルファ-1)、
(40)Ly6E(リンパ球抗原6複合体、遺伝子座E、Ly67、RIG-E、SCA-2、TSA-1)、
(41)TMEM46(shisa相同体2)、
(42)Ly6G6D(リンパ球抗原6複合体、遺伝子座G6D、Ly6-D、MEGT1)、
(43)LGR5(ロイシンリッチ反復含有Gタンパク質結合型受容体5、GPR49、GPR67)、
(44)RET(ret癌原遺伝子、MEN2A、HSCR1、MEN2B、MTC1、PTC、CDHF12、Hs.168114、RET51、RET-ELE1)、
(45)LY6K(リンパ球抗原6複合体、遺伝子座K、LY6K、HSJ001348、FLJ35226)、
(46)GPR19(Gタンパク質結合型受容体19、Mm.4787)、
(47)GPR54(KISS1受容体、KISS1R、GPR54、HOT7T175、AXOR12)、
(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)、
(49)チロシナーゼ(TYR、OCAIA、OCA1A、チロシナーゼ、SHEP3)、
(50)TMEM118(ringフィンガータンパク質、膜貫通2、RNFT2、FLJ14627)、
(51)GPR172A(Gタンパク質結合型受容体172A、GPCR41、FLJ11856、D15Ertd747e)、
(52)CD33、ならびに
(53)CLL-1(CLEC12A、MICL、及びDCAL2)。
相互参照:MIM:604415、NP_036581.1、NM_012449_1
EVQLVESGGGLVQPGGSLRLSCAASGFNIKDTYIHWVRQAPGKGLEWVARIYPTNGYTRYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCSRWGGDGFYAMDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
配列番号18
DIQMTQSPSSLSASVGDRVTITCRASQDVNTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSRSGTDFTLTISSLQPEDFATYYCQQHYTTPPTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
配列番号19
表3.Kabat番号付けによる重鎖システイン変異。
表4.Kabat番号付けによる軽鎖システイン変異。
表5.Kabat番号付けによる重鎖及び軽鎖システイン変異。
表6.PDS-リンカーとコンジュゲートした表3及び4のシステイン操作抗体の平均DAR、濃度、凝集、及び安定性(ELISAラット血漿安定性)
表7.PDS-リンカーとコンジュゲートした表3及び4のシステイン操作抗体の平均DAR、濃度、凝集、及び安定性(質量分析ラット血漿安定性)
表8.-vcリンカーとコンジュゲートした表3及び4のシステイン操作抗体の平均DAR、濃度、凝集、及び安定性(ELISAラット血漿安定性)
表9.-vcリンカーとコンジュゲートした表3及び4のシステイン操作抗体の平均DAR/安定性(質量分析ラット血漿安定性)
表11.表1及び2の好ましいシステイン操作抗体のELISA及びMS安定性の結果(表10及び12に示されるものと同じ試料)
表12.表1及び2の好ましいシステイン操作抗体のシステイン還元アッセイの結果(表10及び11に示されるものと同じ試料)
全長IgGシステイン操作抗体(THIOMAB(商標)抗体)のチオール反応性は、米国特許第7,521,541号(参照によりその全体が組み込まれる)に記載されるように、ビオチニル化及びストレプトアビジン結合によって測定することができる。具体的には、ビオチン-マレイミドと特異的にコンジュゲートしたTHIOMAB(商標)抗体をスクリーニングするように、ウエスタンブロットアッセイを構築することができる。このアッセイにおいて、抗体は還元性SDS-PAGEで分析することができ、ビオチンの存在は、ストレプトアビジン-HRPとともにインキュベートすることによって、特異的にプローブされる。ストレプトアビジン-HRPの相互作用は、操作cys変異形がどこに用いられているかに応じて重鎖または軽鎖のいずれかに観察され得、この結合を、操作システインを有さない野生型IgGのビオチン-ストレプトアビジンの相互作用と比較し、それによって、どのTHIOMAB(商標)抗体が野生型抗体の任意のバックグラウンド結合と比較して特異的にビオチンにコンジュゲートするかを示すことができる。
Ab-(L-D)p I
ABP-Ab-(L-D)p Ia
典型的に、ペプチドベースの薬物部分は、2つ以上のアミノ酸及び/またはペプチドフラグメントの間にペプチド結合を形成することによって調製することができる。そのようなペプチド結合は、例えば、ペプチド化学の分野で周知の液相合成法(例えば、E.Schroder and K.Lubke,“The Peptides”,volume 1,pp76-136,1965,Academic Press)に従って調製することができる。
を有し、式中、XはBrまたはIであり、
Lはリンカーであり、Rは、水素、C1-6アルキル、または-C(=O)C1-6アルキルであり、Raは、水素またはC1-6アルキルである。
いくつかの実施形態では、XはBrであり、Raは水素であり、Rはイソプロピルである。
他の実施形態では、XはBrであり、Raは水素であり、Rはエチルである。
他の実施形態では、XはIであり、Raは水素であり、Rはイソプロピルである。
他の実施形態では、XはIであり、Raは水素であり、Rはエチルである。
いくつかの実施形態では、XはBrであり、Raは水素であり、Rは-C(=O)CH3である。
他の実施形態では、XはIであり、Raは水素であり、Rは-C(=O)CH3である。
他の実施形態では、XはIであり、Raはエチルであり、Rは-C(=O)CH3である。
他の実施形態では、XはBrであり、Raはエチルであり、Rは-C(=O)CH3である。
のもの、ならびにその塩及び溶媒和物であり、式中、
波線は、リンカーへの共有結合部分を示し、
点線は、C1とC2またはC2とC3の間の二重結合の任意の存在を示し、
R2は、独立して、H、OH、=O、=CH2、CN、R、OR、=CH-RD、=C(RD)2、O-SO2-R、CO2R、及びCORから選択され、場合によっては、更にハロまたはジハロから選択され、式中、RDは、独立して、R、CO2R、COR、CHO、CO2H、及びハロから選択され、
R6及びR9は、独立して、H、R、OH、OR、SH、SR、NH2、NHR、NRR’、NO2、Me3Sn、及びハロから選択され、
R7は、独立して、H、R、OH、OR、SH、SR、NH2、NHR、NRR’、NO2、Me3Sn、及びハロから選択され、
Qは、独立して、O、S、及びNHから選択され、
R11は、H若しくはRであるか、またはQがOである場合、SO3Mであるかのいずれかであり、式中、Mは金属カチオンであり、
R及びR’は、それぞれ独立して、任意に置換されたC1-8アルキル、C1-12アルキル、C3-8ヘテロシクリル、C3-20複素環、及びC5-20アリール基から選択され、場合によってはNRR’基との関連で、R及びR’は、それらが結合する窒素原子と一緒になって、任意に置換された4員、5員、6員、または7員の複素環式環を形成し、
R12、R16、R19、及びR17は、それぞれ、R2、R6、R9、及びR7に関して定義される通りであり、
R″は、C3-12アルキレン基であり、その鎖は、1つ以上のヘテロ原子、例えば、O、S、N(H)、NMe、及び/または芳香環、例えば、ベンゼン若しくはピリジンによって分断されてもよく、これらの環は、任意に置換されており、
X及びX’は、独立して、O、S、及びN(H)から選択される。
いくつかの実施形態では、=CH-RDは、立体配置(I)をしている。
の構造を有し、式中、RE及びRE”は、それぞれ独立して、HまたはRDから選択され、式中、RDは、上記の通り定義され、
式中、nは0または1である。
の構造を有し、式中、Ar1及びAr2は、それぞれ独立して、任意に置換されたC5-20アリールであり、式中、Ar1及びAr2は、同じであっても異なってもよく、
式中、nは0または1である。
の構造を有し、式中、Ar1及びAr2は、それぞれ独立して、任意に置換されたC5-20アリールであり、式中、Ar1及びAr2は、同じであっても異なってもよく、
の構造を有し、式中、nは0または1である。
のもの、ならびにその塩及び溶媒和物であり、式中、
波線は、リンカーへの共有結合部分を示し、
OHに繋がった波線は、SまたはR立体配置を示し、
RV1及びRV2は、独立して、H、メチル、エチル、及びフェニル(このフェニルは、特に4位で、フルオロで任意に置換されてもよい)、ならびにC5-6ヘテロシクリルから選択され、式中、RV1及びRV2は、同じであってもことなってもよく、
nは、0または1である。
式中、
Xは、CH2(n=1~5)、N、またはOであり、
Z及びZ’は、独立して、OR及びNR2から選択され、式中、Rは、1~5個の炭素原子を含む第一級、第二級、または第三級アルキル鎖であり、
R1、R’1、R2、及びR’2は、それぞれ独立して、H、C1-C8アルキル、C2-C8アルケニル、C2-C8アルキニル、C5-20アリール(置換アリールを含む)、C5-20ヘテロアリール基、-NH2、-NHMe、-OH、及び-SHから選択され、いくつかの実施形態では、アルキル、アルケニル、及びアルキニル鎖は、最大5個の炭素原子を含み、
R3及びR’3は、独立して、H、OR、NHR、及びNR2から選択され、式中、Rは、1~5個の炭素原子を含む第一級、第二級、または第三級アルキル鎖であり、
R4及びR’4は、独立して、H、Me、及びOMeから選択され、
R5は、C1-C8アルキル、C2-C8アルケニル、C2-C8アルキニル、C5-20アリール(ハロ、ニトロ、シアノ、アルコキシ、アルキル、ヘテロシクリルで置換されたアリールを含む)、及びC5-20ヘテロアリール基から選択され、いくつかの実施形態では、アルキル、アルケニル、及びアルキニル鎖は、最大5個の炭素原子を含み、
R11は、H、C1-C8アルキル、または保護基(アセチル、トリフルオロアセチル、t-ブトキシカルボニル(BOC)、ベンジルオキシカルボニル(CBZ)、9-フルオレニルメチレンオキシカルボニル(Fmoc)、またはバリン-シトルリン-PABなどの自壊性単位を含む部分など)であり、
R12は、H、C1-C8アルキル、または保護基であり、
R1、R’1、R2、R’2、R5、またはR12のうちの1つにおける水素、またはA環の間の-OCH2CH2(X)nCH2CH2O-スペーサーにおける水素は、ADCのリンカー繋がる結合で置き換えられる。
式中、
nは、0~12である。いくつかの実施形態では、nは2~10である。いくつかの実施形態では、nは4~8である。いくつかの実施形態では、nは、4、5、6、7、及び8から選択される。
で示され、式中、R1は、水素原子、ヒドロキシ、またはメトキシ基であり、R2は、C1-C5アルコキシ基、またはその薬学的に許容される塩であり、
L1及びZは、一緒に、本明細書に記載されるリンカー(L)であり、
Tは、本明細書に記載される抗体(Ab)であり、
mは、1~約20である。いくつかの実施形態では、mは、1~10、1~7、1~5、または1~4である。
で示され、式中、R1は、水素原子、ヒドロキシ、またはメトキシ基であり、R2は、C1-C5アルコキシ基、またはその薬学的に許容される塩であり、
L2及びZは、一緒に、本明細書に記載されるリンカー(L)であり、
Tは、本明細書に記載される抗体(Ab)であり、
mは、1~約20である。いくつかの実施形態では、mは、1~10、1~7、1~5、または1~4である。
のうちの1つを有し得、式中、波線は、リンカー(L)への結合を示す。
を有し、式中、
R1は、H、P(O)3H2、C(O)NRaRb、またはリンカー(L)への結合から選択され、R2は、H、P(O)3H2、C(O)NRaRb、またはリンカー(L)への結合から選択され、
Ra及びRbは、独立して、H、及び1つ以上のFで置換されていてもよいC1-C6アルキルから選択されるか、またはRa及びRbは、5員若しくは6員のヘテロシクリル基を形成し、
Tは、C3-C12アルキレン、Y、(C1-C6アルキレン)-Y-(C1-C6アルキレン)、(C1-C6アルキレン)-Y-(C1-C6アルキレン)-Y-(C1-C6アルキレン)、(C2-C6アルケニレン)-Y-(C2-C6アルケニレン)、及び(C2-C6アルキニレン)-Y-(C2-C6アルキニレン)から選択されるテザー基であり、
式中、Yは、独立して、O、S、NR1、アリール、及びヘテロアリールから選択され、
アルキレン、アルケニレン、アリール、及びヘテロアリールは、独立して、かつ、F、OH、O(C1-C6アルキル)、NH2、NHCH3、N(CH3)2、OP(O)3H2、及びC1-C6アルキル(アルキルは、1つ以上のFで置換されていてもよい)で置換されていてもよく、
またはアルキレン、アルケニレン、アリール、及びヘテロアリールは、独立して、かつ、Lへの結合で置換されていてもよく、
D’は、
から選択される薬物部分であり、式中、波線は、Tへの結合部位を示し、X1及びX2は、独立して、O及びNR3から選択され、式中、R3は、H、及び1つ以上のFで置換されていてもよいC1-C6アルキルから選択され、R4は、H、CO2R、またはリンカー(L)への結合から選択され、式中、Rは、C1-C6アルキルまたはベンジルであり、R5は、HまたはC1-C6アルキルである。
を有し、式中、Aは「ストレッチャー単位」であり、aは0~1の整数であり、Wは「アミノ酸単位」であり、wは0~12の整数であり、Yは「スペーサー単位」であり、yは0、1、または2であり、Ab、D、及びpは、式Iに関して上記の通り定義されている。そのようなリンカーの例示的な実施形態は、米国特許第7,498,298号に記載されており、これは、参照により明示的に本明細書に組み込まれる。
いくつかの実施形態では、リンカーは、国際公開第WO2015/095227号、同第WO2015/095124号、または同第WO2015/095223号に記載されるものといった、ペプチド模倣リンカーであってもよく、これらの文書は、参照によりその全体が本明細書に組み込まれる。
1.培地中の約104個の細胞(SKBR-3、BT474、MCF7、またはMDA-MB-468)を含有する100μlの細胞培養物のアリコートを、96ウェルの不透明ウェルプレートの各ウェルに入れることができる。
2.培地を含有するが細胞を含まない対照ウェルを調製することができる。
3.THIOMAB(商標)抗体を実験ウェルに添加し、3~5日間インキュベーすることができる。
4.プレートは、およそ30分間室温で平衡化することができる。
5.各ウェルに存在する細胞培養培地の量と等しい量のCellTiter-Glo Reagentを添加することができる。
6.オービタルシェーカーで内容物を2分間混合して、細胞溶解を誘導することができる。
7.プレートを室温で10分間インクベートして、発光シグナルを安定させることができる。
8.発光は、RLU=相対発光単位としてグラフで記録し、報告することができる。
1.1000細胞/ウェルのPC3/Muc16、PC3/neo(50μL/ウェル)を培地に播種する。Ovcar3細胞は、2000細胞/ウェル(50μL中)で播種すべきである(PC3/neo及びPC3/MUC16は、50/50/10%FBS/グルタミン/250μg/mLのG-418で成長し、OVCAR-3はRPMI/20%FBS/グルタミンで成長する)。一晩、細胞を付着させる。
2.THIOMAB(商標)抗体を18μg/mlの作用濃度から初めて1:3で連続希釈する(これにより、最終濃度が9μg/mlとなる)。既にウェルに入っている50μLの細胞及び培地に、50μLの希釈ADCを添加する。
3.72~96時間インキュベートする(72時間が標準であるが、0ug/mL濃度を監視して細胞が85~95%コンフルエントになったときにアッセイを停止させる)。
4.100μL/ウェルのPromega Cell Titer Glo試薬を添加し、3分間振盪し、ルミノメーターで読み取る。
<本発明の更なる実施態様>
[実施態様1]
EU番号付けによるT114C、A140C、L174C、L179C、T187C、T209C、V262C、G371C、Y373C、E382C、S424C、N434C、及びQ438Cからなる群から選択される重鎖のシステインアミノ酸、またはKabat番号付けによるI106C、R108C、R142C、及びK149Cからなる群から選択される軽鎖のシステインアミノ酸を含む、システイン操作抗体。
[実施態様2]
前記システイン操作抗体は、
[実施態様3]
前記重鎖の前記システイン変異は、EU番号付けによるL174C、A140C、及びY373Cからなる群から選択される、実施態様1または2に記載のシステイン操作抗体。
[実施態様4]
前記重鎖の前記システイン変異は、EU番号付けによるA140Cである、実施態様1または2に記載のシステイン操作抗体。
[実施態様5]
前記重鎖の前記システイン変異は、EU番号付けによるL174Cである、実施態様1または2に記載のシステイン操作抗体。
[実施態様6]
前記重鎖の前記システイン変異は、EU番号付けによるY373Cである、実施態様1または2に記載のシステイン操作抗体。
[実施態様7]
前記軽鎖の前記システイン変異は、K149Cである、実施態様1または2に記載のシステイン操作抗体。
[実施態様8]
(i)前記システイン操作抗体をコードするように、1つ以上のアミノ酸残基をシステインで置き換えることによって親抗体の核酸配列に変異生成を行うことと、
(ii)前記システイン操作抗体を発現させることと、
(iii)前記システイン操作抗体を単離することと、を含むプロセスによって調製される、実施態様1~7のいずれかに記載のシステイン操作抗体。
[実施態様9]
前記変異生成は、部位指向性変異生成を含む、実施態様8に記載のシステイン操作抗体。
[実施態様10]
前記システインは、遊離システインであり、前記プロセスは、
(i)前記システイン操作抗体の前記遊離システインを、チオール反応性親和性試薬と反応させて、前記遊離システインに共有結合した前記親和性試薬を含む、親和性標識化システイン操作抗体を生成することと、
(ii)前記親和性標識化システイン操作抗体と捕捉媒体との結合を測定することと、を更に含む、実施態様8に記載のシステイン操作抗体。
[実施態様11]
前記チオール反応性試薬は、マレイミド部分を含む、実施態様10に記載のシステイン操作抗体。
[実施態様12]
前記チオール反応性試薬は、ビオチン部分を含み、前記捕捉媒体は、ストレプトアビジンを含む、実施態様10に記載のシステイン操作抗体。
[実施態様13]
前記システイン操作抗体は、モノクローナル抗体、抗体フラグメント、二重特異性抗体、キメラ抗体、ヒト抗体、及びヒト化抗体から選択される、実施態様1~12のいずれかに記載のシステイン操作抗体。
[実施態様14]
前記抗体フラグメントは、Fabフラグメントである、実施態様1~13のいずれかに記載のシステイン操作抗体。
[実施態様15]
前記システイン操作抗体は、抗HER2抗体である、実施態様1~14のいずれかに記載のシステイン抗体。
[実施態様16]
前記抗HER2抗体は、トラスツズマブである、実施態様15に記載のシステイン操作抗体。
[実施態様17]
前記システイン操作抗体は、抗Ly6E抗体である、実施態様1~14のいずれかに記載のシステイン操作抗体。
[実施態様18]
前記抗Ly6E抗体は、
(i)配列番号179のアミノ酸配列を含むHVR-H1、及び配列番号180のアミノ酸配列を含むHVR-H2、配列番号181のアミノ酸配列を含むHVR-H3、配列番号176のアミノ酸配列を含むHVR-L1、配列番号177のアミノ酸配列を含むHVR-L2、ならびに配列番号178のアミノ酸配列を含むHVR-L3、または
(ii)配列番号175のアミノ酸配列を含む重鎖可変領域及び配列番号174のアミノ酸配列を含む軽鎖可変領域を含む、実施態様17に記載のシステイン操作抗体。
[実施態様19]
前記システイン操作抗体は、抗CD79b抗体である、実施態様1~14のいずれかに記載のシステイン操作抗体。
[実施態様20]
前記抗CD79b抗体は、
(i)配列番号186のアミノ酸配列を含むHVR-H1、及び配列番号187のアミノ酸配列を含むHVR-H2、配列番号188のアミノ酸配列を含むHVR-H3、配列番号189のアミノ酸配列を含むHVR-L1、配列番号190のアミノ酸配列を含むHVR-L2、ならびに配列番号191のアミノ酸配列を含むHVR-L3、または
(ii)配列番号184のアミノ酸配列を含む重鎖可変領域及び配列番号185のアミノ酸配列を含む軽鎖可変領域を含む、実施態様19に記載のシステイン操作抗体。
[実施態様21]
前記システイン操作抗体は、抗MUC16抗体である、実施態様1~14のいずれかに記載のシステイン操作抗体。
[実施態様22]
前記抗MUC16抗体は、
(i)配列番号152のアミノ酸配列を含むHVR-H1、及び配列番号153のアミノ酸配列を含むHVR-H2、配列番号154のアミノ酸配列を含むHVR-H3、配列番号150のアミノ酸配列を含むHVR-L1、配列番号151のアミノ酸配列を含むHVR-L2、ならびに配列番号152のアミノ酸配列を含むHVR-L3、または
(ii)配列番号156のアミノ酸配列を含む重鎖可変領域及び配列番号157のアミノ酸配列を含む軽鎖可変領域を含む、実施態様21に記載のシステイン操作抗体。
[実施態様23]
前記システイン操作抗体は、抗STEAP1抗体である、実施態様1~14のいずれかに記載のシステイン操作抗体。
[実施態様24]
前記抗STEAP1抗体は、
(i)配列番号157のアミノ酸配列を含むHVR-H1、及び配列番号158のアミノ酸配列を含むHVR-H2、配列番号159のアミノ酸配列を含むHVR-H3、配列番号160のアミノ酸配列を含むHVR-L1、配列番号161のアミノ酸配列を含むHVR-L2、ならびに配列番号162のアミノ酸配列を含むHVR-L3、または
(ii)配列番号163のアミノ酸配列を含む重鎖可変領域及び配列番号164のアミノ酸配列を含む軽鎖可変領域を含む、実施態様23に記載のシステイン操作抗体。
[実施態様25]
前記システイン操作抗体は、抗NaPi2b抗体である、実施態様1~14のいずれかに記載のシステイン操作抗体。
[実施態様26]
前記抗STEAP1抗体は、
(i)配列番号165のアミノ酸配列を含むHVR-H1、及び配列番号167のアミノ酸配列を含むHVR-H2、配列番号168のアミノ酸配列を含むHVR-H3、配列番号169のアミノ酸配列を含むHVR-L1、配列番号170のアミノ酸配列を含むHVR-L2、ならびに配列番号171のアミノ酸配列を含むHVR-L3、または
(ii)配列番号172のアミノ酸配列を含む重鎖可変領域及び配列番号173のアミノ酸配列を含む軽鎖可変領域を含む、実施態様25に記載のシステイン操作抗体。
[実施態様27]
前記システイン操作抗体は、抗CD22抗体である、実施態様1~14のいずれかに記載のシステイン操作抗体。
[実施態様28]
前記抗CD22抗体は、
(i)配列番号192のアミノ酸配列を含むHVR-H1、及び配列番号193のアミノ酸配列を含むHVR-H2、配列番号194のアミノ酸配列を含むHVR-H3、配列番号195のアミノ酸配列を含むHVR-L1、配列番号196のアミノ酸配列を含むHVR-L2、ならびに配列番号197のアミノ酸配列を含むHVR-L3を含む、実施態様25に記載のシステイン操作抗体。
[実施態様29]
前記システイン操作抗体は、受容体(1)~(53):
(1)BMPR1B(骨形成タンパク質受容体IB型)、
(2)E16(LAT1、SLC7A5)、
(3)STEAP1(前立腺の6回膜貫通上皮抗原)、
(4)0772P(CA125、MUC16)、
(5)MPF(MPF、MSLN、SMR、巨核球増強因子、メソテリン)、
(6)Napi3b(NaPi2b、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)、
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、セマフォリン5b Hlog、セマドメイン、7回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)、
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA 2700050C12、RIKEN cDNA 2700050C12遺伝子)、
(9)ETBR(エンドセリンB型受容体)、
(10)MSG783(RNF124、仮説上のタンパク質FLJ20315)、
(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回膜貫通上皮抗原2、6回膜貫通前立腺タンパク質)、
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、一過性受容器電位カチオンチャネル、サブファミリーM、メンバー4)、
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1、奇形癌由来の成長因子)、
(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.73792)、
(15)CD79b(CD79B、CD79β、IGb(免疫グロブリン関連ベータ)、B29)、
(16)FcRH2(IFGP4、IRTA4、SPAP1A(SH2ドメイン含有ホスファターゼアンカータンパク質1a)、SPAP1B、SPAP1C)、
(17)HER2、
(18)NCA、
(19)MDP、
(20)IL20Rα、
(21)ブレビカン、
(22)EphB2R、
(23)ASLG659、
(24)PSCA、
(25)GEDA、
(26)BAFF-R(B細胞活性化因子受容体、BLyS受容体3、BR3、
(27)CD22(B細胞受容体CD22-Bアイソフォーム)、
(28)CD79a(CD79A、CD79α、免疫グロブリン関連アルファ、B細胞特異的タンパク質)、
(29)CXCR5(バーキットリンパ腫受容体1、Gタンパク質結合型受容体)、
(30)HLA-DOB(MHCクラスII分子のベータサブユニット(Ia抗原)、
(31)P2X5(プリン受容体P2Xリガンド開口型イオンチャネル5)、
(32)CD72(B細胞分化抗原CD72、Lyb-2)、
(33)LY64(リンパ球抗原64(RP105)、ロイシンリッチ反復(LRR)ファミリーのI型膜タンパク質)、
(34)FcRH1(Fc受容体様タンパク質1)、
(35)IRTA2(免疫グロブリンスーパーファミリー受容体転位関連2)、
(36)TENB2(推定上の膜貫通プロテオグリカン)、
(37)PMEL17(silver相同体、SILV、D12S53E、PMEL17、SI、SIL)、
(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を有する膜貫通タンパク質1、トモレグリン(Tomoregulin)1)、
(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-アルファ-1)、
(40)Ly6E(リンパ球抗原6複合体、遺伝子座E、Ly67、RIG-E、SCA-2、TSA-1)、
(41)TMEM46(shisa相同体2)、
(42)Ly6G6D(リンパ球抗原6複合体、遺伝子座G6D、Ly6-D、MEGT1)、
(43)LGR5(ロイシンリッチ反復含有Gタンパク質結合型受容体5、GPR49、GPR67)、
(44)RET(ret癌原遺伝子、MEN2A、HSCR1、MEN2B、MTC1、PTC、CDHF12、Hs.168114、RET51、RET-ELE1)、
(45)LY6K(リンパ球抗原6複合体、遺伝子座K、LY6K、HSJ001348、FLJ35226)、
(46)GPR19(Gタンパク質結合型受容体19、Mm.4787)、
(47)GPR54(KISS1受容体、KISS1R、GPR54、HOT7T175、AXOR12)、
(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)、
(49)チロシナーゼ(TYR、OCAIA、OCA1A、チロシナーゼ、SHEP3)、
(50)TMEM118(ringフィンガータンパク質、膜貫通2、RNFT2、FLJ14627)、
(51)GPR172A(Gタンパク質結合型受容体172A、GPCR41、FLJ11856、D15Ertd747e)、
(52)CD33、ならびに
(53)CLL-1(CLEC12A、MICL、及びDCAL2)のうちの1つ以上と結合する、実施態様1~14のいずれかに記載のシステイン操作抗体。
[実施態様30]
前記抗体は、捕捉標識、検出標識、薬物部分、または固体支持体に共有結合する、実施態様1~29のいずれかに記載のシステイン操作抗体。
[実施態様31]
前記抗体は、ビオチン捕捉標識に共有結合する、実施態様30に記載のシステイン操作抗体。
[実施態様32]
前記抗体は、蛍光色素検出標識に共有結合する、実施態様30に記載のシステイン操作抗体。
[実施態様33]
前記蛍光色素は、フルオロセイン型、ローダミン型、ダンシル、リサミン、シアニン、フィコエリトリン、テキサスレッド、及びこれらの類似体から選択される、実施態様30に記載のシステイン操作抗体。
[実施態様34]
前記抗体は、 3 H、 11 C、 14 C、 18 F、 32 P、 35 S、 64 Cu、 68 Ga、 86 Y、 89 Zr、 99 Tc、 111 In、 123 I、 124 I、 125 I、 131 I、 133 Xe、 177 Lu、 211 At、及び 213 Biから選択される放射性核種検出標識に共有結合する、実施態様30に記載のシステイン操作抗体。
[実施態様35]
前記抗体は、キレートリガンドによって検出標識に共有結合する、実施態様30に記載のシステイン操作抗体。
[実施態様36]
前記キレートリガンドは、DOTA、DOTP、DOTMA、DTPA、及びTETAから選択される、実施態様35に記載のシステイン操作抗体。
[実施態様37]
前記抗体は、薬物部分に共有結合して、式I
Ab-(L-D) p I
を有する抗体-薬物コンジュゲートを形成し、式中、Abが前記抗体であり、Lがリンカーであり、Dが前記薬物部分であり、pが1、2、3、または4であり、前記薬物部分は、実施態様1または2に記載の操作システインアミノ酸にコンジュゲートされる、実施態様1~36に記載のシステイン操作抗体。
[実施態様38]
Lは、6-マレイミドカプロイル(MC)、マレイミドプロパノイル(MP)、バリン-シトルリン(val-cit(-vc))、アラニン-フェニルアラニン(ala-phe)、及びp-アミノベンジルオキシカルボニル(PAB)から選択される基を含む、実施態様37に記載の抗体薬物コンジュゲート。
[実施態様39]
N-スクシンイミジル4-(2-ピリジルチオ)ペンタノエート(SPP)、N-スクシンイミジル4-(N-マレイミドメチル)シクロヘキサン-1カルボキシレート(SMCC)、4-(2-ピリジルジチオ)酪酸-N-ヒドロキシスクシンイミドエステル(SPDB)、及びN-スクシンイミジル(4-ヨード-アセチル)アミノベンゾエート(SIAB)から選択されるリンカー試薬から調製される、実施態様37に記載の抗体-薬物コンジュゲート。
[実施態様40]
マレイミド、ヨードアセトアミド、ブロモアセトアミド、またはジスルフィドを含むリンカー試薬から調製される、実施態様37に記載の抗体-薬物コンジュゲート。
[実施態様41]
Lは、ジスルフィドリンカーを形成する、実施態様37に記載の抗体-薬物コンジュゲート。
[実施態様42]
前記リンカー試薬は、ピリジルジスルフィド(PDS)を含む、実施態様40に記載の抗体-薬物コンジュゲート。
[実施態様43]
Lは、バリン-シトルリン(val-cit(-vc))を含む、実施態様37に記載の抗体-薬物コンジュゲート。
[実施態様44]
前記薬物部分(D)は、マイタンシノイド、オーリスタチン、ドラスタチン、トリコテセン、CC1065、カリケアマイシン、エンジイン抗生物質、タキサン、ピロロベンゾジアゼピン(PBD)二量体、1-(クロロメチル)-2,3-ジヒドロ-1H-ベンゾ[e]インドール(CBI)二量体、CBI-PBDヘテロ二量体、またはアントラサイクリンである、実施態様37~43のいずれかに記載の抗体-薬物コンジュゲート。
[実施態様45]
Dは、構造:
を有するモノメチルオーリスタチン薬物部分MMAEであり、式中、波線は前記リンカーへの前記共有結合部位を示す、実施態様44に記載の抗体-薬物コンジュゲート。
[実施態様46]
前記抗体-薬物コンジュゲートは、構造:
から選択され、式中、Valはバリンであり、Citはシトルリンであり、pは、1、2、3、または4である、実施態様44に記載の抗体-薬物コンジュゲート。
[実施態様47]
Dは、構造:
を有するPBD二量体薬物、ならびにその塩及び溶媒和物であり、
波線は、リンカーへの共有結合部分を示し、
点線は、C1とC2またはC2とC3の間の二重結合の任意の存在を示し、
R 2 は、独立して、H、OH、=O、=CH 2 、CN、R、OR、=CH-R D 、=C(R D ) 2 、O-SO 2- R、CO 2 R、及びCORから選択され、任意にハロまたはジヒドロから更に選択され、式中、R D は、独立して、R、CO 2 R、COR、CHO、CO 2 H、及びハロから選択され、
R 6 及びR 9 は、独立して、H、R、OH、OR、SH、SR、NH 2 、NHR、NRR’、NO 2 、Me 3 Sn、及びハロから選択され、
R 7 は、独立して、H、R、OH、OR、SH、SR、NH 2 、NHR、NRR’、NO 2 、Me 3 Sn、及びハロから選択され、
Qは、独立して、O、S、及びNHから選択され、
R 11 は、H若しくはRであるか、またはQがOである場合にはSO 3 Mであるかのいずれかであり、式中、Mは金属カチオンであり、
R及びR’は、それぞれ独立して、任意に置換されたC 1-8 アルキル、C 1-12 アルキル、C 3-8 ヘテロシクリル、C 3-20 複素環、及びC 5-20 アリール基から選択され、任意に基NRR’との関連で、R及びR’は、それらが結合する窒素と一緒に、任意に置換された4、5、6、または7員の複素環式環を形成し、
R 12 、R 16 、R 19 、及びR 17 は、それぞれR 2 、R 6 、R 9 、及びR 7 に関して定義される通りであり、
R″は、C 3-12 アルキレン基であり、その鎖は、1つ以上のヘテロ原子、例えば、O、S、N(H)、NMe、及び/または芳香環、例えば、ベンゼン若しくはピリジンによって分断されてもよく、これらの環は、任意に置換されており、
X及びX’は、独立して、O、S、及びN(H)から選択される、実施態様44に記載の抗体薬物コンジュゲート。
[実施態様48]
前記PBD二量体の構造は、
であり、その塩及び溶媒和物が含まれ、波線は、前記リンカーへの前記共有結合部位を示し、OHに繋がった波線は、SまたはR立体配置を示し、R V1 及びR V2 は、独立して、H、メチル、エチル、及びフェニル(このフェニルは、特に4位においてフルオロで任意に置換されてもよい)、ならびにC 5-6 ヘテロシクリルから選択され、R V1 及びR V2 は、同じかまたは異なってもよく、nは、0または1である、実施態様47に記載の抗体薬物コンジュゲート。
[実施態様49]
から選択される、実施態様47に記載の抗体薬物コンジュゲート。
[実施態様50]
Dは、構造:
を有するCBI二量体であり、式中、
R 1 は、H、P(O) 3 H 2 、C(O)NR a R b 、またはリンカー(L)への結合から選択され、
R 2 は、H、P(O) 3 H 2 、C(O)NR a R b 、またはリンカー(L)への結合から選択され、
R a 及びR b は、独立して、H、及び1つ以上の抗体Fで任意に置換されたC 1 -C 6 アルキルから選択されるか、またはR a 及びR b は、5若しくは6員のヘテロシクリル基を形成し、
Tは、C 3 -C 12 アルキレン、Y、(C 1 -C 6 アルキレン)-Y-(C 1 -C 6 アルキレン)、(C 1 -C 6 アルキレン)-Y-(C 1 -C 6 アルキレン)-Y-(C 1 -C 6 アルキレン)、(C 2 -C 6 アルケニレン)-Y-(C 2 -C 6 アルケニレン)、及び(C 2 -C 6 アルケニレン)-Y-(C 2 -C 6 アルケニレン)から選択される、連結基であり、
式中、Yは、独立して、O、S、NR 1 、アリール、及びヘテロアリールから選択され、
アルキレン、アルケニレン、アリール、及びヘテロアリールは、独立して、かつ任意に、F、OH、O(C 1 -C 6 アルキル)、NH 2 、NHCH 3 、N(CH 3 ) 2 、OP(O) 3 H 2 、及びC 1 -C 6 アルキルで置換され、アルキルは、1つ以上のFで任意に置換されるか、
またはアルキレン、アルケニレン、アリール、及びヘテロアリールは、独立して、かつ任意に、Lへの結合で置換され、
D’は、
から選択される薬物部分であり、式中、波線は、Tへの結合部位を示し、
X 1 及びX 2 は、独立して、O及びNR 3 から選択され、R 3 は、H、及び1つ以上の任意Fで任意に置換されたC 1 -C 6 アルキルから選択され、
R 4 は、H、CO 2 R、またはリンカー(L)への結合であり、Rは、C 1 -C 6 アルキルまたはベンジルであり、
R 5 は、HまたはC 1 -C 6 アルキルである、実施態様44に記載のシステイン操作抗体。
[実施態様51]
から選択される、実施態様50に記載の抗体薬物コンジュゲート。
[実施態様52]
システイン操作抗体(Ab)の少なくとも1つのシステインを、リンカー-薬物中間体と反応させて、式Iを有する抗体-薬物コンジュゲートを形成することを含み、
Ab-(L-D) p I
式中、Abは、実施態様1~50のいずれかに記載のシステイン操作抗体であり、Lはリンカーであり、Dは薬物部分であり、pは1、2、3、または4であり、前記システイン操作抗体は、1つ以上のシステインアミノ酸を含む、抗体-薬物コンジュゲートの調製方法。
[実施態様53]
前記システイン変異は、EU番号付けによるHC-L174C、HC-A140C、及びHC-Y373Cからなる群から選択される、実施態様52に記載の抗体-薬物コンジュゲートの調製方法。
[実施態様54]
前記システイン変異は、EU番号付けによるHC-A140Cである、実施態様52に記載の抗体-薬物コンジュゲートの調製方法。
[実施態様55]
前記システイン変異は、EU番号付けによるHC-L174Cである、実施態様52に記載の抗体-薬物コンジュゲートの調製方法。
[実施態様56]
前記システイン変異は、EU番号付けによるHC-A373Cである、実施態様52に記載の抗体-薬物コンジュゲートの調製方法。
[実施態様57]
前記システイン変異は、LC-K149Cである、実施態様52に記載の抗体-薬物コンジュゲートの調製方法。
[実施態様58]
前記システイン操作抗体は、EU番号付けによるA140Cの重鎖変異を有し、Lは、ピリジルジスルフィド(PDS)を含み、Dは、CBI-PBDヘテロ二量体、クリプトフィシン、タキソイド、及びチューブリシン(tubulysin)Mからなる群から選択される、実施態様37に記載の抗体薬物コンジュゲート。
[実施態様59]
前記システイン操作抗体は、EU番号付けによるA140Cの重鎖変異を有し、Lは、-vcリンカーを含み、Dは、CBI-PBDヘテロ二量体、クリプトフィシン、タキソイド、及びチューブリシンMからなる群から選択される、実施態様37に記載の抗体薬物コンジュゲート。
[実施態様60]
Dは、前記CBI-PBDヘテロ二量体:
である、実施態様59に記載の抗体薬物コンジュゲート。
[実施態様61]
前記システイン操作抗体は、EU番号付けによるR142C及びK149Cからなる群から選択される軽鎖変異を有し、Lは、ピリジルジスルフィド(PDS)を含む、実施態様37に記載の抗体薬物コンジュゲート。
[実施態様62]
前記システイン操作抗体は、EU番号付けによるA140C、L174C、L179C、G371C、Y373C、及びS424Cからなる群から選択される重鎖変異を有し、Lは、ピリジルジスルフィド(PDS)を含む、実施態様37に記載の抗体薬物コンジュゲート。
[実施態様63]
前記システイン操作抗体は、EU番号付けによるL106C及びR108Cからなる群から選択される軽鎖変異を有し、Lは-vcリンカーである、実施態様37に記載の抗体薬物コンジュゲート。
[実施態様64]
前記システイン操作抗体は、EU番号付けによるT114C、T187C、T209C、V262C、G371C、E382C、及びN434Cからなる群から選択される重鎖変異を有し、Lは-vcリンカーである、実施態様37に記載の抗体薬物コンジュゲート。
[実施態様65]
前記抗体薬物コンジュゲートは、表18または表19に列挙される抗体薬物コンジュゲートのうちの1つから選択される、抗体薬物コンジュゲート。
[実施態様66]
実施態様1~65のいずれかに記載のシステイン操作抗体または抗体薬物コンジュゲートを含む、薬学的組成物。
Claims (66)
- EU番号付けによるT114C、A140C、L174C、L179C、T187C、T209C、V262C、G371C、Y373C、E382C、S424C、N434C、及びQ438Cからなる群から選択される重鎖のシステインアミノ酸、またはKabat番号付けによるI106C、R108C、R142C、及びK149Cからなる群から選択される軽鎖のシステインアミノ酸を含む、システイン操作抗体。
- 前記重鎖の前記システイン変異は、EU番号付けによるL174C、A140C、及びY373Cからなる群から選択される、請求項1または2に記載のシステイン操作抗体。
- 前記重鎖の前記システイン変異は、EU番号付けによるA140Cである、請求項1または2に記載のシステイン操作抗体。
- 前記重鎖の前記システイン変異は、EU番号付けによるL174Cである、請求項1または2に記載のシステイン操作抗体。
- 前記重鎖の前記システイン変異は、EU番号付けによるY373Cである、請求項1または2に記載のシステイン操作抗体。
- 前記軽鎖の前記システイン変異は、K149Cである、請求項1または2に記載のシステイン操作抗体。
- (i)前記システイン操作抗体をコードするように、1つ以上のアミノ酸残基をシステインで置き換えることによって親抗体の核酸配列に変異生成を行うことと、
(ii)前記システイン操作抗体を発現させることと、
(iii)前記システイン操作抗体を単離することと、を含むプロセスによって調製される、請求項1~7のいずれかに記載のシステイン操作抗体。 - 前記変異生成は、部位指向性変異生成を含む、請求項8に記載のシステイン操作抗体。
- 前記システインは、遊離システインであり、前記プロセスは、
(i)前記システイン操作抗体の前記遊離システインを、チオール反応性親和性試薬と反応させて、前記遊離システインに共有結合した前記親和性試薬を含む、親和性標識化システイン操作抗体を生成することと、
(ii)前記親和性標識化システイン操作抗体と捕捉媒体との結合を測定することと、を更に含む、請求項8に記載のシステイン操作抗体。 - 前記チオール反応性試薬は、マレイミド部分を含む、請求項10に記載のシステイン操作抗体。
- 前記チオール反応性試薬は、ビオチン部分を含み、前記捕捉媒体は、ストレプトアビジンを含む、請求項10に記載のシステイン操作抗体。
- 前記システイン操作抗体は、モノクローナル抗体、抗体フラグメント、二重特異性抗体、キメラ抗体、ヒト抗体、及びヒト化抗体から選択される、請求項1~12のいずれかに記載のシステイン操作抗体。
- 前記抗体フラグメントは、Fabフラグメントである、請求項1~13のいずれかに記載のシステイン操作抗体。
- 前記システイン操作抗体は、抗HER2抗体である、請求項1~14のいずれかに記載のシステイン抗体。
- 前記抗HER2抗体は、トラスツズマブである、請求項15に記載のシステイン操作抗体。
- 前記システイン操作抗体は、抗Ly6E抗体である、請求項1~14のいずれかに記載のシステイン操作抗体。
- 前記抗Ly6E抗体は、
(i)配列番号179のアミノ酸配列を含むHVR-H1、及び配列番号180のアミノ酸配列を含むHVR-H2、配列番号181のアミノ酸配列を含むHVR-H3、配列番号176のアミノ酸配列を含むHVR-L1、配列番号177のアミノ酸配列を含むHVR-L2、ならびに配列番号178のアミノ酸配列を含むHVR-L3、または
(ii)配列番号175のアミノ酸配列を含む重鎖可変領域及び配列番号174のアミノ酸配列を含む軽鎖可変領域を含む、請求項17に記載のシステイン操作抗体。 - 前記システイン操作抗体は、抗CD79b抗体である、請求項1~14のいずれかに記載のシステイン操作抗体。
- 前記抗CD79b抗体は、
(i)配列番号186のアミノ酸配列を含むHVR-H1、及び配列番号187のアミノ酸配列を含むHVR-H2、配列番号188のアミノ酸配列を含むHVR-H3、配列番号189のアミノ酸配列を含むHVR-L1、配列番号190のアミノ酸配列を含むHVR-L2、ならびに配列番号191のアミノ酸配列を含むHVR-L3、または
(ii)配列番号184のアミノ酸配列を含む重鎖可変領域及び配列番号185のアミノ酸配列を含む軽鎖可変領域を含む、請求項19に記載のシステイン操作抗体。 - 前記システイン操作抗体は、抗MUC16抗体である、請求項1~14のいずれかに記載のシステイン操作抗体。
- 前記抗MUC16抗体は、
(i)配列番号152のアミノ酸配列を含むHVR-H1、及び配列番号153のアミノ酸配列を含むHVR-H2、配列番号154のアミノ酸配列を含むHVR-H3、配列番号150のアミノ酸配列を含むHVR-L1、配列番号151のアミノ酸配列を含むHVR-L2、ならびに配列番号152のアミノ酸配列を含むHVR-L3、または
(ii)配列番号156のアミノ酸配列を含む重鎖可変領域及び配列番号157のアミノ酸配列を含む軽鎖可変領域を含む、請求項21に記載のシステイン操作抗体。 - 前記システイン操作抗体は、抗STEAP1抗体である、請求項1~14のいずれかに記載のシステイン操作抗体。
- 前記抗STEAP1抗体は、
(i)配列番号157のアミノ酸配列を含むHVR-H1、及び配列番号158のアミノ酸配列を含むHVR-H2、配列番号159のアミノ酸配列を含むHVR-H3、配列番号160のアミノ酸配列を含むHVR-L1、配列番号161のアミノ酸配列を含むHVR-L2、ならびに配列番号162のアミノ酸配列を含むHVR-L3、または
(ii)配列番号163のアミノ酸配列を含む重鎖可変領域及び配列番号164のアミノ酸配列を含む軽鎖可変領域を含む、請求項23に記載のシステイン操作抗体。 - 前記システイン操作抗体は、抗NaPi2b抗体である、請求項1~14のいずれかに記載のシステイン操作抗体。
- 前記抗STEAP1抗体は、
(i)配列番号165のアミノ酸配列を含むHVR-H1、及び配列番号167のアミノ酸配列を含むHVR-H2、配列番号168のアミノ酸配列を含むHVR-H3、配列番号169のアミノ酸配列を含むHVR-L1、配列番号170のアミノ酸配列を含むHVR-L2、ならびに配列番号171のアミノ酸配列を含むHVR-L3、または
(ii)配列番号172のアミノ酸配列を含む重鎖可変領域及び配列番号173のアミノ酸配列を含む軽鎖可変領域を含む、請求項25に記載のシステイン操作抗体。 - 前記システイン操作抗体は、抗CD22抗体である、請求項1~14のいずれかに記載のシステイン操作抗体。
- 前記抗CD22抗体は、
(i)配列番号192のアミノ酸配列を含むHVR-H1、及び配列番号193のアミノ酸配列を含むHVR-H2、配列番号194のアミノ酸配列を含むHVR-H3、配列番号195のアミノ酸配列を含むHVR-L1、配列番号196のアミノ酸配列を含むHVR-L2、ならびに配列番号197のアミノ酸配列を含むHVR-L3を含む、請求項25に記載のシステイン操作抗体。 - 前記システイン操作抗体は、受容体(1)~(53):
(1)BMPR1B(骨形成タンパク質受容体IB型)、
(2)E16(LAT1、SLC7A5)、
(3)STEAP1(前立腺の6回膜貫通上皮抗原)、
(4)0772P(CA125、MUC16)、
(5)MPF(MPF、MSLN、SMR、巨核球増強因子、メソテリン)、
(6)Napi3b(NaPi2b、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)、
(7)Sema 5b(FLJ10372、KIAA1445、Mm.42015、SEMA5B、SEMAG、セマフォリン5b Hlog、セマドメイン、7回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)、
(8)PSCA hlg(2700050C12Rik、C530008O16Rik、RIKEN cDNA 2700050C12、RIKEN cDNA 2700050C12遺伝子)、
(9)ETBR(エンドセリンB型受容体)、
(10)MSG783(RNF124、仮説上のタンパク質FLJ20315)、
(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回膜貫通上皮抗原2、6回膜貫通前立腺タンパク質)、
(12)TrpM4(BR22450、FLJ20041、TRPM4、TRPM4B、一過性受容器電位カチオンチャネル、サブファミリーM、メンバー4)、
(13)CRIPTO(CR、CR1、CRGF、CRIPTO、TDGF1、奇形癌由来の成長因子)、
(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.73792)、
(15)CD79b(CD79B、CD79β、IGb(免疫グロブリン関連ベータ)、B29)、
(16)FcRH2(IFGP4、IRTA4、SPAP1A(SH2ドメイン含有ホスファターゼアンカータンパク質1a)、SPAP1B、SPAP1C)、
(17)HER2、
(18)NCA、
(19)MDP、
(20)IL20Rα、
(21)ブレビカン、
(22)EphB2R、
(23)ASLG659、
(24)PSCA、
(25)GEDA、
(26)BAFF-R(B細胞活性化因子受容体、BLyS受容体3、BR3、
(27)CD22(B細胞受容体CD22-Bアイソフォーム)、
(28)CD79a(CD79A、CD79α、免疫グロブリン関連アルファ、B細胞特異的タンパク質)、
(29)CXCR5(バーキットリンパ腫受容体1、Gタンパク質結合型受容体)、
(30)HLA-DOB(MHCクラスII分子のベータサブユニット(Ia抗原)、
(31)P2X5(プリン受容体P2Xリガンド開口型イオンチャネル5)、
(32)CD72(B細胞分化抗原CD72、Lyb-2)、
(33)LY64(リンパ球抗原64(RP105)、ロイシンリッチ反復(LRR)ファミリーのI型膜タンパク質)、
(34)FcRH1(Fc受容体様タンパク質1)、
(35)IRTA2(免疫グロブリンスーパーファミリー受容体転位関連2)、
(36)TENB2(推定上の膜貫通プロテオグリカン)、
(37)PMEL17(silver相同体、SILV、D12S53E、PMEL17、SI、SIL)、
(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を有する膜貫通タンパク質1、トモレグリン(Tomoregulin)1)、
(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-アルファ-1)、
(40)Ly6E(リンパ球抗原6複合体、遺伝子座E、Ly67、RIG-E、SCA-2、TSA-1)、
(41)TMEM46(shisa相同体2)、
(42)Ly6G6D(リンパ球抗原6複合体、遺伝子座G6D、Ly6-D、MEGT1)、
(43)LGR5(ロイシンリッチ反復含有Gタンパク質結合型受容体5、GPR49、GPR67)、
(44)RET(ret癌原遺伝子、MEN2A、HSCR1、MEN2B、MTC1、PTC、CDHF12、Hs.168114、RET51、RET-ELE1)、
(45)LY6K(リンパ球抗原6複合体、遺伝子座K、LY6K、HSJ001348、FLJ35226)、
(46)GPR19(Gタンパク質結合型受容体19、Mm.4787)、
(47)GPR54(KISS1受容体、KISS1R、GPR54、HOT7T175、AXOR12)、
(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)、
(49)チロシナーゼ(TYR、OCAIA、OCA1A、チロシナーゼ、SHEP3)、
(50)TMEM118(ringフィンガータンパク質、膜貫通2、RNFT2、FLJ14627)、
(51)GPR172A(Gタンパク質結合型受容体172A、GPCR41、FLJ11856、D15Ertd747e)、
(52)CD33、ならびに
(53)CLL-1(CLEC12A、MICL、及びDCAL2)のうちの1つ以上と結合する、請求項1~14のいずれかに記載のシステイン操作抗体。 - 前記抗体は、捕捉標識、検出標識、薬物部分、または固体支持体に共有結合する、請求項1~29のいずれかに記載のシステイン操作抗体。
- 前記抗体は、ビオチン捕捉標識に共有結合する、請求項30に記載のシステイン操作抗体。
- 前記抗体は、蛍光色素検出標識に共有結合する、請求項30に記載のシステイン操作抗体。
- 前記蛍光色素は、フルオロセイン型、ローダミン型、ダンシル、リサミン、シアニン、フィコエリトリン、テキサスレッド、及びこれらの類似体から選択される、請求項30に記載のシステイン操作抗体。
- 前記抗体は、3H、11C、14C、18F、32P、35S、64Cu、68Ga、86Y、89Zr、99Tc、111In、123I、124I、125I、131I、133Xe、177Lu、211At、及び213Biから選択される放射性核種検出標識に共有結合する、請求項30に記載のシステイン操作抗体。
- 前記抗体は、キレートリガンドによって検出標識に共有結合する、請求項30に記載のシステイン操作抗体。
- 前記キレートリガンドは、DOTA、DOTP、DOTMA、DTPA、及びTETAから選択される、請求項35に記載のシステイン操作抗体。
- 前記抗体は、薬物部分に共有結合して、式I
Ab-(L-D)p I
を有する抗体-薬物コンジュゲートを形成し、式中、Abが前記抗体であり、Lがリンカーであり、Dが前記薬物部分であり、pが1、2、3、または4であり、前記薬物部分は、請求項1または2に記載の操作システインアミノ酸にコンジュゲートされる、請求項1~36に記載のシステイン操作抗体。 - Lは、6-マレイミドカプロイル(MC)、マレイミドプロパノイル(MP)、バリン-シトルリン(val-cit(-vc))、アラニン-フェニルアラニン(ala-phe)、及びp-アミノベンジルオキシカルボニル(PAB)から選択される基を含む、請求項37に記載の抗体薬物コンジュゲート。
- N-スクシンイミジル4-(2-ピリジルチオ)ペンタノエート(SPP)、N-スクシンイミジル4-(N-マレイミドメチル)シクロヘキサン-1カルボキシレート(SMCC)、4-(2-ピリジルジチオ)酪酸-N-ヒドロキシスクシンイミドエステル(SPDB)、及びN-スクシンイミジル(4-ヨード-アセチル)アミノベンゾエート(SIAB)から選択されるリンカー試薬から調製される、請求項37に記載の抗体-薬物コンジュゲート。
- マレイミド、ヨードアセトアミド、ブロモアセトアミド、またはジスルフィドを含むリンカー試薬から調製される、請求項37に記載の抗体-薬物コンジュゲート。
- Lは、ジスルフィドリンカーを形成する、請求項37に記載の抗体-薬物コンジュゲート。
- 前記リンカー試薬は、ピリジルジスルフィド(PDS)を含む、請求項40に記載の抗体-薬物コンジュゲート。
- Lは、バリン-シトルリン(val-cit(-vc))を含む、請求項37に記載の抗体-薬物コンジュゲート。
- 前記薬物部分(D)は、マイタンシノイド、オーリスタチン、ドラスタチン、トリコテセン、CC1065、カリケアマイシン、エンジイン抗生物質、タキサン、ピロロベンゾジアゼピン(PBD)二量体、1-(クロロメチル)-2,3-ジヒドロ-1H-ベンゾ[e]インドール(CBI)二量体、CBI-PBDヘテロ二量体、またはアントラサイクリンである、請求項37~43のいずれかに記載の抗体-薬物コンジュゲート。
- Dは、構造:
を有するPBD二量体薬物、ならびにその塩及び溶媒和物であり、
波線は、リンカーへの共有結合部分を示し、
点線は、C1とC2またはC2とC3の間の二重結合の任意の存在を示し、
R2は、独立して、H、OH、=O、=CH2、CN、R、OR、=CH-RD、=C(RD)2、O-SO2-R、CO2R、及びCORから選択され、任意にハロまたはジヒドロから更に選択され、式中、RD は、独立して、R、CO2R、COR、CHO、CO2H、及びハロから選択され、
R6及びR9は、独立して、H、R、OH、OR、SH、SR、NH2、NHR、NRR’、NO2、Me3Sn、及びハロから選択され、
R7は、独立して、H、R、OH、OR、SH、SR、NH2、NHR、NRR’、NO2、Me3Sn、及びハロから選択され、
Qは、独立して、O、S、及びNHから選択され、
R11は、H若しくはRであるか、またはQがOである場合にはSO3Mであるかのいずれかであり、式中、Mは金属カチオンであり、
R及びR’は、それぞれ独立して、任意に置換されたC1-8アルキル、C1-12アルキル、C3-8ヘテロシクリル、C3-20複素環、及びC5-20アリール基から選択され、任意に基NRR’との関連で、R及びR’は、それらが結合する窒素と一緒に、任意に置換された4、5、6、または7員の複素環式環を形成し、
R12、R16、R19、及びR17は、それぞれR2、R6、R9、及びR7に関して定義される通りであり、
R″は、C3-12アルキレン基であり、その鎖は、1つ以上のヘテロ原子、例えば、O、S、N(H)、NMe、及び/または芳香環、例えば、ベンゼン若しくはピリジンによって分断されてもよく、これらの環は、任意に置換されており、
X及びX’は、独立して、O、S、及びN(H)から選択される、請求項44に記載の抗体薬物コンジュゲート。 - Dは、構造:
を有するCBI二量体であり、式中、
R1は、H、P(O)3H2、C(O)NRaRb、またはリンカー(L)への結合から選択され、
R2は、H、P(O)3H2、C(O)NRaRb、またはリンカー(L)への結合から選択され、
Ra及びRbは、独立して、H、及び1つ以上の抗体Fで任意に置換されたC1-C6アルキルから選択されるか、またはRa及びRb は、5若しくは6員のヘテロシクリル基を形成し、
Tは、C3-C12アルキレン、Y、(C1-C6アルキレン)-Y-(C1-C6アルキレン)、(C1-C6アルキレン)-Y-(C1-C6アルキレン)-Y-(C1-C6アルキレン)、(C2-C6アルケニレン)-Y-(C2-C6アルケニレン)、及び(C2-C6アルケニレン)-Y-(C2-C6アルケニレン)から選択される、連結基であり、
式中、Yは、独立して、O、S、NR1、アリール、及びヘテロアリールから選択され、
アルキレン、アルケニレン、アリール、及びヘテロアリールは、独立して、かつ任意に、F、OH、O(C1-C6アルキル)、NH2、NHCH3、N(CH3)2、OP(O)3H2、及びC1-C6アルキルで置換され、アルキルは、1つ以上のFで任意に置換されるか、
またはアルキレン、アルケニレン、アリール、及びヘテロアリールは、独立して、かつ任意に、Lへの結合で置換され、
D’は、
から選択される薬物部分であり、式中、波線は、Tへの結合部位を示し、
X1及びX2は、独立して、O及びNR3から選択され、R3は、H、及び1つ以上の任意Fで任意に置換されたC1-C6アルキルから選択され、
R4は、H、CO2R、またはリンカー(L)への結合であり、Rは、C1-C6アルキルまたはベンジルであり、
R5は、HまたはC1-C6アルキルである、請求項44に記載のシステイン操作抗体。 - システイン操作抗体(Ab)の少なくとも1つのシステインを、リンカー-薬物中間体と反応させて、式Iを有する抗体-薬物コンジュゲートを形成することを含み、
Ab-(L-D)p I
式中、Abは、請求項1~50のいずれかに記載のシステイン操作抗体であり、Lはリンカーであり、Dは薬物部分であり、pは1、2、3、または4であり、前記システイン操作抗体は、1つ以上のシステインアミノ酸を含む、抗体-薬物コンジュゲートの調製方法。 - 前記システイン変異は、EU番号付けによるHC-L174C、HC-A140C、及びHC-Y373Cからなる群から選択される、請求項52に記載の抗体-薬物コンジュゲートの調製方法。
- 前記システイン変異は、EU番号付けによるHC-A140Cである、請求項52に記載の抗体-薬物コンジュゲートの調製方法。
- 前記システイン変異は、EU番号付けによるHC-L174Cである、請求項52に記載の抗体-薬物コンジュゲートの調製方法。
- 前記システイン変異は、EU番号付けによるHC-A373Cである、請求項52に記載の抗体-薬物コンジュゲートの調製方法。
- 前記システイン変異は、LC-K149Cである、請求項52に記載の抗体-薬物コンジュゲートの調製方法。
- 前記システイン操作抗体は、EU番号付けによるA140Cの重鎖変異を有し、Lは、ピリジルジスルフィド(PDS)を含み、Dは、CBI-PBDヘテロ二量体、クリプトフィシン、タキソイド、及びチューブリシン(tubulysin)Mからなる群から選択される、請求項37に記載の抗体薬物コンジュゲート。
- 前記システイン操作抗体は、EU番号付けによるA140Cの重鎖変異を有し、Lは、-vcリンカーを含み、Dは、CBI-PBDヘテロ二量体、クリプトフィシン、タキソイド、及びチューブリシンMからなる群から選択される、請求項37に記載の抗体薬物コンジュゲート。
- 前記システイン操作抗体は、EU番号付けによるR142C及びK149Cからなる群から選択される軽鎖変異を有し、Lは、ピリジルジスルフィド(PDS)を含む、請求項37に記載の抗体薬物コンジュゲート。
- 前記システイン操作抗体は、EU番号付けによるA140C、L174C、L179C、G371C、Y373C、及びS424Cからなる群から選択される重鎖変異を有し、Lは、ピリジルジスルフィド(PDS)を含む、請求項37に記載の抗体薬物コンジュゲート。
- 前記システイン操作抗体は、EU番号付けによるL106C及びR108Cからなる群から選択される軽鎖変異を有し、Lは-vcリンカーである、請求項37に記載の抗体薬物コンジュゲート。
- 前記システイン操作抗体は、EU番号付けによるT114C、T187C、T209C、V262C、G371C、E382C、及びN434Cからなる群から選択される重鎖変異を有し、Lは-vcリンカーである、請求項37に記載の抗体薬物コンジュゲート。
- 前記抗体薬物コンジュゲートは、表18または表19に列挙される抗体薬物コンジュゲートのうちの1つから選択される、抗体薬物コンジュゲート。
- 請求項1~65のいずれかに記載のシステイン操作抗体または抗体薬物コンジュゲートを含む、薬学的組成物。
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Families Citing this family (87)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP6707445B2 (ja) * | 2013-10-21 | 2020-06-10 | ジェネンテック, インコーポレイテッド | 抗Ly6E抗体及び使用方法 |
EA033456B1 (ru) | 2013-12-16 | 2019-10-31 | Genentech Inc | Конъюгаты антитело-лекарственное средство, содержащие пептидомиметические линкеры |
KR20170042495A (ko) | 2013-12-16 | 2017-04-19 | 제넨테크, 인크. | 펩티드모방체 화합물 및 그의 항체-약물 접합체 |
MA40576B1 (fr) | 2014-09-12 | 2020-11-30 | Genentech Inc | Anticorps et immunoconjugués anti-her2 |
PL3262071T3 (pl) * | 2014-09-23 | 2020-08-10 | F. Hoffmann-La Roche Ag | Sposób stosowania immunokoniugatów anty-CD79b |
CN107207582A (zh) | 2015-02-16 | 2017-09-26 | 隆萨有限公司 | 用于药物缀合的cl和/或ch1突变抗体 |
US10017577B2 (en) | 2015-06-15 | 2018-07-10 | Genentech, Inc. | Antibodies and immunoconjugates |
MA43345A (fr) | 2015-10-02 | 2018-08-08 | Hoffmann La Roche | Conjugués anticorps-médicaments de pyrrolobenzodiazépine et méthodes d'utilisation |
US11793880B2 (en) | 2015-12-04 | 2023-10-24 | Seagen Inc. | Conjugates of quaternized tubulysin compounds |
CA3006000A1 (en) | 2015-12-04 | 2017-06-08 | Seattle Genetics, Inc. | Conjugates of quaternized tubulysin compounds |
EP3394096A1 (en) | 2015-12-21 | 2018-10-31 | Bristol-Myers Squibb Company | Variant antibodies for site-specific conjugation |
CN108697799A (zh) | 2016-03-22 | 2018-10-23 | 生态学有限公司 | 抗lgr5单克隆抗体的施用 |
JP2019530434A (ja) * | 2016-08-05 | 2019-10-24 | ジェネンテック, インコーポレイテッド | アゴニスト活性を有する多価及び多重エピトープ抗体ならびに使用方法 |
CA3035254A1 (en) * | 2016-09-01 | 2018-03-08 | Immunomab, Inc. | Bispecific antibodies |
CN110248962A (zh) * | 2016-12-06 | 2019-09-17 | 希望之城 | 半胱氨酸肽使能抗体 |
WO2018114578A1 (de) * | 2016-12-21 | 2018-06-28 | Bayer Pharma Aktiengesellschaft | Binder-wirkstoff-konjugate (adcs) mit enzymatisch spaltbaren gruppen |
EP3589320A4 (en) * | 2017-02-28 | 2020-12-23 | Seagen Inc. | CYSTEIN-MUTED ANTIBODIES FOR CONJUGATION |
JP7227151B2 (ja) | 2017-03-22 | 2023-02-21 | ジェネンテック, インコーポレイテッド | 眼障害の治療のために最適化された抗体組成物 |
JP7247101B2 (ja) | 2017-04-03 | 2023-03-28 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Steap-1に結合する抗体 |
TW201836647A (zh) * | 2017-04-06 | 2018-10-16 | 美商艾伯維有限公司 | 抗-prlr抗體藥物軛合物(adc)及其用途 |
US20200114017A1 (en) * | 2017-06-16 | 2020-04-16 | Bionomics Limited | Antibody drug conjugates that bind lgr5 |
JP7153082B2 (ja) * | 2017-06-20 | 2022-10-13 | バイリ-バイオ(チェンドゥ)ファーマスーティカル シーオー.,エルティーディー. | システイン改変抗体-毒素複合体(tdc)の部位特異的結合サイトのスクリーニング |
GB201711208D0 (en) | 2017-07-12 | 2017-08-23 | Iontas Ltd | Ion channel inhibitors |
JP7117088B2 (ja) * | 2017-08-04 | 2022-08-12 | シスメックス株式会社 | 抗体及びその製造方法、並びに抗体の熱安定性を向上させる方法 |
CN107446050A (zh) | 2017-08-11 | 2017-12-08 | 百奥泰生物科技(广州)有限公司 | Trop2阳性疾病治疗的化合物及方法 |
EP3668545A2 (en) | 2017-08-16 | 2020-06-24 | Bristol-Myers Squibb Company | Prodruggable antibodies, prodrugs thereof, and methods of use and making |
US20230158141A1 (en) * | 2017-11-08 | 2023-05-25 | Yafei Shanghai Biolog Medicine Science & Technolog Co., Ltd | Conjugates of Biomolecule and Use Thereof |
CN111527107A (zh) | 2017-12-21 | 2020-08-11 | 豪夫迈·罗氏有限公司 | 结合hla-a2/wt1的抗体 |
EP3731864A1 (en) | 2017-12-29 | 2020-11-04 | F. Hoffmann-La Roche SA | Anti-vegf antibodies and methods of use |
US20200339686A1 (en) | 2018-01-16 | 2020-10-29 | Lakepharma, Inc. | Bispecific antibody that binds cd3 and another target |
CN111867621A (zh) * | 2018-01-18 | 2020-10-30 | 美真达治疗公司 | 用于耗尽cd134+细胞的组合物和方法 |
TWI829667B (zh) | 2018-02-09 | 2024-01-21 | 瑞士商赫孚孟拉羅股份公司 | 結合gprc5d之抗體 |
CN111936625A (zh) | 2018-03-29 | 2020-11-13 | 豪夫迈·罗氏有限公司 | 调节哺乳动物细胞中的生乳活性 |
CN112584859A (zh) | 2018-07-02 | 2021-03-30 | 美国安进公司 | 抗steap1抗原结合蛋白 |
KR20210040989A (ko) | 2018-08-03 | 2021-04-14 | 추가이 세이야쿠 가부시키가이샤 | 서로 연결된 2개의 항원 결합 도메인을 포함하는 항원 결합 분자 |
CA3113645A1 (en) * | 2018-09-20 | 2020-03-26 | Arizona Board Of Regents On Behalf Of The University Of Arizona | Targeting moiety-drug grafted immune cell compositions and methods of use |
EP3873534A1 (en) * | 2018-10-29 | 2021-09-08 | Mersana Therapeutics, Inc. | Cysteine engineered antibody-drug conjugates with peptide-containing linkers |
PE20211603A1 (es) | 2018-12-21 | 2021-08-18 | Hoffmann La Roche | Anticuerpos que se unen a cd3 |
US11130804B2 (en) | 2018-12-21 | 2021-09-28 | Hoffmann-La Roche Inc. | Antibody that binds to VEGF and IL-1beta and methods of use |
CA3127556A1 (en) | 2019-01-28 | 2020-08-06 | Tuojie Biotech (Shanghai) Co., Ltd. | Anti-cd79b antibody, antigen-binding fragment thereof, and pharmaceutical use thereof |
CN111675762B (zh) * | 2019-03-11 | 2023-12-01 | 凯惠科技发展(上海)有限公司 | 一种含半胱氨酸的抗体、药物偶联物及其应用 |
WO2020191306A1 (en) | 2019-03-21 | 2020-09-24 | Immunogen, Inc. | Methods of preparing cell-binding agent-drug conjugates |
AR119393A1 (es) | 2019-07-15 | 2021-12-15 | Hoffmann La Roche | Anticuerpos que se unen a nkg2d |
JP2022543551A (ja) | 2019-07-31 | 2022-10-13 | エフ・ホフマン-ラ・ロシュ・アクチェンゲゼルシャフト | Gprc5dに結合する抗体 |
CR20220019A (es) | 2019-07-31 | 2022-02-11 | Hoffmann La Roche | Anticuerpos que se fijan a gprc5d |
WO2021031930A1 (zh) * | 2019-08-19 | 2021-02-25 | 沈阳药科大学 | 抗体的突变体及其应用 |
EP4025609A4 (en) * | 2019-09-05 | 2023-10-04 | Memorial Sloan Kettering Cancer Center | ANTI-STEAP1 ANTIBODIES AND USES THEREOF |
PE20221906A1 (es) | 2019-09-18 | 2022-12-23 | Genentech Inc | Anticuerpos anti-klk7, anticuerpos anti-klk5, anticuerpos multiespecificos anti-klk5/klk7 y metodos de uso |
US20210230278A1 (en) | 2019-12-18 | 2021-07-29 | Hoffmann-La Roche Inc. | Antibodies binding to HLA-A2/MAGE-A4 |
CA3168510A1 (en) | 2020-02-05 | 2021-08-12 | Chugai Seiyaku Kabushiki Kaisha | Methods for producing and/or enriching recombinant antigen-binding molecules |
WO2021168274A1 (en) | 2020-02-21 | 2021-08-26 | Silverback Therapeutics, Inc. | Nectin-4 antibody conjugates and uses thereof |
JP2021134154A (ja) | 2020-02-25 | 2021-09-13 | シスメックス株式会社 | 改変抗体及びその製造方法、並びに抗体の熱安定性を向上させる方法 |
EP4127153A2 (en) | 2020-03-26 | 2023-02-08 | Genentech, Inc. | Modified mammalian cells having reduced host cell proteins |
CN115397850A (zh) | 2020-03-30 | 2022-11-25 | 豪夫迈·罗氏有限公司 | 与vegf和pdgf-b结合的抗体及其使用方法 |
CR20220541A (es) | 2020-03-31 | 2022-11-28 | Chugai Pharmaceutical Co Ltd | Moléculas de unión al antígeno multiespecíficas dirigidas a ligando de tipo delta 3 (dll3) y sus usos |
AR122569A1 (es) | 2020-06-08 | 2022-09-21 | Hoffmann La Roche | Anticuerpos anti-vhb y métodos de uso |
AU2021291011A1 (en) | 2020-06-19 | 2023-01-05 | F. Hoffmann-La Roche Ag | Antibodies binding to CD3 and CD19 |
WO2021255146A1 (en) | 2020-06-19 | 2021-12-23 | F. Hoffmann-La Roche Ag | Antibodies binding to cd3 and cea |
WO2021255143A1 (en) | 2020-06-19 | 2021-12-23 | F. Hoffmann-La Roche Ag | Antibodies binding to cd3 and folr1 |
TW202216766A (zh) | 2020-06-19 | 2022-05-01 | 瑞士商赫孚孟拉羅股份公司 | 與cd3結合之抗體 |
JP2023533217A (ja) | 2020-06-24 | 2023-08-02 | ジェネンテック, インコーポレイテッド | アポトーシス耐性細胞株 |
EP4175673A1 (en) | 2020-07-01 | 2023-05-10 | ARS Pharmaceuticals Inc. | Anti-asgr1 antibody conjugates and uses thereof |
PE20231300A1 (es) | 2020-07-17 | 2023-08-24 | Genentech Inc | Anticuerpos anti-notch2 y metodos de uso |
CA3192344A1 (en) | 2020-08-28 | 2022-03-03 | Genentech, Inc. | Crispr/cas9 multiplex knockout of host cell proteins |
KR20230061458A (ko) | 2020-09-04 | 2023-05-08 | 에프. 호프만-라 로슈 아게 | Vegf-a 및 ang2에 결합하는 항체 및 사용 방법 |
AR123855A1 (es) | 2020-10-20 | 2023-01-18 | Genentech Inc | Anticuerpos anti-mertk conjugados con peg y métodos de uso |
WO2022169872A1 (en) | 2021-02-03 | 2022-08-11 | Genentech, Inc. | Multispecific binding protein degrader platform and methods of use |
WO2022192647A1 (en) | 2021-03-12 | 2022-09-15 | Genentech, Inc. | Anti-klk7 antibodies, anti-klk5 antibodies, multispecific anti-klk5/klk7 antibodies, and methods of use |
CN117279664A (zh) | 2021-04-10 | 2023-12-22 | 普方生物制药美国公司 | Folr1结合剂、其偶联物及其使用方法 |
JP2024514222A (ja) | 2021-04-19 | 2024-03-28 | ジェネンテック, インコーポレイテッド | 改変された哺乳動物細胞 |
EP4326768A1 (en) | 2021-04-23 | 2024-02-28 | Profoundbio Us Co. | Anti-cd70 antibodies, conjugates thereof and methods of using the same |
WO2022246259A1 (en) | 2021-05-21 | 2022-11-24 | Genentech, Inc. | Modified cells for the production of a recombinant product of interest |
WO2023288182A1 (en) | 2021-07-12 | 2023-01-19 | Genentech, Inc. | Structures for reducing antibody-lipase binding |
IL309856A (en) | 2021-07-14 | 2024-02-01 | Genentech Inc | Antibodies anti-C-C motif receptor 8 (CCR8) and methods of use |
WO2023001884A1 (en) | 2021-07-22 | 2023-01-26 | F. Hoffmann-La Roche Ag | Heterodimeric fc domain antibodies |
CA3226393A1 (en) * | 2021-07-28 | 2023-02-02 | Doron Shabat | Water soluble prodrug, conjugates and uses thereof |
CN117794953A (zh) | 2021-08-03 | 2024-03-29 | 豪夫迈·罗氏有限公司 | 双特异性抗体及使用方法 |
WO2023092099A1 (en) | 2021-11-19 | 2023-05-25 | Ardeagen Corporation | Gpc3 binding agents, conjugates thereof and methods of using the same |
AR127887A1 (es) | 2021-12-10 | 2024-03-06 | Hoffmann La Roche | Anticuerpos que se unen a cd3 y plap |
TW202340251A (zh) | 2022-01-19 | 2023-10-16 | 美商建南德克公司 | 抗notch2抗體及結合物及其使用方法 |
WO2023215737A1 (en) * | 2022-05-03 | 2023-11-09 | Genentech, Inc. | Anti-ly6e antibodies, immunoconjugates, and uses thereof |
WO2023217933A1 (en) | 2022-05-11 | 2023-11-16 | F. Hoffmann-La Roche Ag | Antibody that binds to vegf-a and il6 and methods of use |
WO2023240067A2 (en) * | 2022-06-07 | 2023-12-14 | Ngb Biopharmaceuticals, Inc. | Multimerization of binding molecules having an antibody constant region variant and mutations that reduce effector functions |
WO2024028282A1 (en) | 2022-08-01 | 2024-02-08 | Gate2Brain, S.L. | Site-specific modification by a bbb-shuttle of antibody-based entities for crossing the blood-brain barrier |
CN115850449A (zh) * | 2022-09-29 | 2023-03-28 | 苏州智核生物医药科技有限公司 | 抗体和缀合物 |
WO2024077239A1 (en) | 2022-10-07 | 2024-04-11 | Genentech, Inc. | Methods of treating cancer with anti-c-c motif chemokine receptor 8 (ccr8) antibodies |
CN116650660B (zh) * | 2023-07-27 | 2023-11-03 | 上海偌妥生物科技有限公司 | 制备抗体偶联小分子药物的方法及其应用 |
Family Cites Families (405)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4307016A (en) | 1978-03-24 | 1981-12-22 | Takeda Chemical Industries, Ltd. | Demethyl maytansinoids |
US4275149A (en) | 1978-11-24 | 1981-06-23 | Syva Company | Macromolecular environment control in specific receptor assays |
US4318980A (en) | 1978-04-10 | 1982-03-09 | Miles Laboratories, Inc. | Heterogenous specific binding assay employing a cycling reactant as label |
US4256746A (en) | 1978-11-14 | 1981-03-17 | Takeda Chemical Industries | Dechloromaytansinoids, their pharmaceutical compositions and method of use |
JPS55102583A (en) | 1979-01-31 | 1980-08-05 | Takeda Chem Ind Ltd | 20-acyloxy-20-demethylmaytansinoid compound |
JPS55162791A (en) | 1979-06-05 | 1980-12-18 | Takeda Chem Ind Ltd | Antibiotic c-15003pnd and its preparation |
JPS5645483A (en) | 1979-09-19 | 1981-04-25 | Takeda Chem Ind Ltd | C-15003phm and its preparation |
JPS5645485A (en) | 1979-09-21 | 1981-04-25 | Takeda Chem Ind Ltd | Production of c-15003pnd |
EP0028683A1 (en) | 1979-09-21 | 1981-05-20 | Takeda Chemical Industries, Ltd. | Antibiotic C-15003 PHO and production thereof |
US4458066A (en) | 1980-02-29 | 1984-07-03 | University Patents, Inc. | Process for preparing polynucleotides |
WO1982001188A1 (en) | 1980-10-08 | 1982-04-15 | Takeda Chemical Industries Ltd | 4,5-deoxymaytansinoide compounds and process for preparing same |
US4450254A (en) | 1980-11-03 | 1984-05-22 | Standard Oil Company | Impact improvement of high nitrile resins |
US4315929A (en) | 1981-01-27 | 1982-02-16 | The United States Of America As Represented By The Secretary Of Agriculture | Method of controlling the European corn borer with trewiasine |
US4313946A (en) | 1981-01-27 | 1982-02-02 | The United States Of America As Represented By The Secretary Of Agriculture | Chemotherapeutically active maytansinoids from Trewia nudiflora |
US4415732A (en) | 1981-03-27 | 1983-11-15 | University Patents, Inc. | Phosphoramidite compounds and processes |
JPS57192389A (en) | 1981-05-20 | 1982-11-26 | Takeda Chem Ind Ltd | Novel maytansinoid |
US4816567A (en) | 1983-04-08 | 1989-03-28 | Genentech, Inc. | Recombinant immunoglobin preparations |
JPS6098584A (ja) | 1983-11-02 | 1985-06-01 | Canon Inc | カメラ―体形vtr |
US5807715A (en) | 1984-08-27 | 1998-09-15 | The Board Of Trustees Of The Leland Stanford Junior University | Methods and transformed mammalian lymphocyte cells for producing functional antigen-binding protein including chimeric immunoglobulin |
US5316757A (en) | 1984-10-18 | 1994-05-31 | Board Of Regents, The University Of Texas System | Synthesis of polyazamacrocycles with more than one type of side-chain chelating groups |
US5342606A (en) | 1984-10-18 | 1994-08-30 | Board Of Regents, The University Of Texas System | Polyazamacrocyclic compounds for complexation of metal ions |
US4737456A (en) | 1985-05-09 | 1988-04-12 | Syntex (U.S.A.) Inc. | Reducing interference in ligand-receptor binding assays |
US4676980A (en) | 1985-09-23 | 1987-06-30 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Target specific cross-linked heteroantibodies |
US5583024A (en) | 1985-12-02 | 1996-12-10 | The Regents Of The University Of California | Recombinant expression of Coleoptera luciferase |
US5091178A (en) | 1986-02-21 | 1992-02-25 | Oncogen | Tumor therapy with biologically active anti-tumor antibodies |
IL85035A0 (en) | 1987-01-08 | 1988-06-30 | Int Genetic Eng | Polynucleotide molecule,a chimeric antibody with specificity for human b cell surface antigen,a process for the preparation and methods utilizing the same |
AU600575B2 (en) | 1987-03-18 | 1990-08-16 | Sb2, Inc. | Altered antibodies |
GB8720833D0 (en) | 1987-09-04 | 1987-10-14 | Celltech Ltd | Recombinant dna product |
US5606040A (en) | 1987-10-30 | 1997-02-25 | American Cyanamid Company | Antitumor and antibacterial substituted disulfide derivatives prepared from compounds possessing a methyl-trithio group |
US5770701A (en) | 1987-10-30 | 1998-06-23 | American Cyanamid Company | Process for preparing targeted forms of methyltrithio antitumor agents |
JP3040121B2 (ja) | 1988-01-12 | 2000-05-08 | ジェネンテク,インコーポレイテッド | 増殖因子レセプターの機能を阻害することにより腫瘍細胞を処置する方法 |
FI102355B1 (fi) | 1988-02-11 | 1998-11-30 | Bristol Myers Squibb Co | Menetelmä yhdistävän välikappaleen omaavien antrasykliini-immunokonjugaattien valmistamiseksi |
WO1991002536A1 (en) | 1989-08-23 | 1991-03-07 | Scripps Clinic And Research Foundation | Compositions and methods for detection and treatment of epstein-barr virus infection and immune disorders |
US5208020A (en) | 1989-10-25 | 1993-05-04 | Immunogen Inc. | Cytotoxic agents comprising maytansinoids and their therapeutic use |
US5256643A (en) | 1990-05-29 | 1993-10-26 | The Government Of The United States | Human cripto protein |
WO1992007574A1 (en) | 1990-10-25 | 1992-05-14 | Tanox Biosystems, Inc. | Glycoproteins associated with membrane-bound immunoglobulins as antibody targets on b cells |
US5571894A (en) | 1991-02-05 | 1996-11-05 | Ciba-Geigy Corporation | Recombinant antibodies specific for a growth factor receptor |
US5543503A (en) | 1991-03-29 | 1996-08-06 | Genentech Inc. | Antibodies to human IL-8 type A receptor |
US5440021A (en) | 1991-03-29 | 1995-08-08 | Chuntharapai; Anan | Antibodies to human IL-8 type B receptor |
WO1992017497A1 (en) | 1991-03-29 | 1992-10-15 | Genentech, Inc. | Human pf4a receptors and their use |
LU91067I2 (fr) | 1991-06-14 | 2004-04-02 | Genentech Inc | Trastuzumab et ses variantes et dérivés immuno chimiques y compris les immotoxines |
JP3050424B2 (ja) | 1991-07-12 | 2000-06-12 | 塩野義製薬株式会社 | ヒトエンドセリンリセプター |
US5264557A (en) | 1991-08-23 | 1993-11-23 | The United States Of America As Represented By The Department Of Health And Human Services | Polypeptide of a human cripto-related gene, CR-3 |
US5587458A (en) | 1991-10-07 | 1996-12-24 | Aronex Pharmaceuticals, Inc. | Anti-erbB-2 antibodies, combinations thereof, and therapeutic and diagnostic uses thereof |
WO1993008829A1 (en) | 1991-11-04 | 1993-05-13 | The Regents Of The University Of California | Compositions that mediate killing of hiv-infected cells |
US6153408A (en) | 1991-11-15 | 2000-11-28 | Institut Pasteur And Institut National De La Sante Et De La Recherche Medicale | Altered major histocompatibility complex (MHC) determinant and methods of using the determinant |
US5976551A (en) | 1991-11-15 | 1999-11-02 | Institut Pasteur And Institut Nationale De La Sante Et De La Recherche Medicale | Altered major histocompatibility complex (MHC) determinant and method of using the determinant |
US5428139A (en) | 1991-12-10 | 1995-06-27 | The Dow Chemical Company | Bicyclopolyazamacrocyclophosphonic acid complexes for use as radiopharmaceuticals |
US5480990A (en) | 1991-12-10 | 1996-01-02 | The Dow Chemical Company | Bicyclopolyazamacrocyclocarboxylic acid complexes for use as contrast agents |
US5739294A (en) | 1991-12-10 | 1998-04-14 | The Dow Chemical Company | Bicyclopol yazamacrocyclophosphonic acid complexes for use as contrast agents |
DE69333807T2 (de) | 1992-02-06 | 2006-02-02 | Chiron Corp., Emeryville | Marker für krebs und biosynthetisches bindeprotein dafür |
AU4025193A (en) | 1992-04-08 | 1993-11-18 | Cetus Oncology Corporation | Humanized C-erbB-2 specific antibodies |
ZA932522B (en) | 1992-04-10 | 1993-12-20 | Res Dev Foundation | Immunotoxins directed against c-erbB-2(HER/neu) related surface antigens |
WO1994006474A1 (en) | 1992-09-16 | 1994-03-31 | Galagen Inc. | ANTIBODY TREATMENT OF $i(HELICOBACTER PYLORI) |
IL107366A (en) | 1992-10-23 | 2003-03-12 | Chugai Pharmaceutical Co Ltd | Genes coding for megakaryocyte potentiator |
WO1994011026A2 (en) | 1992-11-13 | 1994-05-26 | Idec Pharmaceuticals Corporation | Therapeutic application of chimeric and radiolabeled antibodies to human b lymphocyte restricted differentiation antigen for treatment of b cell lymphoma |
US5635483A (en) | 1992-12-03 | 1997-06-03 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Tumor inhibiting tetrapeptide bearing modified phenethyl amides |
US5644033A (en) | 1992-12-22 | 1997-07-01 | Health Research, Inc. | Monoclonal antibodies that define a unique antigen of human B cell antigen receptor complex and methods of using same for diagnosis and treatment |
US5780588A (en) | 1993-01-26 | 1998-07-14 | Arizona Board Of Regents | Elucidation and synthesis of selected pentapeptides |
US5801005A (en) | 1993-03-17 | 1998-09-01 | University Of Washington | Immune reactivity to HER-2/neu protein for diagnosis of malignancies in which the HER-2/neu oncogene is associated |
US5869445A (en) | 1993-03-17 | 1999-02-09 | University Of Washington | Methods for eliciting or enhancing reactivity to HER-2/neu protein |
US5385893A (en) | 1993-05-06 | 1995-01-31 | The Dow Chemical Company | Tricyclopolyazamacrocyclophosphonic acids, complexes and derivatives thereof, for use as contrast agents |
US5462725A (en) | 1993-05-06 | 1995-10-31 | The Dow Chemical Company | 2-pyridylmethylenepolyazamacrocyclophosphonic acids, complexes and derivatives thereof, for use as contrast agents |
US6214345B1 (en) | 1993-05-14 | 2001-04-10 | Bristol-Myers Squibb Co. | Lysosomal enzyme-cleavable antitumor drug conjugates |
EP0714409A1 (en) | 1993-06-16 | 1996-06-05 | Celltech Therapeutics Limited | Antibodies |
US5773223A (en) | 1993-09-02 | 1998-06-30 | Chiron Corporation | Endothelin B1, (ETB1) receptor polypeptide and its encoding nucleic acid methods, and uses thereof |
US5767237A (en) | 1993-10-01 | 1998-06-16 | Teikoku Hormone Mfg. Co., Ltd. | Peptide derivatives |
US5773001A (en) | 1994-06-03 | 1998-06-30 | American Cyanamid Company | Conjugates of methyltrithio antitumor agents and intermediates for their synthesis |
US5750370A (en) | 1995-06-06 | 1998-05-12 | Human Genome Sciences, Inc. | Nucleic acid encoding human endothlein-bombesin receptor and method of producing the receptor |
US5663149A (en) | 1994-12-13 | 1997-09-02 | Arizona Board Of Regents Acting On Behalf Of Arizona State University | Human cancer inhibitory pentapeptide heterocyclic and halophenyl amides |
US5731168A (en) | 1995-03-01 | 1998-03-24 | Genentech, Inc. | Method for making heteromultimeric polypeptides |
JPH08336393A (ja) | 1995-04-13 | 1996-12-24 | Mitsubishi Chem Corp | 光学活性なγ−置換−β−ヒドロキシ酪酸エステルの製造法 |
US5712374A (en) | 1995-06-07 | 1998-01-27 | American Cyanamid Company | Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates |
US5714586A (en) | 1995-06-07 | 1998-02-03 | American Cyanamid Company | Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates |
US5707829A (en) | 1995-08-11 | 1998-01-13 | Genetics Institute, Inc. | DNA sequences and secreted proteins encoded thereby |
US6267958B1 (en) | 1995-07-27 | 2001-07-31 | Genentech, Inc. | Protein formulation |
US20020193567A1 (en) | 1995-08-11 | 2002-12-19 | Genetics Institute, Inc. | Secreted proteins and polynucleotides encoding them |
WO1997011177A1 (en) | 1995-09-18 | 1997-03-27 | Intracel Corporation | Neutralizing monoclonal antibodies to respiratory syncytial virus |
US5834456A (en) | 1996-02-23 | 1998-11-10 | The Dow Chemical Company | Polyazamacrocyclofluoromonoalkylphosphonic acids, and their complexes, for use as contrast agents |
JP3646191B2 (ja) | 1996-03-19 | 2005-05-11 | 大塚製薬株式会社 | ヒト遺伝子 |
SK157498A3 (en) | 1996-05-17 | 1999-10-08 | Schering Corp | Isolated and recombinant nucleic acid, bas-1 protein or peptide thereof, and agent, antibody, expression vector, host cell and method of their use |
US5945511A (en) | 1997-02-20 | 1999-08-31 | Zymogenetics, Inc. | Class II cytokine receptor |
US7033827B2 (en) | 1997-02-25 | 2006-04-25 | Corixa Corporation | Prostate-specific polynucleotide compositions |
US20030185830A1 (en) | 1997-02-25 | 2003-10-02 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of prostate cancer |
US6261791B1 (en) | 1997-03-10 | 2001-07-17 | The Regents Of The University Of California | Method for diagnosing cancer using specific PSCA antibodies |
US6541212B2 (en) | 1997-03-10 | 2003-04-01 | The Regents Of The University Of California | Methods for detecting prostate stem cell antigen protein |
NZ337413A (en) | 1997-03-10 | 2003-02-28 | Univ California | Antibodies that bind to Prostate Stem Cell Antigen (PSCA) to treat prostate cancer. |
US5994071A (en) | 1997-04-04 | 1999-11-30 | Albany Medical College | Assessment of prostate cancer |
US6555339B1 (en) | 1997-04-14 | 2003-04-29 | Arena Pharmaceuticals, Inc. | Non-endogenous, constitutively activated human protein-coupled receptors |
US6319688B1 (en) | 1997-04-28 | 2001-11-20 | Smithkline Beecham Corporation | Polynucleotide encoding human sodium dependent phosphate transporter (IPT-1) |
JP4213224B2 (ja) | 1997-05-02 | 2009-01-21 | ジェネンテック,インコーポレーテッド | ヘテロマルチマー及び共通成分を有する多重特異性抗体の製造方法 |
WO1998051824A1 (en) | 1997-05-15 | 1998-11-19 | Abbott Laboratories | Reagents and methods useful for detecting disease of the urinary tract |
WO1998051805A1 (en) | 1997-05-15 | 1998-11-19 | Abbott Laboratories | Reagents and methods useful for detecting diseases of the prostate |
US6171586B1 (en) | 1997-06-13 | 2001-01-09 | Genentech, Inc. | Antibody formulation |
US6753165B1 (en) | 1999-01-14 | 2004-06-22 | Bolder Biotechnology, Inc. | Methods for making proteins containing free cysteine residues |
US6248564B1 (en) | 1997-08-29 | 2001-06-19 | Harvard University | Mutant MHC class I molecules |
US6602677B1 (en) | 1997-09-19 | 2003-08-05 | Promega Corporation | Thermostable luciferases and methods of production |
US20030060612A1 (en) | 1997-10-28 | 2003-03-27 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
US20020034749A1 (en) | 1997-11-18 | 2002-03-21 | Billing-Medel Patricia A. | Reagents and methods useful for detecting diseases of the breast |
US6110695A (en) | 1997-12-02 | 2000-08-29 | The Regents Of The University Of California | Modulating the interaction of the chemokine, B Lymphocyte Hemoattractant, and its Receptor, BLR1 |
US7005504B2 (en) | 1998-01-22 | 2006-02-28 | Genentech, Inc. | Antibody fragment-peg conjugates |
WO1999046284A2 (en) | 1998-03-13 | 1999-09-16 | The Burnham Institute | Molecules that home to various selected organs or tissues |
US6528624B1 (en) | 1998-04-02 | 2003-03-04 | Genentech, Inc. | Polypeptide variants |
IL138608A0 (en) | 1998-04-02 | 2001-10-31 | Genentech Inc | Antibody variants and fragments thereof |
US6194551B1 (en) | 1998-04-02 | 2001-02-27 | Genentech, Inc. | Polypeptide variants |
JP2002520000A (ja) | 1998-05-13 | 2002-07-09 | エピミューン, インコーポレイテッド | 免疫応答を刺激するための発現ベクターおよびそのベクターの使用方法 |
US20030064397A1 (en) | 1998-05-22 | 2003-04-03 | Incyte Genomics, Inc. | Transmembrane protein differentially expressed in prostate and lung tumors |
US20020187472A1 (en) | 2001-03-09 | 2002-12-12 | Preeti Lal | Steap-related protein |
AU757510C (en) | 1998-08-27 | 2003-09-11 | Medimmune Limited | Pyrrolobenzodiazepines |
WO2000012130A1 (en) | 1998-08-27 | 2000-03-09 | Smithkline Beecham Corporation | Rp105 agonists and antagonists |
GB9818731D0 (en) | 1998-08-27 | 1998-10-21 | Univ Portsmouth | Compounds |
JP4689781B2 (ja) | 1998-09-03 | 2011-05-25 | 独立行政法人科学技術振興機構 | アミノ酸輸送蛋白及びその遺伝子 |
WO2000020579A1 (en) | 1998-10-02 | 2000-04-13 | Mcmaster University | Spliced form of erbb-2/neu oncogene |
WO2001057188A2 (en) | 2000-02-03 | 2001-08-09 | Hyseq, Inc. | Novel nucleic acids and polypeptides |
US20020119158A1 (en) | 1998-12-17 | 2002-08-29 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US6858710B2 (en) | 1998-12-17 | 2005-02-22 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US20030091580A1 (en) | 2001-06-18 | 2003-05-15 | Mitcham Jennifer L. | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US6468546B1 (en) | 1998-12-17 | 2002-10-22 | Corixa Corporation | Compositions and methods for therapy and diagnosis of ovarian cancer |
US6962980B2 (en) | 1999-09-24 | 2005-11-08 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
JP2002536966A (ja) | 1998-12-30 | 2002-11-05 | ベス・イスラエル・ディーコニス・メディカル・センター・インコーポレーテッド | カルシウムチャネルファミリーの特徴付け |
WO2000042072A2 (en) | 1999-01-15 | 2000-07-20 | Genentech, Inc. | Polypeptide variants with altered effector function |
US6737056B1 (en) | 1999-01-15 | 2004-05-18 | Genentech, Inc. | Polypeptide variants with altered effector function |
ES2348708T3 (es) | 1999-01-29 | 2010-12-13 | Corixa Corporation | Proteinas de fusion de her-2/neu. |
GB9905124D0 (en) | 1999-03-05 | 1999-04-28 | Smithkline Beecham Biolog | Novel compounds |
US7465785B2 (en) | 1999-03-08 | 2008-12-16 | Genentech, Inc. | Polypeptide encoded by a nucleic acid over-expressed in melanoma |
AU3395900A (en) | 1999-03-12 | 2000-10-04 | Human Genome Sciences, Inc. | Human lung cancer associated gene sequences and polypeptides |
US7304126B2 (en) | 1999-05-11 | 2007-12-04 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
WO2000075655A1 (fr) | 1999-06-03 | 2000-12-14 | Takeda Chemical Industries, Ltd. | Procede de criblage avec cd100 |
CN100340575C (zh) | 1999-06-25 | 2007-10-03 | 杰南技术公司 | 人源化抗ErbB2抗体及其在制备药物中的应用 |
SI2803367T1 (en) | 1999-06-25 | 2018-04-30 | Immunogen, Inc. | Treatment methods with maytansinoid conjugated antibody anti-ERBB |
US20030119113A1 (en) | 1999-07-20 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US7297770B2 (en) | 1999-08-10 | 2007-11-20 | Genentech, Inc. | PRO6496 polypeptides |
US7294696B2 (en) | 1999-08-17 | 2007-11-13 | Genentech Inc. | PRO7168 polypeptides |
EP1208202A2 (en) | 1999-09-01 | 2002-05-29 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US20030129192A1 (en) | 1999-09-10 | 2003-07-10 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US20030232056A1 (en) | 1999-09-10 | 2003-12-18 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
US20030206918A1 (en) | 1999-09-10 | 2003-11-06 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of ovarian cancer |
CA2385528C (en) | 1999-10-01 | 2013-12-10 | Immunogen, Inc. | Compositions and methods for treating cancer using immunoconjugates and chemotherapeutic agents |
US6750054B2 (en) | 2000-05-18 | 2004-06-15 | Lexicon Genetics Incorporated | Human semaphorin homologs and polynucleotides encoding the same |
JP4028237B2 (ja) | 1999-10-29 | 2007-12-26 | ジェネンテック・インコーポレーテッド | 抗前立腺幹細胞抗原(psca)抗体組成物及び使用方法 |
ES2581239T3 (es) | 1999-11-29 | 2016-09-02 | The Trustees Of Columbia University In The City Of New York | Aislamiento de cinco genes novedosos que codifican nuevos melanomas de tipo receptor de Fc implicados en la patogénesis del linfoma/melanoma |
EP1248800A2 (en) | 1999-11-30 | 2002-10-16 | Corixa Corporation | Compositions and methods for therapy and diagnosis of breast cancer |
EP1239866A4 (en) | 1999-12-10 | 2005-02-09 | Epimmune Inc | INDUCTION OF HER2 / NEU CELLULAR IMMUNE RESPONSES USING PEPTIDE AND NUCLEIC ACID-CONTAINING COMPOSITIONS |
JP4741139B2 (ja) | 1999-12-23 | 2011-08-03 | ザイモジェネティクス, インコーポレイテッド | 可溶性インターロイキン−20レセプター |
NZ502058A (en) | 1999-12-23 | 2003-11-28 | Ovita Ltd | Isolated mutated nucleic acid molecule for regulation of ovulation rate |
ES2387394T3 (es) | 1999-12-23 | 2012-09-21 | Zymogenetics, Inc. | Procedimiento de tratamiento de la inflamación |
US6610286B2 (en) | 1999-12-23 | 2003-08-26 | Zymogenetics, Inc. | Method for treating inflammation using soluble receptors to interleukin-20 |
US20040001827A1 (en) | 2002-06-28 | 2004-01-01 | Dennis Mark S. | Serum albumin binding peptides for tumor targeting |
WO2001045746A2 (en) | 1999-12-24 | 2001-06-28 | Genentech, Inc. | Methods and compositions for prolonging elimination half-times of bioactive compounds |
DK1242438T3 (da) | 1999-12-29 | 2007-02-12 | Immunogen Inc | Cytotoksiske midler omfattende modificerede doxorubiciner og daunorubiciner og deres terapeutiske anvendelse |
US7297333B2 (en) | 2000-01-20 | 2007-11-20 | Genentech, Inc. | Anti-PRO10268 antibodies |
US20030224379A1 (en) | 2000-01-21 | 2003-12-04 | Tang Y. Tom | Novel nucleic acids and polypeptides |
WO2001053463A2 (en) | 2000-01-21 | 2001-07-26 | Corixa Corporation | COMPOUNDS AND METHODS FOR PREVENTION AND TREATMENT OF HER-2/neu ASSOCIATED MALIGNANCIES |
US20030186372A1 (en) | 2000-02-11 | 2003-10-02 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US20030219806A1 (en) | 2000-02-22 | 2003-11-27 | Millennium Pharmaceuticals, Inc. | Novel 18607, 15603, 69318, 12303, 48000, 52920, 5433, 38554, 57301, 58324, 55063, 52991, 59914, 59921 and 33751 molecules and uses therefor |
WO2001062794A2 (en) | 2000-02-22 | 2001-08-30 | Millennium Pharmaceuticals, Inc. | 18607, a human calcium channel |
US20040002068A1 (en) | 2000-03-01 | 2004-01-01 | Corixa Corporation | Compositions and methods for the detection, diagnosis and therapy of hematological malignancies |
US20040005561A1 (en) | 2000-03-01 | 2004-01-08 | Corixa Corporation | Compositions and methods for the detection, diagnosis and therapy of hematological malignancies |
CA2402293A1 (en) | 2000-03-07 | 2001-09-13 | Hyseq, Inc. | Novel nucleic acids and polypeptides |
US7097840B2 (en) | 2000-03-16 | 2006-08-29 | Genentech, Inc. | Methods of treatment using anti-ErbB antibody-maytansinoid conjugates |
AU4941101A (en) | 2000-03-24 | 2001-10-08 | Fahri Saatcioglu | Novel prostate-specific or testis-specific nucleic acid molecules, polypeptides,and diagnostic and therapeutic methods |
WO2001072830A2 (de) | 2000-03-31 | 2001-10-04 | Ipf Pharmaceuticals Gmbh | Diagnostik- und arzneimittel zur untersuchung des zelloberflächenproteoms von tumor- und entzündungszellen sowie zur behandlung von tumorerkrankungen und entzündlichen erkrankungen vorzugsweise mit hilfe einer spezifischen chemokinrezeptor-analyse und der chemokinrezeptor-ligand-interaktion |
WO2001075177A2 (en) | 2000-04-03 | 2001-10-11 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Tumor markers in ovarian cancer |
AU2001249885A1 (en) | 2000-04-07 | 2001-10-23 | Arena Pharmaceuticals, Inc. | Non-endogenous, constitutively activated known g protein-coupled receptors |
LT2857516T (lt) | 2000-04-11 | 2017-09-11 | Genentech, Inc. | Multivalentiniai antikūnai ir jų panaudojimas |
AU2001274888A1 (en) | 2000-05-19 | 2001-12-03 | Human Genome Sciences, Inc. | Nucleic acids, proteins, and antibodies |
US20020051990A1 (en) | 2000-06-09 | 2002-05-02 | Eric Ople | Novel gene targets and ligands that bind thereto for treatment and diagnosis of ovarian carcinomas |
AU2001268471A1 (en) | 2000-06-16 | 2002-01-02 | Incyte Genomics, Inc. | G-protein coupled receptors |
EP1294885A2 (en) | 2000-06-30 | 2003-03-26 | Amgen, Inc. | B7-like molecules and uses thereof |
CA2406649A1 (en) | 2000-06-30 | 2002-01-10 | Human Genome Sciences, Inc. | B7-like polynucleotides, polypeptides, and antibodies |
AU2001273151A1 (en) | 2000-06-30 | 2002-01-14 | Incyte Genomics, Inc. | Human extracellular matrix and cell adhesion polypeptides |
WO2002006339A2 (en) | 2000-07-03 | 2002-01-24 | Curagen Corporation | Proteins and nucleic acids encoding same |
US20040044179A1 (en) | 2000-07-25 | 2004-03-04 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
WO2002010187A1 (en) | 2000-07-27 | 2002-02-07 | Mayo Foundation For Medical Education And Research | B7-h3 and b7-h4, novel immunoregulatory molecules |
EP1366158B1 (en) | 2000-07-28 | 2008-05-21 | Ulrich Wissenbach | Trp8 markers for cancer |
US7229623B1 (en) | 2000-08-03 | 2007-06-12 | Corixa Corporation | Her-2/neu fusion proteins |
WO2002013847A2 (en) | 2000-08-14 | 2002-02-21 | Corixa Corporation | Methods for diagnosis and therapy of hematological and virus-associated malignancies |
HUP0600780A2 (en) | 2000-08-14 | 2007-01-29 | Corixa Corp | Compositions and methods for the therapy and diagnosis of her-2/neu-associated malignancies |
GB0020953D0 (en) | 2000-08-24 | 2000-10-11 | Smithkline Beecham Biolog | Vaccine |
KR20030029847A (ko) | 2000-08-24 | 2003-04-16 | 제넨테크, 인크. | 종양의 진단 및 치료를 위한 조성물 및 방법 |
CA2421949A1 (en) | 2000-09-11 | 2002-03-21 | Hyseq, Inc. | Novel nucleic acids and polypeptides |
AR030612A1 (es) | 2000-09-12 | 2003-08-27 | Smithkline Beecham Corp | Procedimiento e intermedios |
US20030119121A1 (en) | 2000-09-15 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
EP1351703B1 (en) | 2000-09-15 | 2006-07-26 | ZymoGenetics, Inc. | Use of a polypeptide comprising the extracellular domains of il-20ra and il-20rb for the treatment of inflammation |
US6613567B1 (en) | 2000-09-15 | 2003-09-02 | Isis Pharmaceuticals, Inc. | Antisense inhibition of Her-2 expression |
UA83458C2 (uk) | 2000-09-18 | 2008-07-25 | Байоджен Айдек Ма Інк. | Виділений поліпептид baff-r (рецептор фактора активації в-клітин сімейства tnf) |
NZ525380A (en) | 2000-09-18 | 2008-06-30 | Biogen Idec Inc | Non-fucosylated forms of Cripto and their use as tumor blocking agents |
CA2425569A1 (en) | 2000-10-13 | 2002-04-18 | Eos Biotechnology, Inc. | Methods of diagnosis of prostate cancer, compositions and methods of screening for modulators of prostate cancer |
DK1407017T3 (en) | 2000-11-07 | 2009-09-21 | Zymogenetics Inc | Human receptor for tumor nekrose faktor |
US20020150573A1 (en) | 2000-11-10 | 2002-10-17 | The Rockefeller University | Anti-Igalpha-Igbeta antibody for lymphoma therapy |
WO2002061087A2 (en) | 2000-12-19 | 2002-08-08 | Lifespan Biosciences, Inc. | Antigenic peptides, such as for g protein-coupled receptors (gpcrs), antibodies thereto, and systems for identifying such antigenic peptides |
US20020159986A1 (en) | 2001-01-12 | 2002-10-31 | John Langenfeld | Bone morphogenetic protein-2 in the treatment and diagnosis of cancer |
US20030119133A1 (en) | 2001-01-16 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US20030119119A1 (en) | 2001-01-16 | 2003-06-26 | Genentech, Inc. | Secreted and transmembrane polypeptides and nucleic acids encoding the same |
US7754208B2 (en) | 2001-01-17 | 2010-07-13 | Trubion Pharmaceuticals, Inc. | Binding domain-immunoglobulin fusion proteins |
EP1425302A2 (en) | 2001-01-24 | 2004-06-09 | Protein Design Labs | Methods of diagnosis of breast cancer, compositions and methods of screening for modulators of breast cancer |
AU2002251841A1 (en) | 2001-01-30 | 2002-08-12 | Corixa Corporation | Compositions and methods for the therapy and diagnosis of pancreatic cancer |
WO2002064780A1 (en) | 2001-02-12 | 2002-08-22 | Bionomics Limited | Dna sequences for human tumour suppressor genes |
AU2002258518A1 (en) | 2001-03-14 | 2002-09-24 | Millennium Pharmaceuticals, Inc. | Nucleic acid molecules and proteins for the identification, assessment, prevention, and therapy of ovarian cancer |
US20040236091A1 (en) | 2001-03-28 | 2004-11-25 | Chicz Roman M. | Translational profiling |
WO2003008537A2 (en) | 2001-04-06 | 2003-01-30 | Mannkind Corporation | Epitope sequences |
US6820011B2 (en) | 2001-04-11 | 2004-11-16 | The Regents Of The University Of Colorado | Three-dimensional structure of complement receptor type 2 and uses thereof |
CA2443617C (en) | 2001-04-17 | 2013-12-10 | The Board Of Trustees Of The University Of Arkansas | Repeat sequences of the ca125 gene and their use for diagnostic and therapeutic interventions |
AU2002309583A1 (en) | 2001-04-18 | 2002-11-05 | Protein Desing Labs, Inc. | Methods of diagnosis of lung cancer, compositions and methods of screening for modulators of lung cancer |
WO2003083041A2 (en) | 2002-03-22 | 2003-10-09 | Biogen, Inc. | Cripto-specific antibodies |
SK14432003A3 (sk) | 2001-04-26 | 2004-07-07 | Biogen, Inc. | Protilátka špecifická pre Cripto, kompozícia obsahujúca takúto protilátku a jej použitie |
US6884869B2 (en) | 2001-04-30 | 2005-04-26 | Seattle Genetics, Inc. | Pentapeptide compounds and uses related thereto |
JP2005504513A (ja) | 2001-05-09 | 2005-02-17 | コリクサ コーポレイション | 前立腺癌の治療及び診断のための組成物及び方法 |
AU2002344326A1 (en) | 2001-05-11 | 2002-11-25 | Sloan-Kettering Institute For Cancer Research | Nucleic acid sequence encoding ovarian antigen, ca125, and uses thereof |
ES2334772T7 (es) | 2001-05-24 | 2012-11-19 | Zymogenetics, Inc. | Proteinas hibridas taci-inmunoglobulina. |
US6441163B1 (en) | 2001-05-31 | 2002-08-27 | Immunogen, Inc. | Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents |
US7157558B2 (en) | 2001-06-01 | 2007-01-02 | Genentech, Inc. | Polypeptide encoded by a polynucleotide overexpresses in tumors |
AU2002314901A1 (en) | 2001-06-04 | 2002-12-16 | Eos Biotechnology, Inc. | Methods of diagnosis and treatment of androgen-dependent prostate cancer, prostate cancer undergoing androgen-withdrawal, and androgen-independent prostate cancer |
JP2005518185A (ja) | 2001-06-04 | 2005-06-23 | キュラジェン コーポレイション | 新規タンパク質およびそれをコード化する核酸 |
WO2002099140A1 (en) | 2001-06-05 | 2002-12-12 | Exelixis, Inc. | GLRAs AS MODIFIERS OF THE p53 PATHWAY AND METHODS OF USE |
JP2005505257A (ja) | 2001-06-05 | 2005-02-24 | エクセリクシス・インコーポレイテッド | p53経路のモディファイヤーとしてのIGsおよび使用方法 |
US7235358B2 (en) | 2001-06-08 | 2007-06-26 | Expression Diagnostics, Inc. | Methods and compositions for diagnosing and monitoring transplant rejection |
US7125663B2 (en) | 2001-06-13 | 2006-10-24 | Millenium Pharmaceuticals, Inc. | Genes, compositions, kits and methods for identification, assessment, prevention, and therapy of cervical cancer |
MXPA03011979A (es) | 2001-06-18 | 2005-04-08 | Eos Biotechnology Inc | Metodos de diagnostico de cancer de ovario composiciones y metodos para rastrear moduladores de cancer de ovario. |
US7189507B2 (en) | 2001-06-18 | 2007-03-13 | Pdl Biopharma, Inc. | Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer |
AU2002322280A1 (en) | 2001-06-21 | 2003-01-21 | Millennium Pharmaceuticals, Inc. | Compositions, kits, and methods for identification, assessment, prevention, and therapy of breast cancer |
WO2003002717A2 (en) | 2001-06-28 | 2003-01-09 | Schering Corporation | Biological activity of ak155 |
WO2003004529A2 (en) | 2001-07-02 | 2003-01-16 | Licentia Ltd. | Ephrin-tie receptor materials and methods |
US20040076955A1 (en) | 2001-07-03 | 2004-04-22 | Eos Biotechnology, Inc. | Methods of diagnosis of bladder cancer, compositions and methods of screening for modulators of bladder cancer |
WO2003003984A2 (en) | 2001-07-05 | 2003-01-16 | Curagen Corporation | Novel proteins and nucleic acids encoding same |
US7446185B2 (en) | 2001-07-18 | 2008-11-04 | The Regents Of The University Of California | Her2/neu target antigen and use of same to stimulate an immune response |
US20030108963A1 (en) | 2001-07-25 | 2003-06-12 | Millennium Pharmaceuticals, Inc. | Novel genes, compositions, kit, and methods for identification, assessment, prevention and therapy of prostate cancer |
CN1636067A (zh) | 2001-08-03 | 2005-07-06 | 杰南技术公司 | TACls和BR3多肽及其用途 |
CA2457819A1 (en) | 2001-08-14 | 2003-02-27 | The General Hospital Corporation | Nucleic acid and amino acid sequences involved in pain |
US20030092013A1 (en) | 2001-08-16 | 2003-05-15 | Vitivity, Inc. | Diagnosis and treatment of vascular disease |
AU2002313559A1 (en) | 2001-08-23 | 2003-03-10 | Oxford Biomedica (Uk) Limited | Genes |
WO2003029262A2 (en) | 2001-08-29 | 2003-04-10 | Vanderbilt University | The human mob-5 (il-24) receptors and uses thereof |
US20040235068A1 (en) | 2001-09-05 | 2004-11-25 | Levinson Arthur D. | Methods for the identification of polypeptide antigens associated with disorders involving aberrant cell proliferation and compositions useful for the treatment of such disorders |
US20030124579A1 (en) | 2001-09-05 | 2003-07-03 | Eos Biotechnology, Inc. | Methods of diagnosis of ovarian cancer, compositions and methods of screening for modulators of ovarian cancer |
AU2002336446B2 (en) | 2001-09-06 | 2008-03-06 | Agensys, Inc. | Nucleic acid and corresponding protein entitled STEAP-1 useful in treatment and detection of cancer |
WO2003025138A2 (en) | 2001-09-17 | 2003-03-27 | Protein Design Labs, Inc. | Methods of diagnosis of cancer compositions and methods of screening for modulators of cancer |
WO2003025228A1 (en) | 2001-09-18 | 2003-03-27 | Proteologics, Inc. | Methods and compositions for treating hcap associated diseases |
ES2390531T3 (es) | 2001-09-18 | 2012-11-13 | Genentech, Inc. | Composiciones y procedimientos para el diagnósitco y tratamiento de tumor |
CA2460621A1 (en) | 2001-09-19 | 2003-03-27 | Nuvelo, Inc. | Novel nucleic acids and polypeptides |
US7091186B2 (en) | 2001-09-24 | 2006-08-15 | Seattle Genetics, Inc. | p-Amidobenzylethers in drug delivery agents |
WO2003026577A2 (en) | 2001-09-24 | 2003-04-03 | Seattle Genetics, Inc. | P-amidobenzylethers in drug delivery agents |
WO2003026493A2 (en) | 2001-09-28 | 2003-04-03 | Bing Yang | Diagnosis and treatment of diseases caused by mutations in cd72 |
WO2003029277A2 (en) | 2001-10-03 | 2003-04-10 | Rigel Pharmaceuticals, Inc. | Modulators of lymphocyte activation and migration |
US20040249144A1 (en) | 2001-10-03 | 2004-12-09 | Zairen Sun | Regulated breast cancer genes |
AU2002351505B2 (en) | 2001-10-19 | 2008-04-03 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of inflammatory bowel disorders |
US20050123925A1 (en) | 2002-11-15 | 2005-06-09 | Genentech, Inc. | Compositions and methods for the diagnosis and treatment of tumor |
WO2003035846A2 (en) | 2001-10-24 | 2003-05-01 | National Jewish Medical And Research Center | Structure of tall-1 and its cognate receptor |
MXPA04003697A (es) | 2001-10-31 | 2005-04-08 | Alcon Inc | Proteinas morfogenicas de hueso (bmp), receptores de bmp y proteinas de enlace de bmp y su uso en el diagnostico y tratamiento de glaucoma. |
US20030232350A1 (en) | 2001-11-13 | 2003-12-18 | Eos Biotechnology, Inc. | Methods of diagnosis of cancer, compositions and methods of screening for modulators of cancer |
WO2003042661A2 (en) | 2001-11-13 | 2003-05-22 | Protein Design Labs, Inc. | Methods of diagnosis of cancer, compositions and methods of screening for modulators of cancer |
WO2003043583A2 (en) | 2001-11-20 | 2003-05-30 | Seattle Genetics, Inc. | Treatment of immunological disorders using anti-cd30 antibodies |
AU2002339691A1 (en) | 2001-11-29 | 2003-06-10 | Genset | Agonists and antagonists of prolixin for the treatment of metabolic disorders |
AU2002349784A1 (en) | 2001-12-03 | 2003-06-17 | Asahi Kasei Pharma Corporation | Nf-kappab activating genes |
EP1504099A4 (en) | 2001-12-10 | 2006-05-10 | Nuvelo Inc | NEW NUCLEIC ACIDS AND POLYPEPTIDES |
WO2003049704A2 (en) | 2001-12-11 | 2003-06-19 | University Of Massachusetts | Antibodies to treat cancer |
AU2002359851A1 (en) | 2001-12-21 | 2003-07-30 | Idexx Laboratories, Inc. | Canine immunoglobulin variable domains, caninized antibodies, and methods for making and using them |
US6716821B2 (en) | 2001-12-21 | 2004-04-06 | Immunogen Inc. | Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same |
US20030134790A1 (en) | 2002-01-11 | 2003-07-17 | University Of Medicine And Dentistry Of New Jersey | Bone Morphogenetic Protein-2 And Bone Morphogenetic Protein-4 In The Treatment And Diagnosis Of Cancer |
US7452675B2 (en) | 2002-01-25 | 2008-11-18 | The Queen's Medical Center | Methods of screening for TRPM4b modulators |
WO2003072736A2 (en) | 2002-02-21 | 2003-09-04 | Duke University | Reagents and treatment methods for autoimmune diseases |
EP1575480A4 (en) | 2002-02-22 | 2008-08-06 | Genentech Inc | COMPOSITIONS AND METHODS FOR TREATING DISEASES RELATED TO THE IMMUNE SYSTEM |
AU2003216482A1 (en) | 2002-03-01 | 2003-09-16 | Exelixis, Inc. | MSRAs AS MODIFIERS OF THE p53 PATHWAY AND METHODS OF USE |
US20050220798A1 (en) | 2002-06-04 | 2005-10-06 | Reinhard Ebner | Cancer-linked gene as target for chemotherapy |
EP2258712A3 (en) | 2002-03-15 | 2011-05-04 | Multicell Immunotherapeutics, Inc. | Compositions and Methods to Initiate or Enhance Antibody and Major-histocompatibility Class I or Class II-restricted T Cell Responses by Using Immunomodulatory, Non-coding RNA Motifs |
WO2004000997A2 (en) | 2002-03-19 | 2003-12-31 | Curagen Corporation | Therapeutic polypeptides, nucleic acids encoding same, and methods of use |
WO2003081210A2 (en) | 2002-03-21 | 2003-10-02 | Sunesis Pharmaceuticals, Inc. | Identification of kinase inhibitors |
US7193069B2 (en) | 2002-03-22 | 2007-03-20 | Research Association For Biotechnology | Full-length cDNA |
CA2480404A1 (en) | 2002-03-25 | 2003-10-30 | Uab Research Foundation | Fc receptor homolog, reagents, and uses thereof |
AU2003222103A1 (en) | 2002-03-28 | 2003-10-13 | Idec Pharmaceuticals Corporation | Novel gene targets and ligands that bind thereto for treatment and diagnosis of colon carcinomas |
US20030194704A1 (en) | 2002-04-03 | 2003-10-16 | Penn Sharron Gaynor | Human genome-derived single exon nucleic acid probes useful for gene expression analysis two |
AU2003223469A1 (en) | 2002-04-05 | 2003-10-27 | Agensys, Inc. | Nucleic acid and corresponding protein entitled 98p4b6 useful in treatment and detection of cancer |
AU2003223520A1 (en) | 2002-04-12 | 2003-10-27 | Mitokor | Targets for therapeutic intervention identified in the mitochondrial proteome |
NZ535925A (en) | 2002-04-16 | 2008-06-30 | Genentech Inc | An isolated antibody that binds to a particular polypeptide |
AU2003239158A1 (en) | 2002-04-17 | 2003-11-03 | Baylor College Of Medicine | Aib1 as a prognostic marker and predictor of resistance to encocrine therapy |
WO2003093444A2 (en) | 2002-05-03 | 2003-11-13 | Incyte Corporation | Transporters and ion channels |
EP1572925A4 (en) | 2002-05-15 | 2007-08-15 | Avalon Pharmaceuticals | CANCER-RELATED GENE AS A TARGET FOR CHEMOTHERAPY |
US20030224454A1 (en) | 2002-05-30 | 2003-12-04 | Ryseck Rolf Peter | Human solute carrier family 7, member 11 (hSLC7A11) |
WO2003101283A2 (en) | 2002-06-04 | 2003-12-11 | Incyte Corporation | Diagnostics markers for lung cancer |
WO2003104270A2 (en) | 2002-06-06 | 2003-12-18 | Ingenium Pharmaceuticals Ag | Dudulin 2 genes, expression products, non-human animal model: uses in human hematological disease |
DK1513934T3 (da) | 2002-06-06 | 2011-05-02 | Oncotherapy Science Inc | Gener og polypeptider relateret til humane coloncancersygdomme |
EP1576111A4 (en) | 2002-06-07 | 2006-10-18 | Avalon Pharmaceuticals | CANCER-ASSOCIATED GENE AS A TARGET FOR CHEMOTHERAPY |
WO2003105758A2 (en) | 2002-06-12 | 2003-12-24 | Avalon Pharmaceuticals, Inc. | Cancer-linked gene as target for chemotherapy |
US20040249130A1 (en) | 2002-06-18 | 2004-12-09 | Martin Stanton | Aptamer-toxin molecules and methods for using same |
WO2003106659A2 (en) | 2002-06-18 | 2003-12-24 | Archemix Corp. | Aptamer-toxin molecules and methods for using same |
MXPA04012725A (es) | 2002-06-20 | 2005-09-30 | Snaptrack Inc | Reduccion de interferencia cruzada en un receptor de gps y sistema de comunicacion combinado. |
AU2003245615A1 (en) | 2002-06-20 | 2004-01-06 | The Regents Of The University Of California | Compositions and methods for modulating lymphocyte activity |
JP2005530856A (ja) | 2002-06-21 | 2005-10-13 | ジョンズ ホプキンス ユニバーシティー スクール オブ メディシン | 膜関連腫瘍内皮マーカー |
US7776814B2 (en) | 2002-07-09 | 2010-08-17 | R&D-Biopharmaceuticals Gmbh | Tubulysin conjugates |
WO2004009622A2 (en) | 2002-07-19 | 2004-01-29 | Cellzome Ag | Protein complexes of cellular networks underlying the development of cancer and other diseases |
CN1692127A (zh) | 2002-07-25 | 2005-11-02 | 健泰科生物技术公司 | Taci抗体及其用途 |
AU2003294210A1 (en) | 2002-07-31 | 2004-05-04 | Seattle Genetics, Inc | Anti-cd20 antibody-drug conjugates for the treatment of cancer and immune disorders |
ES2544527T3 (es) | 2002-07-31 | 2015-09-01 | Seattle Genetics, Inc. | Conjugados de fármacos y su uso para tratar el cáncer, una enfermedad autoinmune o una enfermedad infecciosa |
JP2004121218A (ja) | 2002-08-06 | 2004-04-22 | Jenokkusu Soyaku Kenkyusho:Kk | 気管支喘息または慢性閉塞性肺疾患の検査方法 |
WO2004015426A1 (en) | 2002-08-06 | 2004-02-19 | Bayer Healthcare Ag | Diagnostics and therapeutics for diseases associated with human cxc chemokine receptor 5(cxcr5) |
US6913748B2 (en) | 2002-08-16 | 2005-07-05 | Immunogen, Inc. | Cross-linkers with high reactivity and solubility and their use in the preparation of conjugates for targeted delivery of small molecule drugs |
MXPA05001933A (es) | 2002-08-19 | 2005-04-28 | Genentech Inc | Composiciones y metodos para el diagnostico y tratamiento de tumores. |
EP1572957A4 (en) | 2002-08-27 | 2007-10-10 | Bristol Myers Squibb Pharma Co | IDENTIFICATION OF POLYNUCLEOTIDES FOR PREDICTING THE ACTIVITY OF COMPOUNDS INTERACTING WITH AND / OR MODULATING TYROSINE KINASE PROTEINS AND / OR TYROSINE KINASE PROTEIN PATHWAYS IN MAMMARY CELLS |
WO2004020595A2 (en) | 2002-08-29 | 2004-03-11 | Five Prime Therapeutics, Inc. | Novel human polypeptides encoded by polynucleotides |
AU2002951346A0 (en) | 2002-09-05 | 2002-09-26 | Garvan Institute Of Medical Research | Diagnosis of ovarian cancer |
CA2496888A1 (en) | 2002-09-06 | 2004-03-18 | Mannkind Corporation | Epitope sequences |
US20060134109A1 (en) | 2002-09-09 | 2006-06-22 | Nura Inc. | G protein coupled receptors and uses thereof |
JP2004113151A (ja) | 2002-09-27 | 2004-04-15 | Sankyo Co Ltd | 癌遺伝子及びその用途 |
AU2003278002A1 (en) | 2002-10-03 | 2004-04-23 | Mcgill Univeristy | Antibodies and cyclic peptides which bind cea (carcinoembryonic antigen) and their use as cancer therapeutics |
EP1570078A4 (en) | 2002-10-04 | 2006-09-13 | Van Andel Res Inst | MOLECULAR CLASSIFICATION OF RENAL TUMORS AND DISCOVERING NEW DIAGNOSTIC MARKERS |
US7361740B2 (en) | 2002-10-15 | 2008-04-22 | Pdl Biopharma, Inc. | Alteration of FcRn binding affinities or serum half-lives of antibodies by mutagenesis |
EP1578447A4 (en) | 2002-10-31 | 2009-06-03 | Genentech Inc | METHODS AND COMPOSITIONS THAT CAN INCREASE ANTIBODY PRODUCTION |
CA2503748A1 (en) | 2002-11-08 | 2004-05-27 | Genentech, Inc. | Compositions and methods for the treatment of natural killer cell related diseases |
WO2004044178A2 (en) | 2002-11-13 | 2004-05-27 | Genentech, Inc. | Methods and compositions for diagnosing dysplasia |
JP4915980B2 (ja) | 2002-11-15 | 2012-04-11 | エムユーエスシー ファウンデーション フォー リサーチ デベロップメント | 補体レセプター2標的化補体調節因子 |
EP1578372A4 (en) | 2002-11-15 | 2007-10-17 | Univ Arkansas | CA125 GENE AND ITS USE IN DIAGNOSTIC AND THERAPEUTIC INTERVENTIONS |
AU2003297300A1 (en) | 2002-11-20 | 2004-06-15 | Biogen Idec Inc. | Novel gene targets and ligands that bind thereto for treatment and diagnosis of carcinomas |
US7557092B2 (en) | 2002-11-21 | 2009-07-07 | University Of Utah Research Foundation | Purinergic modulation of smell |
WO2004048938A2 (en) | 2002-11-26 | 2004-06-10 | Protein Design Labs, Inc. | Methods of detecting soft tissue sarcoma, compositions and methods of screening for soft tissue sarcoma modulators |
AU2003298794A1 (en) | 2002-12-02 | 2004-06-23 | Us Gov Health & Human Serv | Recombinant immunotoxin and use in treating tumors |
WO2004053079A2 (en) | 2002-12-06 | 2004-06-24 | Diadexus, Inc. | Compositions, splice variants and methods relating to ovarian specific genes and proteins |
JP2004198419A (ja) | 2002-12-13 | 2004-07-15 | Bayer Healthcare Llc | Timp1を用いた検出方法 |
AR042485A1 (es) | 2002-12-16 | 2005-06-22 | Genentech Inc | Anticuerpo humanizado que se une al cd20 humano |
EP1581171B1 (en) | 2002-12-20 | 2012-06-27 | Abbott Biotherapeutics Corp. | Antibodies against gpr64 and uses thereof |
WO2004058309A1 (en) | 2002-12-23 | 2004-07-15 | Human Genome Sciences, Inc. | Neutrokine-alpha conjugate, neutrokine-alpha complex, and uses thereof |
EP1597558A2 (en) | 2003-01-08 | 2005-11-23 | Bristol-Myers Squibb Company | Biomarkers and methods for determining sensitivity to epidermal growth factor receptor modulators |
US20050181375A1 (en) | 2003-01-10 | 2005-08-18 | Natasha Aziz | Novel methods of diagnosis of metastatic cancer, compositions and methods of screening for modulators of metastatic cancer |
US20050227301A1 (en) | 2003-01-10 | 2005-10-13 | Polgen | Cell cycle progression proteins |
US20040171823A1 (en) | 2003-01-14 | 2004-09-02 | Nadler Steven G. | Polynucleotides and polypeptides associated with the NF-kappaB pathway |
JP2007520996A (ja) | 2003-01-15 | 2007-08-02 | ミレニアム・ファーマシューティカルズ・インコーポレイテッド | 44390、54181、211、5687、884、1405、636、4421、5410、30905、2045、16405、18560、2047、33751、52872、14063、20739、32544、43239、44373、51164、53010、16852、1587、2207、22245、2387、52908、69112、14990、18547、115、579、15985、15625、760、18603、2395、2554、8675、32720、4809、14303、16816、17827、32620、577、619、1423、2158、8263、15402、16209、16386、21165、30911、41897、1643、2543、9626、13231、32409、84260、2882、8203、32678または55053を用いて泌尿器科障害を処置するための方法および組成物 |
US7575893B2 (en) | 2003-01-23 | 2009-08-18 | Genentech, Inc. | Methods for producing humanized antibodies and improving yield of antibodies or antigen binding fragments in cell culture |
EP2196474A3 (en) | 2003-02-14 | 2010-12-15 | Sagres Discovery, Inc. | Therapeutic targets in cancer |
US20060104968A1 (en) | 2003-03-05 | 2006-05-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminogly ycanases |
US7871607B2 (en) | 2003-03-05 | 2011-01-18 | Halozyme, Inc. | Soluble glycosaminoglycanases and methods of preparing and using soluble glycosaminoglycanases |
US20030224411A1 (en) | 2003-03-13 | 2003-12-04 | Stanton Lawrence W. | Genes that are up- or down-regulated during differentiation of human embryonic stem cells |
ATE421967T1 (de) | 2003-03-31 | 2009-02-15 | Council Scient Ind Res | Nichtvernetzende pyrroloä2,1-cüä1, 4übenzodiazepine als potentielle antitumor- agentien und ihre herstellung |
US8088387B2 (en) | 2003-10-10 | 2012-01-03 | Immunogen Inc. | Method of targeting specific cell populations using cell-binding agent maytansinoid conjugates linked via a non-cleavable linker, said conjugates, and methods of making said conjugates |
GB0321295D0 (en) | 2003-09-11 | 2003-10-15 | Spirogen Ltd | Synthesis of protected pyrrolobenzodiazepines |
AU2004284075A1 (en) | 2003-10-22 | 2005-05-06 | Government Of The United States Of America, Represented By The Secretary, Department Of Health And Human Services | Pyrrolobenzodiazepine derivatives, compositions comprising the same and methods related thereto |
ZA200603619B (en) | 2003-11-06 | 2008-10-29 | Seattle Genetics Inc | Monomethylvaline compounds capable of conjugation to ligands |
JP5064037B2 (ja) | 2004-02-23 | 2012-10-31 | ジェネンテック, インコーポレイテッド | 複素環式自壊的リンカーおよび結合体 |
GB0404577D0 (en) | 2004-03-01 | 2004-04-07 | Spirogen Ltd | Pyrrolobenzodiazepines |
US7528126B2 (en) | 2004-03-09 | 2009-05-05 | Spirogen Limited | Pyrrolobenzodiazepines |
AU2005227326B2 (en) | 2004-03-24 | 2009-12-03 | Xencor, Inc. | Immunoglobulin variants outside the Fc region |
WO2005101017A1 (en) * | 2004-04-07 | 2005-10-27 | Genentech, Inc. | Mass spectrometry of antibody conjugates |
CA2561533C (en) | 2004-04-13 | 2015-06-16 | Yvo Graus | Anti-p-selectin antibodies |
KR20120064120A (ko) | 2004-06-01 | 2012-06-18 | 제넨테크, 인크. | 항체 약물 접합체 및 방법 |
TWI309240B (en) | 2004-09-17 | 2009-05-01 | Hoffmann La Roche | Anti-ox40l antibodies |
NZ580115A (en) | 2004-09-23 | 2010-10-29 | Genentech Inc | Cysteine engineered antibody light chains and conjugates |
US20100111856A1 (en) | 2004-09-23 | 2010-05-06 | Herman Gill | Zirconium-radiolabeled, cysteine engineered antibody conjugates |
AU2005289685B2 (en) | 2004-09-24 | 2009-07-16 | Amgen Inc. | Modified Fc molecules |
JO3000B1 (ar) | 2004-10-20 | 2016-09-05 | Genentech Inc | مركبات أجسام مضادة . |
JP2008521828A (ja) | 2004-11-29 | 2008-06-26 | シアトル ジェネティックス, インコーポレイテッド | 操作された抗体およびイムノコンジュゲート |
WO2008020827A2 (en) | 2005-08-01 | 2008-02-21 | Biogen Idec Ma Inc. | Altered polypeptides, immunoconjugates thereof, and methods related thereto |
US8008453B2 (en) | 2005-08-12 | 2011-08-30 | Amgen Inc. | Modified Fc molecules |
EA032466B1 (ru) | 2005-10-07 | 2019-05-31 | Экселиксис, Инк. | Способы получения ингибиторов mek |
SI1813614T1 (sl) | 2006-01-25 | 2012-01-31 | Sanofi 174 | Citotoksična sredstva, ki obsegajo nove tomajmicinske derivate |
CN101037475B (zh) | 2006-03-15 | 2012-08-15 | 上海中信国健药业股份有限公司 | 一种嵌合受体及其制备方法和用途 |
RS53168B (en) | 2006-05-30 | 2014-06-30 | Genentech Inc. | Antibodies and Immunoconjugates and Their Use |
JP2009541275A (ja) | 2006-06-22 | 2009-11-26 | ノボ・ノルデイスク・エー/エス | 二重特異性抗体の生産 |
JP5622390B2 (ja) | 2006-07-18 | 2014-11-12 | サノフイ | 癌治療用対epha2アンタゴニスト抗体 |
US10118970B2 (en) | 2006-08-30 | 2018-11-06 | Genentech, Inc. | Multispecific antibodies |
GB0619291D0 (en) | 2006-09-29 | 2006-11-08 | Ucb Sa | Altered antibodies |
EP1914242A1 (en) | 2006-10-19 | 2008-04-23 | Sanofi-Aventis | Novel anti-CD38 antibodies for the treatment of cancer |
ES2523915T5 (es) | 2006-12-01 | 2022-05-26 | Seagen Inc | Agentes de unión a la diana variantes y usos de los mismos |
BRPI0806403A2 (pt) | 2007-02-09 | 2011-09-06 | Genentech Inc | anticorpo anti-robo4, usode um anticorpo e método de obtenção de imagem |
WO2008141044A2 (en) | 2007-05-08 | 2008-11-20 | Genentech, Inc. | Cysteine engineered anti-muc16 antibodies and antibody drug conjugates |
PL2474557T3 (pl) | 2007-07-16 | 2015-02-27 | Genentech Inc | Przeciwciała anty- CD79b i immunokoniugaty i sposoby stosowania |
US9845355B2 (en) | 2007-07-16 | 2017-12-19 | Genentech, Inc. | Humanized anti-CD79b antibodies and immunoconjugates and methods of use |
ES2435779T3 (es) | 2007-07-19 | 2013-12-23 | Sanofi | Agentes citotóxicos que comprenden nuevos derivados de tomaimicina y su uso terapéutico |
WO2009052249A1 (en) | 2007-10-19 | 2009-04-23 | Genentech, Inc. | Cysteine engineered anti-tenb2 antibodies and antibody drug conjugates |
ES2774337T3 (es) | 2008-01-07 | 2020-07-20 | Amgen Inc | Método para fabricación de moléculas heterodímeras Fc de anticuerpos utilizando efectos de conducción electrostática |
BRPI0907046A2 (pt) | 2008-01-18 | 2015-07-28 | Medimmune Llc | Anticorpo de cisteína engenheirada, ácido nucleico isolado, vetor, célula hospedeira, conjugado de anticorpo, composição farmacêutica, métodos de detecção de câncer, doenças ou distúrbios autoimunes, inflamatórios ou infecciosos em um indivíduo e de inibição de proliferação de uma célula alvo |
US8742076B2 (en) | 2008-02-01 | 2014-06-03 | Genentech, Inc. | Nemorubicin metabolite and analog reagents, antibody-drug conjugates and methods |
PE20110571A1 (es) | 2008-07-15 | 2011-08-29 | Genentech Inc | Conjugados derivados de antraciclina, como compuestos antitumorales |
LT2700651T (lt) | 2008-07-18 | 2019-06-25 | Bristol-Myers Squibb Company | Vienvalentinės cd28 prisijungimo atžvilgiu kompozicijos ir panaudojimo būdai |
EP3100745B1 (en) | 2009-02-05 | 2018-04-18 | Immunogen, Inc. | Novel benzodiazepine derivatives |
MA33221B1 (fr) * | 2009-03-27 | 2012-04-02 | Glaxo Group Ltd | Fusions de médicament et conjugués afférents |
SI3192529T1 (sl) | 2009-04-08 | 2020-07-31 | Faulstich, Heinz Dr. | Z amatoksinom ojačane vezne komponente terapevtske celične površine, zasnovane za zdravljenje tumorjev |
KR20180056805A (ko) | 2009-06-04 | 2018-05-29 | 노파르티스 아게 | IgG 콘쥬게이션을 위한 자리의 확인 방법 |
JP5918129B2 (ja) | 2009-06-22 | 2016-05-18 | メディミューン,エルエルシー | 部位特異的共役のための操作されたFc領域 |
DE102009035875A1 (de) | 2009-08-03 | 2011-02-24 | Dge Dr.-Ing. Günther Engineering Gmbh | Verfahren zur Herstellung von Bio- oder Klärgas |
US8394922B2 (en) | 2009-08-03 | 2013-03-12 | Medarex, Inc. | Antiproliferative compounds, conjugates thereof, methods therefor, and uses thereof |
GB0920127D0 (en) | 2009-11-17 | 2009-12-30 | Ucb Pharma Sa | Antibodies |
AU2011218294A1 (en) | 2010-02-16 | 2012-08-30 | Medimmune, Llc | HSA-related compositions and methods of use |
WO2011118739A1 (ja) * | 2010-03-26 | 2011-09-29 | 協和発酵キリン株式会社 | 新規修飾部位導入抗体および抗体フラグメント |
JP5972864B2 (ja) | 2010-04-15 | 2016-08-17 | メディミューン リミテッド | ピロロベンゾジアゼピン及びそれらのコンジュゲート |
TWI586806B (zh) | 2010-04-23 | 2017-06-11 | 建南德克公司 | 異多聚體蛋白質之製造 |
SG10201600791TA (en) | 2010-06-08 | 2016-03-30 | Genentech Inc | Cysteine engineered antibodies and conjugates |
EP2593688B1 (en) | 2010-07-15 | 2016-09-14 | Thomson Industries, Inc. | Linear motion bearing with interlock structure |
ES2402254T3 (es) | 2010-09-30 | 2013-04-30 | Heidelberg Pharma Ag | Conjugados de amatoxinas con ligadores mejorados |
ES2544608T3 (es) * | 2010-11-17 | 2015-09-02 | Genentech, Inc. | Conjugados de anticuerpo y de alaninil-maitansinol |
BR112013019499B1 (pt) | 2011-02-04 | 2023-01-10 | Genentech, Inc. | Proteína heteromultimérica variante ou anticorpo igg modificado, método para produzir uma proteína heteromultimérica variante ou anticorpo igg modificado, composição, método para preparar uma proteína heteromultimérica e proteína heteromultimérica variante |
EP2497499A1 (en) | 2011-03-10 | 2012-09-12 | Heidelberg Pharma GmbH | Amatoxin-conjugates with improved linkages |
MX354359B (es) | 2011-03-29 | 2018-02-28 | Roche Glycart Ag | Variantes de fragmento cristalizable (fc) de los anticuerpos. |
RS54446B1 (en) | 2011-10-14 | 2016-06-30 | Medimmune Limited | PIROLOBENZIDIAZEPINE AND ITS CONJUGATES |
EP3539982A3 (en) * | 2011-12-23 | 2020-01-15 | Pfizer Inc | Engineered antibody constant regions for site-specific conjugation and methods and uses therefor |
CA2872327A1 (en) | 2012-05-21 | 2013-11-28 | Genentech, Inc. | Anti-ly6e antibodies and immunoconjugates and methods of use |
AU2013288929A1 (en) | 2012-07-09 | 2014-12-04 | Genentech, Inc. | Immunoconjugates comprising anti-CD22 antibodies |
RU2015106673A (ru) | 2012-08-02 | 2016-09-20 | Дженентек, Инк. | Антитела к рецептору эндотелина типа в (etbr) и иммуноконъюгаты |
US20150218220A1 (en) | 2012-09-12 | 2015-08-06 | Brian Alan MENDELSOHN | Amatoxin derivatives and cell-permeable conjugates thereof as inhibitors of rna polymerase |
CN115925957A (zh) * | 2013-02-08 | 2023-04-07 | Irm责任有限公司 | 用于修饰抗体以制备免疫缀合物的特定位点 |
EP2774624A1 (en) | 2013-03-04 | 2014-09-10 | Heidelberg Pharma GmbH | Amatoxin derivatives |
AU2014307080B2 (en) * | 2013-08-12 | 2018-06-07 | Genentech, Inc. | 1-(chloromethyl)-2,3-dihydro-1H-benzo(E)indole dimer antibody-drug conjugate compounds, and methods of use and treatment |
WO2015095212A1 (en) | 2013-12-16 | 2015-06-25 | Genentech, Inc. | 1-(chloromethyl)-2,3-dihydro-1h-benzo[e]indole dimer antibody-drug conjugate compounds, and methods of use and treatment |
CA2928952A1 (en) | 2013-12-16 | 2015-06-25 | Genentech, Inc. | Peptidomimetic compounds and antibody-drug conjugates thereof |
KR20170042495A (ko) | 2013-12-16 | 2017-04-19 | 제넨테크, 인크. | 펩티드모방체 화합물 및 그의 항체-약물 접합체 |
EA033456B1 (ru) | 2013-12-16 | 2019-10-31 | Genentech Inc | Конъюгаты антитело-лекарственное средство, содержащие пептидомиметические линкеры |
SG11201605437YA (en) | 2014-01-27 | 2016-08-30 | Pfizer | Bifunctional cytotoxic agents |
SG11201701311YA (en) | 2014-09-11 | 2017-03-30 | Seattle Genetics Inc | Targeted delivery of tertiary amine-containing drug substances |
MA40576B1 (fr) * | 2014-09-12 | 2020-11-30 | Genentech Inc | Anticorps et immunoconjugués anti-her2 |
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2015
- 2015-09-11 AU AU2015314826A patent/AU2015314826A1/en not_active Abandoned
- 2015-09-11 JP JP2017513087A patent/JP2017531620A/ja active Pending
- 2015-09-11 EP EP15771364.5A patent/EP3191521A2/en not_active Withdrawn
- 2015-09-11 SG SG11201701128YA patent/SG11201701128YA/en unknown
- 2015-09-11 CA CA2957354A patent/CA2957354A1/en not_active Abandoned
- 2015-09-11 AR ARP150102905A patent/AR101844A1/es unknown
- 2015-09-11 KR KR1020177008038A patent/KR20170052600A/ko unknown
- 2015-09-11 RU RU2017107502A patent/RU2017107502A/ru not_active Application Discontinuation
- 2015-09-11 TW TW104130168A patent/TW201625688A/zh unknown
- 2015-09-11 US US14/851,348 patent/US10077318B2/en active Active
- 2015-09-11 WO PCT/US2015/049771 patent/WO2016040856A2/en active Application Filing
- 2015-09-11 EP EP17198468.5A patent/EP3388449A3/en not_active Withdrawn
- 2015-09-11 BR BR112017003236A patent/BR112017003236A2/pt not_active IP Right Cessation
- 2015-09-11 CN CN201580054050.0A patent/CN107108724A/zh active Pending
- 2015-09-11 MX MX2017003123A patent/MX2017003123A/es unknown
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2017
- 2017-02-05 IL IL250449A patent/IL250449A0/en unknown
- 2017-02-07 ZA ZA2017/00944A patent/ZA201700944B/en unknown
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2018
- 2018-02-23 HK HK18102603.5A patent/HK1243103A1/zh unknown
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2019
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2020
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2022
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JP2017531620A (ja) | 2017-10-26 |
BR112017003236A2 (pt) | 2017-11-28 |
JP2021073176A (ja) | 2021-05-13 |
TW201625688A (zh) | 2016-07-16 |
KR20170052600A (ko) | 2017-05-12 |
WO2016040856A3 (en) | 2016-05-06 |
AU2015314826A1 (en) | 2017-03-02 |
ZA201700944B (en) | 2019-06-26 |
EP3191521A2 (en) | 2017-07-19 |
US20200017601A1 (en) | 2020-01-16 |
EP3388449A2 (en) | 2018-10-17 |
IL250449A0 (en) | 2017-03-30 |
AR101844A1 (es) | 2017-01-18 |
US10077318B2 (en) | 2018-09-18 |
MX2017003123A (es) | 2017-05-12 |
US20230130874A1 (en) | 2023-04-27 |
SG11201701128YA (en) | 2017-03-30 |
RU2017107502A (ru) | 2018-10-12 |
WO2016040856A2 (en) | 2016-03-17 |
RU2017107502A3 (ja) | 2019-07-24 |
HK1243103A1 (zh) | 2018-07-06 |
CA2957354A1 (en) | 2016-03-17 |
US20160130358A1 (en) | 2016-05-12 |
EP3388449A3 (en) | 2018-10-24 |
CN107108724A (zh) | 2017-08-29 |
JP2020143067A (ja) | 2020-09-10 |
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