JP2012521216A - Lightに対するヒト化抗体およびその使用 - Google Patents
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Images
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- C07K16/2875—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the NGF/TNF superfamily, e.g. CD70, CD95L, CD153, CD154
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Abstract
【選択図】 図1
Description
(1) X1Y X2X3X4 (配列番号18)[ここで、X1はアミノ酸D、S、TまたはNであり; X2はアミノ酸Y、LまたはWであり; X3はアミノ酸IまたはMであり; そしてX4はアミノ酸Y、H、EまたはNである]のアミノ酸配列を含むCDR-H1;
(2) X5IX6PX7X8X9X10X11X12X13NX14X15FX16X17 (配列番号19)[ここで、X5はアミノ酸Y、M、VまたはWであり; X6はアミノ酸D、N、HまたはFであり; X7はアミノ酸Y、GまたはSであり; X8はアミノ酸N、S、TまたはDであり; X9はアミノ酸G、SまたはDであり; X10はアミノ酸G、D、EまたはIであり; X11はアミノ酸TまたはSであり; X12はアミノ酸KまたはRであり; X13はアミノ酸YまたはLであり; X14はアミノ酸QまたはEであり; X15はアミノ酸KまたはNであり; X16はアミノ酸K、IまたはRであり; そしてX17はアミノ酸G、AまたはDである]のアミノ酸配列を含むCDR-H2; ならびに
(3) (i) WX18X19 (配列番号20); (ii) X20X21X22X23X24X25X26X27X28 (配列番号21); および(iii) X20X21X22X23X24X25X26X27X28AMDF (配列番号22)[ここで、X18はアミノ酸DまたはNであり; X19はアミノ酸RまたはYであり; X20はアミノ酸E、TまたはGであり; X21はアミノ酸D、Sまたは Nであり; X22はアミノ酸YまたはGであり; X23はアミノ酸G、SまたはVであり; X24はアミノ酸I、SまたはWであり; X25はアミノ酸S、WまたはAであり; X26はアミノ酸T、FまたはMであり; X27はアミノ酸Y、PまたはDであり; そしてX28はアミノ酸SまたはYである]からなる群より選択されるアミノ酸配列を含むCDR-H3
を含むヒト化抗体重鎖可変領域を含む、LIGHTポリペプチドと特異的に結合する抗原結合性ポリペプチドを包含する。
(1) (i) X29X30SX31X32X33X34X35X36X37X38 (配列番号38); (ii) X29X30SX31X32X33X34X35X36X37X38X39X40X41X42 (配列番号39); および(iii) X29X30SX31X32X33X34X35X36X37X38X39X40X41X42H (配列番号40)[ここで、X29はアミノ酸KまたはRであり; X30はアミノ酸AまたはSであり; X31はアミノ酸QまたはKであり; X32はアミノ酸D、SまたはNであり; X33はアミノ酸V、IまたはLであり; X34はアミノ酸G、S、VまたはLであり; X35はアミノ酸T、NまたはHであり; X36はアミノ酸A、NまたはSであり; X37はアミノ酸V、L、NまたはGであり; X38はアミノ酸A、H、GまたはYであり; X39はアミノ酸NまたはTであり; X40はアミノ酸TまたはYであり; X41はアミノ酸YまたはMであり; X42はアミノ酸FまたはHである]からなる群より選択されるアミノ酸配列を含むCDR-L1;
(2) X43X44X45X46X47X48X49 (配列番号41)[ここで、X43はアミノ酸W、Y、KまたはIであり; X44はアミノ酸A、TまたはVであり; X45はアミノ酸SまたはYであり; X46はアミノ酸T、QまたはNであり; X47はアミノ酸R、SまたはLであり; X48はアミノ酸H、I、FまたはEであり; そしてX49はアミノ酸TまたはSである]のアミノ酸配列を含むCDR-L2; ならびに
(3) X50X51X52X53X54X55PX56T (配列番号42)[ここで、X50はアミノ酸QまたはSであり; X51はアミノ酸QまたはHであり; X52はアミノ酸SまたはYであり; X53はアミノ酸S、N、TまたはRであり; X54はアミノ酸S、R、HまたはEであり; X55はアミノ酸Y、W、VまたはLであり; そしてX56はアミノ酸LまたはYである]のアミノ酸配列を含むCDR-L3
を含むヒト化抗体軽鎖可変領域を含む、LIGHTポリペプチドと特異的に結合する抗原結合性ポリペプチドを包含する。
(1) X1Y X2X3X4 (配列番号18)[ここで、X1はアミノ酸D、S、TまたはNであり; X2はアミノ酸Y、LまたはWであり; X3はアミノ酸IまたはMであり; そしてX4はアミノ酸Y、H、EまたはNである]のアミノ酸配列を含むCDR-H1;
(2) X5IX6PX7X8X9X10X11X12X13NX14X15FX16X17 (配列番号19)[ここで、X5はアミノ酸Y、M、VまたはWであり; X6はアミノ酸D、N、HまたはFであり; X7はアミノ酸Y、GまたはSであり; X8はアミノ酸N、S、TまたはDであり; X9はアミノ酸G、SまたはDであり; X10はアミノ酸G、D、EまたはIであり; X11はアミノ酸TまたはSであり; X12はアミノ酸KまたはRであり; X13はアミノ酸YまたはLであり; X14はアミノ酸QまたはEであり; X15はアミノ酸KまたはNであり; X16はアミノ酸K、IまたはRであり; そしてX17はアミノ酸G、AまたはDである]のアミノ酸配列を含むCDR-H2; ならびに
(3) (i) WX18X19 (配列番号20); (ii) X20X21X22X23X24X25X26X27X28 (配列番号21); および(iii) X20X21X22X23X24X25X26X27X28AMDF (配列番号22)[ここで、X18はアミノ酸DまたはNであり; X19はアミノ酸RまたはYであり; X20はアミノ酸E、TまたはGであり; X21はアミノ酸D、Sまたは Nであり; X22はアミノ酸YまたはGであり; X23はアミノ酸G、SまたはVであり; X24はアミノ酸I、SまたはWであり; X25はアミノ酸S、WまたはAであり; X26はアミノ酸T、FまたはMであり; X27はアミノ酸Y、PまたはDであり; そしてX28はアミノ酸SまたはYである]からなる群より選択されるアミノ酸配列を含むCDR-H3
を含むヒト化抗体重鎖可変領域と;
(1) (i) X29X30SX31X32X33X34X35X36X37X38 (配列番号38); (ii) X29X30SX31X32X33X34 X35X36X37X38X39X40X41X42 (配列番号39); および(iii) X29X30SX31X32X33X34X35X36X37X38 X39X40X41X42H (配列番号40)[ここで、X29はアミノ酸KまたはRであり; X30はアミノ酸AまたはSであり; X31はアミノ酸QまたはKであり; X32はアミノ酸D、SまたはNであり; X33はアミノ酸V、IまたはLであり; X34はアミノ酸G、S、VまたはLであり; X35はアミノ酸T、NまたはHであり; X36はアミノ酸A、NまたはSであり; X37はアミノ酸V、L、NまたはGであり; X38はアミノ酸A、H、GまたはYであり; X39はアミノ酸NまたはTであり; X40はアミノ酸TまたはYであり; X41はアミノ酸YまたはMであり; X42はアミノ酸FまたはHである]からなる群より選択されるアミノ酸配列を含むCDR-L1;
(2) X43X44X45X46X47X48X49 (配列番号41)[ここで、X43はアミノ酸W、Y、KまたはIであり; X44はアミノ酸A、TまたはVであり; X45はアミノ酸SまたはYであり; X46はアミノ酸T、QまたはNであり; X47はアミノ酸R、SまたはLであり; X48はアミノ酸H、I、FまたはEであり; そしてX49はアミノ酸TまたはSである]のアミノ酸配列を含むCDR-L2; ならびに
(3) X50X51X52X53X54X55PX56T (配列番号42)[ここで、X50はアミノ酸QまたはSであり; X51はアミノ酸QまたはHであり; X52はアミノ酸SまたはYであり; X53はアミノ酸S、N、TまたはRであり; X54はアミノ酸S、R、HまたはEであり; X55はアミノ酸Y、W、VまたはLであり; そしてX56はアミノ酸LまたはYである]のアミノ酸配列を含むCDR-L3
を含むヒト化抗体軽鎖可変領域と
を含む、LIGHTポリペプチドと特異的に結合する抗原結合性ポリペプチドを包含する。
(1) (i) SSYIH (配列番号23); (ii) DYYIY (配列番号26); (iii) TYLIE (配列番号29); (iv) TYWMN (配列番号32); および(v) NYLIE (配列番号35)からなる群より選択されるアミノ酸配列を含むCDR-H1;
(2) (i) WIFPGSDITKYNEKFKG (配列番号24); (ii) YIDPYNGGTKYNQKFKD (配列番号27); (iii) VINPGTGETKYNENFRA (配列番号30); (iv) MIHPSDSESRLNQKFID (配列番号33); および(v) VINPGSGDTKYNENFKG (配列番号36)からなる群より選択されるアミノ酸配列を含むCDR-H2;ならびに
(3) (i) EDYGISTYSAMDF (配列番号25); (ii) TSGSSWFPY (配列番号28); (iii) WDR (配列番号31); (iv) GNYVWAMDY (配列番号34); および(v) WNY (配列番号37)からなる群より選択されるアミノ酸配列を含むCDR-H3
を含むヒト化抗体重鎖可変領域を含む、LIGHTポリペプチドと特異的に結合する抗原結合性ポリペプチドを包含する。
(1) (i) KASQDVGTAVA (配列番号43); (ii) RASQSISNNLH (配列番号46); (iii) RSSQNLVHSNGNTYFH (配列番号49); (iv) RASKSVSTSGYTYMH (配列番号52); および(v) RSSQSLLHSNGNTYFH (配列番号55)からなる群より選択されるアミノ酸配列を含むCDR-L1;
(2) (i) WASTRHT (配列番号44); (ii) YTYQSIS (配列番号47); (iii) KVSNRFS (配列番号50); および(iv) ITSNLES (配列番号53)からなる群より選択されるアミノ酸配列を含むCDR-L2;ならびに
(3) (i) QQYSSYPLT (配列番号45); (ii) QQSNRWPLT (配列番号48); (iii) SQSTHVPYT (配列番号51); および(iv) QHSRELPYT (配列番号54) からなる群より選択されるアミノ酸配列を含むCDR-L3
を含むヒト化抗体軽鎖可変領域を含む、LIGHTポリペプチドと特異的に結合する抗原結合性ポリペプチドを包含する。
(1)QVQLVQSGAEVKKPGASVKVSCKASGYTFTX1YX2X3X4WVRQAPGQX'1LEWX'2GX5IX6PX7X8X9X10X11X12X13NX14X15FX16X17X'3X'4TX'5TX'6DX'7SX'8STX'9YMELSX'10LRSX'11DTAVYYCARWX18X19WGQGTLVTVSS (配列番号1);
(2)QVQLVQSGAEVKKPGASVKVSCKASGYTFTX1YX2X3X4WVRQAPGQX'1LEWX'2GX5IX6PX7X8X9X10X11X12X13NX14X15FX16X17X'3X'4TX'5TX'6DX'7SX'8STX'9YMELSX'10LRSX'11DTAVYYCARX20X21X22X23X24X25X26X27X28WGQGTLVTVSS (配列番号2); および
(3)QVQLVQSGAEVKKPGASVKVSCKASGYTFTX1YX2X3X4WVRQAPGQX'1LEWX'2GX5IX6PX7X8X9X10X11X12X13NX14X15FX16X17X'3X'4TX'5TX'6DX'7SX'8STX'9YMELSX'10LRSX'11DTAVYYCARX20X21X22X23X24X25X26X27X28AMDFWGQGTLVTVSS (配列番号3);
[ここで、X1はアミノ酸D、S、TまたはNであり; X2はアミノ酸Y、LまたはWであり; X3はアミノ酸IまたはMであり; X4はアミノ酸Y、H、EまたはNであり; X5はアミノ酸Y、M、VまたはWであり; X6はアミノ酸D、N、HまたはFであり; X7はアミノ酸Y、GまたはSであり; X8はアミノ酸N、S、TまたはDであり; X9はアミノ酸G、SまたはDであり; X10はアミノ酸G、D、EまたはIであり; X11はアミノ酸TまたはSであり; X12はアミノ酸KまたはRであり; X13はアミノ酸YまたはLであり; X14はアミノ酸QまたはEであり; X15はアミノ酸KまたはNであり; X16はアミノ酸K、IまたはRであり; X17はアミノ酸G、AまたはDであり; X18はアミノ酸DまたはNであり; X19はアミノ酸RまたはYであり; X20はアミノ酸E、TまたはGであり; X21はアミノ酸D、SまたはNであり; X22はアミノ酸YまたはGであり; X23はアミノ酸G、SまたはVであり; X24はアミノ酸I、SまたはWであり; X25はアミノ酸S、WまたはAであり; X26はアミノ酸T、FまたはMであり; X27はアミノ酸Y、PまたはDであり; X28はアミノ酸SまたはYであり; さらにここで、X'1はアミノ酸RまたはGであり; X'2はアミノ酸MまたはIであり; X'3はアミノ酸KまたはRであり; X'4はアミノ酸VまたはAであり; X'5はアミノ酸M、LまたはIであり; X'6はアミノ酸VまたはRであり; X'7はアミノ酸TまたはKであり; X'8はアミノ酸A、IまたはTであり; X'9はアミノ酸VまたはAであり; X'10はアミノ酸RまたはSであり; そしてX'11はアミノ酸DまたはEである]
からなる群より選択されるアミノ酸配列を含むヒト化抗体重鎖可変領域を含む、LIGHTポリペプチドと特異的に結合する抗原結合性ポリペプチドをも包含する。
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQRLEWMGWIFPGSDITKYNEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCAREDYGISTYSAMDFWGQGTLVTVSS (配列番号4);
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYIYWVRQAPGQGLEWIGYIDPYNGGTKYNQKFKDRVTMTRDTSISTAYMELSRLRSDDTAVYYCARTSGSSWFPYWGQGTLVTVSS (配列番号5);
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYIYWVRQAPGQGLEWIGYIDPYNGGTKYNQKFKDKATLTVDKSTSTAYMELSSLRSEDTAVYYCARTSGSSWFPYWGQGTLVTVSS (配列番号6);
QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYLIEWVRQAPGQGLEWMGVINPGTGETKYNENFRARVTMTRDTSISTAYMELSRLRSDDTAVYYCARWDRWGQGTLVTVSS (配列番号7); および
QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYWMNWVRQAPGQGLEWMGMIHPSDSESRLNQKFIDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGNYVWAMDYWGQGTLVTVSS (配列番号8)
からなる群より選択されるアミノ酸配列を含むヒト化抗体重鎖可変領域を含む、LIGHTポリペプチドと特異的に結合する抗原結合性ポリペプチドを包含する。
(1)X'12X'13X'14X'15TQX'16PX'17X'18X'19X'20X'21X'22X'23X'24X'25X'26X'27X'28X'29X'30CX29X30SX31X32X33X34X35X36X37X38WX'31X'32QX'33PX'34X'35X'36PX'37X'38LIX'39X43X44X45X46X47X48X49GX'40PX'41RFSGSGSGTX'42FTLX'43IX'44X'45X'46X'47X'48EDX'49X'50X'51YYCX50X51X52X53 X54X55PX56TFGQGTX'52VEIKR (配列番号9);
(2)X'12X'13X'14X'15TQX'16PX'17X'18X'19X'20X'21X'22X'23X'24X'25X'26X'27X'28X'29X'30CX29X30SX31X32X33X34X35X36X37X38X39X40X41X42WX'31X'32QX'33PX'34X'35X'36X'37X'38LIX'39X43X44X45X46X47X48X49GX'40PX'41RFSGSGSGTX'42FTLX'43IX'44X'45X'46X'47X'48EDX'49X'50X'51YYCX50X51X52X53X54X55PX56TFGQGTX'52VEIKR (配列番号10); および
(3)X'12X'13X'14X'15TQX'16PX'17X'18X'19X'20X'21X'22X'23X'24X'25X'26X'27X'28X'29X'30CX29X30SX31X32X33X34X35X36X37X38X39X40X41X42HWX'31X'32QX'33PX'34X'35X'36X'37X'38LIX'39X43X44X45X46X47X48X49GX'40PX'41RFSGSGSGTX'42FTLX'43IX'44X'45X'46X'47X'48EDX'49X'50X'51YYCX50X51X52X53X54X55PX56TFGQGTX'52VEIKR (配列番号11);
[ここで、X29はアミノ酸KまたはRであり; X30はアミノ酸AまたはSであり; X31はアミノ酸QまたはKであり; X32はアミノ酸D、SまたはNであり; X33はアミノ酸V、IまたはLであり; X34はアミノ酸G、S、VまたはLであり; X35はアミノ酸T、NまたはHであり; X36はアミノ酸A、NまたはSであり; X37はアミノ酸V、L、NまたはGであり; X38はアミノ酸A、H、GまたはYであり; X39はアミノ酸NまたはTであり; X40はアミノ酸TまたはYであり; X41はアミノ酸YまたはMであり; X42はアミノ酸FまたはHであり; X43はアミノ酸W、Y、KまたはIであり; X44はアミノ酸A、TまたはVであり; X45はアミノ酸SまたはYであり; X46はアミノ酸T、QまたはNであり; X47はアミノ酸R、SまたはLであり; X48はアミノ酸H、I、FまたはEであり; X49はアミノ酸TまたはSであり; X50はアミノ酸QまたはSであり; X51はアミノ酸QまたはHであり; X52はアミノ酸SまたはYであり; X53はアミノ酸S、N、TまたはRであり; X54はアミノ酸S、R、HまたはEであり; X55はアミノ酸Y、W、VまたはLであり; X56はアミノ酸LまたはYであり; さらにここで、X'12はアミノ酸DまたはEであり; X'13はアミノ酸IまたはVであり; X'14はアミノ酸VまたはQであり; X'15はアミノ酸MまたはLであり; X'16はアミノ酸SまたはTであり; X'17はアミノ酸S、D、AまたはLであり; X'18はアミノ酸S、TまたはFであり; X'19はアミノ酸LまたはQであり; X'20はアミノ酸A、SまたはPであり; X'21はアミノ酸VまたはAであり; X'22はアミノ酸SまたはTであり; X'23はアミノ酸P、LまたはVであり; X'24はアミノ酸GまたはKであり; X'25はアミノ酸E、QまたはDであり; X'26はアミノ酸R、KまたはPであり; X'27はアミノ酸AまたはVであり; X'28はアミノ酸TまたはSであり; X'29はアミノ酸IまたはLであり; X'30はアミノ酸S、TまたはNであり; X'31はアミノ酸FまたはYであり; X'32はアミノ酸QまたはLであり; X'33はアミノ酸KまたはRであり; X'34はアミノ酸GまたはDであり; X'35はアミノ酸QまたはKであり; X'36はアミノ酸A、SまたはPであり; X'37はアミノ酸K、RまたはQであり; X'38はアミノ酸LまたはRであり; X'39はアミノ酸YまたはKであり; X'40はアミノ酸VまたはIであり; X'41はアミノ酸S、AまたはDであり; X'42はアミノ酸DまたはEであり; X'43はアミノ酸KまたはTであり; X'44はアミノ酸SまたはNであり; X'45はアミノ酸SまたはRであり; X'46はアミノ酸VまたはLであり; X'47はアミノ酸QまたはEであり; X'48はアミノ酸P、AまたはSであり; X'49はアミノ酸F、AまたはVであり; X'50はアミノ酸AまたはGであり; X'51はアミノ酸TまたはVであり; そしてX'52はアミノ酸RまたはKである]
からなる群より選択されるアミノ酸配列を含むヒト化抗体軽鎖可変領域を含む、LIGHTポリペプチドと特異的に結合する抗原結合性ポリペプチドを包含する。
DIQLTQSPSFLSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYSSYPLTFGQGTKVEIKR (配列番号12);
EIVLTQSPDFQSVTPKEKVTITCRASQSISNNLHWYQQKPDQSPKLLIKYTYQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCQQSNRWPLTFGQGTKVEIKR (配列番号13);
EIVMTQSPATLSVSPGEKATLSCRASQSISNNLHWYQQKPGQAPRLLIYYTYQSISGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQSNRWPLTFGQGTRVEIKR (配列番号14);
DVVMTQSPLSLPVTLGQPASISCRSSQNLVHSNGNTYFHWFQQRPGQSPRRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPYTFGQGTKVEIKR (配列番号15);
DIVMTQTPLSLSVTPGQPASISCRSSQNLVHSNGNTYFHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPYTFGQGTKVEIKR (配列番号16); および
DIVMTQSPDSLAVSLGERATINCRASKSVSTSGYTYMHWYQQKPGQPPKLLIYITSNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQHSRELPYTFGQGTKVEIKR (配列番号17)
からなる群より選択されるアミノ酸配列を含むヒト化抗体軽鎖可変領域を含む、LIGHTポリペプチドと特異的に結合する抗原結合性ポリペプチドをも包含する。
(a)アミノ酸配列:QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQRLEWMGWIFPGSDITKYNEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCAREDYGISTYSAMDFWGQGTLVTVSS (配列番号4)を含む重鎖可変領域、および
(b)アミノ酸配列:DIQLTQSPSFLSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTEFTLTISSLQP EDFATYYCQQYSSYPLTFGQGTKVEIKR (配列番号12)を含む軽鎖可変領域
を含む、LIGHTポリペプチドと特異的に結合する抗原結合性ポリペプチドを包含する。
定義
単数の構成要素はその構成要素の1つ以上を指すことに留意すべきであり、例えば、単数の抗原結合性ポリペプチドは1つ以上の抗原結合性ポリペプチドを表すと理解される。したがって、「1つ」、「1つ以上」および「少なくとも1つ」という語は本明細書では互換的に用いられる。
LIGHT (GenBankアクセッション番号AF036581参照;その全体を参照により本明細書に組み入れる)として知られるTNF様サイトカインポリペプチドに特異的に結合する抗原結合性ポリペプチドが開示される。本発明の特定の抗原結合性ポリペプチドには、本明細書に記載のLIGHT抗体の相補性決定領域を含むヒト化重鎖ポリペプチド、ヒト化軽鎖ポリペプチド、ヒト化重鎖可変領域、ヒト化軽鎖可変領域、ならびにヒト化重鎖・軽鎖ポリペプチドが含まれる。特定の実施形態では、抗原結合性ポリペプチドはLIGHT活性および/またはLIGHTとLIGHT受容体との相互作用のアンタゴニストとして機能する。
i. 配列番号1 および 配列番号9;
ii. 配列番号2 および 配列番号10;
iii. 配列番号3 および 配列番号11;
iv. 配列番号4 および 配列番号12;
v. 配列番号5 および 配列番号13;
vi. 配列番号6 および 配列番号14;
vii. 配列番号7 および 配列番号15;
viii. 配列番号7 および 配列番号16;
ix. 配列番号8 および 配列番号17; ならびに
x. これらの組合せ
からなる群より選択されるヒト化重鎖可変領域とヒト化軽鎖可変領域を含む、から本質的になる、またはからなる。
i. 配列番号18, 19, 20 および 配列番号38, 41, 42;
ii. 配列番号18, 19, 21 および 配列番号39, 41, 42;
iii. 配列番号18, 19, 22 および 配列番号40, 41, 42;
iv. 配列番号23, 24, 25 および 配列番号43, 44, 45;
v. 配列番号26, 27, 28 および 配列番号46, 47, 48;
vi. 配列番号29, 30, 31 および 配列番号49, 50, 51;
vii. 配列番号32, 33, 34 および 配列番号52, 53, 54;
viii. 配列番号35, 36, 37 および 配列番号55, 50, 51; ならびに
ix. これらの組合せ
からなる群より選択されるCDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2およびCDR-L3を含む、から本質的になる、またはからなるヒト化重鎖可変領域とヒト化軽鎖可変領域を含む、から本質的になる、またはからなる。
具体的には、本発明の抗原結合性ポリペプチド、その変異体または誘導体は、治療薬、プロドラッグ、ペプチド、タンパク質、酵素、ウイルス、脂質、生物学的応答調節剤、薬剤、またはPEGにコンジュゲートすることができる。
本発明はさらに、本発明の抗原結合性ポリペプチドまたはその変異体もしくは誘導体をコードするポリヌクレオチドまたは核酸分子を提供する。
i. 配列番号1 および 配列番号9;
ii. 配列番号2 および 配列番号10;
iii. 配列番号3 および 配列番号11;
iv. 配列番号4 および 配列番号12;
v. 配列番号5 および 配列番号13;
vi. 配列番号6 および 配列番号14;
vii. 配列番号7 および 配列番号15;
viii. 配列番号7 および 配列番号16;
ix. 配列番号8 および 配列番号17; ならびに
x. これらの組合せ
からなる群より選択されるヒト化重鎖可変領域とヒト化軽鎖可変領域を含む、から本質的になる、またはからなる、LIGHTポリペプチドと特異的に結合する抗原結合性ポリペプチドをコードする。
i. 配列番号18, 19, 20 および 配列番号38, 41, 42;
ii. 配列番号18, 19, 21 および 配列番号39, 41, 42;
iii. 配列番号18, 19, 22 および 配列番号40, 41, 42;
iv. 配列番号23, 24, 25 および 配列番号43, 44, 45;
v. 配列番号26, 27, 28 および 配列番号46, 47, 48;
vi. 配列番号29, 30, 31 および 配列番号49, 50, 51;
vii. 配列番号32, 33, 34 および 配列番号52, 53, 54;
viii. 配列番号35, 36, 37 および 配列番号55, 50, 51; ならびに
ix. これらの組合せ
からなる群より選択されるCDR-H1、CDR-H2、CDR-H3、CDR-L1、CDR-L2およびCDR-L3を含む、から本質的になる、またはからなるヒト化重鎖可変領域とヒト化軽鎖可変領域を含む、から本質的になる、またはからなる、LIGHTポリペプチドと特異的に結合する抗原結合性ポリペプチドをコードするポリヌクレオチドを包含する。
抗体または抗原結合性ポリペプチドの作製方法は当技術分野でよく知られており、本明細書中で説明される。特定の実施形態では、本発明の抗原結合性ポリペプチドの可変領域と定常領域の両方が完全にヒトである。完全ヒト抗体は、当技術分野で記載されかつ本明細書で説明される技術を用いて作製することができる。例えば、特定の抗原に対する完全ヒト抗体は、抗原投与に応答してそのような抗体を産生するように改変された(しかし、その内在性遺伝子座が無効にされた)トランスジェニック動物に抗原を投与することによって作製することができる。そのような抗体を作製するために使用できる代表的な技術は、米国特許第6,150,584号、第6,458,592号および第6,420,140号に記載されており、それらの全内容を参照により本明細書に組み入れる。
x社(Freemont, Calif.)およびGenPharm社(San Jose, Calif.)のような企業は、上記と同様の技術を用いて所定の抗原に対するヒト抗体を提供することに従事している。
本明細書に記載したように、本発明の抗原結合性ポリペプチド、その変異体または誘導体は、炎症性、免疫性または悪性の疾患または症状と関連した特定の治療および診断方法において使用される。具体的には、本発明の特定の抗原結合性ポリペプチドはLIGHT活性のアンタゴニストであり得る。例えば、特定の抗原結合性ポリペプチドは、T細胞の刺激、前炎症性サイトカイン(IFN-γ、IL-8など)の刺激、ならびにCD3およびTh17細胞によるIL-17産生の刺激といった、LIGHT活性のアンタゴニストである。さらに、本発明のLIGHT抗原結合性ポリペプチドは、LTβ受容体、HVEM受容体およびデコイ受容体3/TR6、ならびにLIGHTが結合する他の受容体に結合するLIGHTの能力を妨げることができる。
さまざまな送達系が知られており、本発明の抗原結合性ポリペプチドまたは本発明の抗原結合性ポリペプチドをコードするポリヌクレオチドを投与するために使用することができ、例えば、リポソーム、微粒子、マイクロカプセルへの封入、化合物を発現できる組換え細胞、受容体介在エンドサイトーシス(例えば、Wu and Wu, 1987, J. Biol. Chem. 262:4429-4432参照)、レトロウイルスまたは他のベクターの一部としての核酸の構築などが用いられる。
BCNU、ロムスチン、CCNU、シトシンアラビノシド、シクロホスファミド、エストラムスチン、ヒドロキシ尿素、プロカルバジン、マイトマイシン、ブスルファン、シスプラチン、および硫酸ビンクリスチン);ホルモン(例:メドロキシプロゲステロン、エストラムスチンリン酸エステルナトリウム、エチニルエストラジオール、エストラジオール、酢酸メゲストロール、メチルテストステロン、2リン酸ジエチルスチルベストロール、クロロトリアニセン、およびテストラクトン);ナイトロジェンマスタード誘導体(例:メルファラン、クロラムブシル、メクロレタミン(ナイトロジェンマスタード)およびチオテパ);ステロイドおよび組合せ(例:ベタメタゾンリン酸エステルナトリウム);ならびにその他(例:ジカルバジン、アスパラギナーゼ、ミトタン、硫酸ビンクリスチン、硫酸ビンブラスチン、およびエトポシド)が挙げられる。
BALB/cマウスを組換えLIGHTタンパク質(細胞外ドメイン断片アミノ酸Leu Ile GluからPhe Met Valまで;Genbankアクセッション番号AF036581)で免疫した。一般的な手順で、50mlの完全フロイントアジュバント(Sigma社, St. Louis, MO)中の10mgのタンパク質をマウスに皮下注射した。不完全フロイントアジュバントで2〜4回の追加の注射を2週間間隔で実施し、続いてPBSで最終ブーストを実施した。これとは別に、注射をフットパッドに行ってもよい。最終接種の3日後、マウスを犠牲にして、脾臓または膝窩リンパ節を採取した。融合のために脾臓またはリンパ節からリンパ球を分離した。リンパ球をP3X63Ag8.653形質細胞腫細胞と、リンパ球対形質細胞腫細胞5:1の比で、融合剤としてPEG/DMSO (Sigma社)を用いて融合させた。融合後、細胞を選択HAT培地に再懸濁させ、96ウェルプレートに1ウェルあたり106個の細胞を播種した。HAT選択を生き残ったハイブリドーマからの上清は、LIGHT結合抗体の存在について、直接結合ELISAによりスクリーニングした。LIGHT結合抗体を分泌するハイブリドーマを同定し、それらの上清を、3種の既知の受容体HVEM、LTβRおよびDcR3へのLIGHTの結合を阻害する抗体について、ELISAでさらにスクリーニングした。その後、LIGHT結合の阻害について陽性と同定されたハイブリドーマは、LIGHTが介在するHT-29細胞死滅の阻害についてスクリーニングして、LIGHTアンタゴニスト抗体を同定した。
ハイブリドーマ細胞をペレット化し、PBSで3回洗浄し、Trizol試薬(Invitrogen社, カタログ番号15596-026)を用いてメーカーのプロトコールに従いRNAを抽出した。全RNAを、5'RACEキット(Rapid Amplification of cDNA Ends, Invitrogen社, カタログ番号18374-058)を用いてメーカーのプロトコールに従いcDNAに変換した。簡単に説明すると、RNAをランダムヘキサマープライマーRandom N6にライゲートし、superscript II RNAase Hネガティブ逆転写酵素を用いて第一鎖cDNAを作製した。そのcDNAを、キットに備わっているGlassMaxスピンカートリッジを用いて精製し、次にdCTPの存在下でTdT(ターミナルデオキシヌクレオチジルトランスフェラーゼ)と反応させて、cDNAに5'末端でC塩基対を付加した。dCテイルを付加したcDNAは、dCテイルに特異的なアンカープライマーと、遺伝子特異的プライマー(VHの場合はマウス定常重鎖1(CH1)中の、そしてVKの場合は定常κ(CK)中の、高度に保存されたDNA配列にハイブリダイズするプライマー)を用いてPCR増幅した。得られたPCR産物は、インタクトのVHまたはVKドメインに対応する正しいサイズについてゲル電気泳動で分析し、その後精製して、TOPO TAベクター(Invitrogen社, Carlsbad, CA, カタログ番号K4575-01)にメーカーのプロトコールに従いライゲートした。細菌への形質転換後、正しいサイズの挿入物を含むクローンからDNAを調製し、そのDNA配列を、Big Dyeターミネーターシークエンシング反応ミックス(Applied Biosystems社, パーツ番号4336699)と3700 ABI/Prism DNAアナライザーをメーカーのプロトコールに従って用いて決定した。
抗LIGHT抗体をヒト化することの1つの目標は、もとの結合親和性および特異性の90〜100%を保持する、70〜100%ヒト化された可変重鎖(VH)ドメインと可変軽鎖(VK)ドメインを得ることであった。
マウス抗LIGHT抗体は、前述のようにして得られた結合データと配列データに基づいて同定した。これらの抗体由来のVHおよびVKドメインのアミノ酸配列を、現在利用可能な公共データベース(すなわち、NCBIのBLAST for IgG、およびMRCのV-base)を使用して、ヒト生殖系列VHおよびVKドメインとアライメントした。マウス配列がヒト生殖系列と異なっていたフレームワークの位置で、反復プロセスを用いてそのマウスフレームワークを変換または変異させ、それが対応するヒト生殖系列フレームワークにマッチするようにした。結合親和性が特定のフレームワーク変異のため失われる場合には、こうした損失を補うために、VHとVKの両方の特定のCDRアミノ酸残基を、チロシンや他の適切なアミノ酸との置き換えによって変異(すなわち、親和性成熟)させることができる。親和性成熟したヒト化マウスVHおよびVKドメインは、オーバーラップする合成DNAオリゴヌクレオチドのパネルを用いて、ポリメラーゼ連鎖反応法により生成することができる。本明細書に記載するとおりにヒト化されたマウス抗LIGHTモノクローナル抗体の可変重鎖および可変軽鎖ドメインのアミノ酸配列を以下の表7および表8に示す。可変ドメインのCDR部分には下線が引いてある。
Claims (30)
- LIGHTポリペプチドと特異的に結合する抗原結合性ポリペプチドであって、
(1) X1YX2X3X4 (配列番号18)[ここで、X1はアミノ酸D、S、TまたはNであり; X2はアミノ酸Y、LまたはWであり; X3はアミノ酸IまたはMであり; そしてX4はアミノ酸Y、H、EまたはNである]のアミノ酸配列を含むCDR-H1;
(2) X5IX6PX7X8X9X10X11X12X13NX14X15FX16X17 (配列番号19)[ここで、X5はアミノ酸Y、M、VまたはWであり; X6はアミノ酸D、N、HまたはFであり; X7はアミノ酸Y、GまたはSであり; X8はアミノ酸N、S、TまたはDであり; X9はアミノ酸G、SまたはDであり; X10はアミノ酸G、D、EまたはIであり; X11はアミノ酸TまたはSであり; X12はアミノ酸KまたはRであり; X13はアミノ酸YまたはLであり; X14はアミノ酸QまたはEであり; X15はアミノ酸KまたはNであり; X16はアミノ酸K、IまたはRであり; そしてX17はアミノ酸G、AまたはDである]のアミノ酸配列を含むCDR-H2; ならびに
(3) (i) WX18X19 (配列番号20);
(ii) X20X21X22X23X24X25X26X27X28 (配列番号21); および
(iii) X20X21X22X23X24X25X26X27X28AMDF (配列番号22)
[ここで、X18はアミノ酸DまたはNであり; X19はアミノ酸RまたはYであり; X20はアミノ酸E、TまたはGであり; X21はアミノ酸D、Sまたは Nであり; X22はアミノ酸YまたはGであり; X23はアミノ酸G、SまたはVであり; X24はアミノ酸I、SまたはWであり; X25はアミノ酸S、WまたはAであり; X26はアミノ酸T、FまたはMであり; X27はアミノ酸Y、PまたはDであり; そしてX28はアミノ酸SまたはYである]からなる群より選択されるアミノ酸配列を含むCDR-H3
を含むヒト化抗体重鎖可変領域を含む、上記抗原結合性ポリペプチド。 - LIGHTポリペプチドと特異的に結合する抗原結合性ポリペプチドであって、
(1) (i) X29X30SX31X32X33X34X35X36X37X38 (配列番号38);
(ii) X29X30SX31X32X33X34X35X36X37X38X39X40X41X42 (配列番号39); および
(iii) X29X30SX31X32X33X34X35X36X37X38X39X40X41X42H (配列番号40)
[ここで、X29はアミノ酸KまたはRであり; X30はアミノ酸AまたはSであり; X31はアミノ酸QまたはKであり; X32はアミノ酸D、SまたはNであり; X33はアミノ酸V、IまたはLであり; X34はアミノ酸G、S、VまたはLであり; X35はアミノ酸T、NまたはHであり; X36はアミノ酸A、NまたはSであり; X37はアミノ酸V、L、NまたはGであり; X38はアミノ酸A、H、GまたはYであり; X39はアミノ酸NまたはTであり; X40はアミノ酸TまたはYであり; X41はアミノ酸YまたはMであり; X42はアミノ酸FまたはHである]からなる群より選択されるアミノ酸配列を含むCDR-L1;
(2) X43X44X45X46X47X48X49 (配列番号41)[ここで、X43はアミノ酸W、Y、KまたはIであり; X44はアミノ酸A、TまたはVであり; X45はアミノ酸SまたはYであり; X46はアミノ酸T、QまたはNであり; X47はアミノ酸R、SまたはLであり; X48はアミノ酸H、I、FまたはEであり; そしてX49はアミノ酸TまたはSである]のアミノ酸配列を含むCDR-L2; ならびに
(3) X50X51X52X53X54X55PX56T (配列番号42)[ここで、X50はアミノ酸QまたはSであり; X51はアミノ酸QまたはHであり; X52はアミノ酸SまたはYであり; X53はアミノ酸S、N、TまたはRであり; X54はアミノ酸S、R、HまたはEであり; X55はアミノ酸Y、W、VまたはLであり; そしてX56はアミノ酸LまたはYである]のアミノ酸配列を含むCDR-L3
を含むヒト化抗体軽鎖可変領域を含む、上記抗原結合性ポリペプチド。 - LIGHTポリペプチドと特異的に結合する抗原結合性ポリペプチドであって、
(a) (1) X1Y X2X3X4 (配列番号18)[ここで、X1はアミノ酸D、S、TまたはNであり; X2はアミノ酸Y、LまたはWであり; X3はアミノ酸IまたはMであり; そしてX4はアミノ酸Y、H、EまたはNである]のアミノ酸配列を含むCDR-H1;
(2) X5IX6PX7X8X9X10X11X12X13NX14X15FX16X17 (配列番号19)[ここで、X5はアミノ酸Y、M、VまたはWであり; X6はアミノ酸D、N、HまたはFであり; X7はアミノ酸Y、GまたはSであり; X8はアミノ酸N、S、TまたはDであり; X9はアミノ酸G、SまたはDであり; X10はアミノ酸G、D、EまたはIであり; X11はアミノ酸TまたはSであり; X12はアミノ酸KまたはRであり; X13はアミノ酸YまたはLであり; X14はアミノ酸QまたはEであり; X15はアミノ酸KまたはNであり; X16はアミノ酸K、IまたはRであり; そしてX17はアミノ酸G、AまたはDである]のアミノ酸配列を含むCDR-H2; ならびに
(3) (i) WX18X19 (配列番号20);
(ii) X20X21X22X23X24X25X26X27X28 (配列番号21); および
(iii) X20X21X22X23X24X25X26X27X28AMDF (配列番号22)
[ここで、X18はアミノ酸DまたはNであり; X19はアミノ酸RまたはYであり; X20はアミノ酸E、TまたはGであり; X21はアミノ酸D、Sまたは Nであり; X22はアミノ酸YまたはGであり; X23はアミノ酸G、SまたはVであり; X24はアミノ酸I、SまたはWであり; X25はアミノ酸S、WまたはAであり; X26はアミノ酸T、FまたはMであり; X27はアミノ酸Y、PまたはDであり; そしてX28はアミノ酸SまたはYである]からなる群より選択されるアミノ酸配列を含むCDR-H3
を含むヒト化抗体重鎖可変領域と;
(b) (1) (i) X29X30SX31X32X33X34X35X36X37X38 (配列番号38);
(ii) X29X30SX31X32X33X34X35X36X37X38X39X40X41X42 (配列番号39); および
(iii) X29X30SX31X32X33X34X35X36X37X38X39X40X41X42H (配列番号40)
[ここで、X29はアミノ酸KまたはRであり; X30はアミノ酸AまたはSであり; X31はアミノ酸QまたはKであり; X32はアミノ酸D、SまたはNであり; X33はアミノ酸V、IまたはLであり; X34はアミノ酸G、S、VまたはLであり; X35はアミノ酸T、NまたはHであり; X36はアミノ酸A、NまたはSであり; X37はアミノ酸V、L、NまたはGであり; X38はアミノ酸A、H、GまたはYであり; X39はアミノ酸NまたはTであり; X40はアミノ酸TまたはYであり; X41はアミノ酸YまたはMであり; X42はアミノ酸FまたはHである]からなる群より選択されるアミノ酸配列を含むCDR-L1;
(2) X43X44X45X46X47X48X49 (配列番号41)[ここで、X43はアミノ酸W、Y、KまたはIであり; X44はアミノ酸A、TまたはVであり; X45はアミノ酸SまたはYであり; X46はアミノ酸T、QまたはNであり; X47はアミノ酸R、SまたはLであり; X48はアミノ酸H、I、FまたはEであり; そしてX49はアミノ酸TまたはSである]のアミノ酸配列を含むCDR-L2; ならびに
(3) X50X51X52X53X54X55PX56T (配列番号42)[ここで、X50はアミノ酸QまたはSであり; X51はアミノ酸QまたはHであり; X52はアミノ酸SまたはYであり; X53はアミノ酸S、N、TまたはRであり; X54はアミノ酸S、R、HまたはEであり; X55はアミノ酸Y、W、VまたはLであり; そしてX56はアミノ酸LまたはYである]のアミノ酸配列を含むCDR-L3
を含むヒト化抗体軽鎖可変領域と
を含む、上記抗原結合性ポリペプチド。 - (1) (i) SSYIH (配列番号23);
(ii) DYYIY (配列番号26);
(iii) TYLIE (配列番号29);
(iv) TYWMN (配列番号32); および
(v) NYLIE (配列番号35)
からなる群より選択されるアミノ酸配列を含むCDR-H1;
(2) (i) WIFPGSDITKYNEKFKG (配列番号24);
(ii) YIDPYNGGTKYNQKFKD (配列番号27);
(iii) VINPGTGETKYNENFRA (配列番号30);
(iv) MIHPSDSESRLNQKFID (配列番号33); および
(v) VINPGSGDTKYNENFKG (配列番号36)
からなる群より選択されるアミノ酸配列を含むCDR-H2;ならびに
(3) (i) EDYGISTYSAMDF (配列番号25);
(ii) TSGSSWFPY (配列番号28);
(iii) WDR (配列番号31);
(iv) GNYVWAMDY (配列番号34); および
(v) WNY (配列番号37)
からなる群より選択されるアミノ酸配列を含むCDR-H3
を含むヒト化抗体重鎖可変領域を含む、請求項1に記載の抗原結合性ポリペプチド。 - (1) (i) KASQDVGTAVA (配列番号43);
(ii) RASQSISNNLH (配列番号46);
(iii) RSSQNLVHSNGNTYFH (配列番号49);
(iv) RASKSVSTSGYTYMH (配列番号52); および
(v) RSSQSLLHSNGNTYFH (配列番号55)
からなる群より選択されるアミノ酸配列を含むCDR-L1;
(2) (i) WASTRHT (配列番号44);
(ii) YTYQSIS (配列番号47);
(iii) KVSNRFS (配列番号50); および
(iv) ITSNLES (配列番号53)
からなる群より選択されるアミノ酸配列を含むCDR-L2;ならびに
(3) (i) QQYSSYPLT (配列番号45);
(ii) QQSNRWPLT (配列番号48);
(iii) SQSTHVPYT (配列番号51); および
(iv) QHSRELPYT (配列番号54)
からなる群より選択されるアミノ酸配列を含むCDR-L3
を含むヒト化抗体軽鎖可変領域を含む、請求項2に記載の抗原結合性ポリペプチド。 - (1) 前記CDR-H1がアミノ酸配列SYYIH (配列番号23)を含み;
(2) 前記CDR-H2がアミノ酸配列WIFPGSDITKYNEKFKG (配列番号24)を含み; そして
(3) 前記CDR-H3がアミノ酸配列EDYGISTYSAMDF (配列番号25)を含む、
請求項4に記載の抗原結合性ポリペプチド。 - (1) 前記CDR-L1がアミノ酸配列KASQDVGTAVA (配列番号43)を含み;
(2) 前記CDR-L2がアミノ酸配列WASTRHT (配列番号44)を含み; そして
(3) 前記CDR-L3がアミノ酸配列QQYSSYPLT (配列番号45)を含む、
請求項5に記載の抗原結合性ポリペプチド。 - (1) アミノ酸配列KASQDVGTAVA (配列番号43)を含むCDR-L1;
(2) アミノ酸配列WASTRHT (配列番号44)を含むCDR-L2; および
(3) アミノ酸配列QQYSSYPLT (配列番号45)を含むCDR-L3
を含むヒト化抗体軽鎖可変領域をさらに含む、請求項6に記載の抗原結合性ポリペプチド。 - ヒト化抗体重鎖可変領域が、以下のアミノ酸配列:
(1)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTX1YX2X3X4WVRQAPGQX'1LEWX'2GX5IX6PX7X8X9X10X11X12X13NX14X15FX16X17X'3X'4TX'5TX'6DX'7SX'8STX'9YMELSX'10LRSX'11 DTAVYYCARWX18X19WGQGTLVTVSS (配列番号1);
(2)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTX1YX2X3X4WVRQAPGQX'1LEWX'2GX5IX6PX7X8X9X10X11X12X13NX14X15FX16X17X'3X'4TX'5TX'6DX'7SX'8STX'9YMELSX'10LRSX'11DTAVYYCARX20X21X22X23X24X25X26X27X28WGQGTLVTVSS (配列番号2); および
(3)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTX1YX2X3X4WVRQAPGQX'1LEWX'2GX5IX6PX7X8X9X10X11X12X13NX14X15FX16X17X'3X'4TX'5TX'6DX'7SX'8STX'9YMELSX'10LRSX'11DTAVYYCARX20X21X22X23X24X25X26X27X28AMDFWGQGTLVTVSS (配列番号3);
[ここで、X1はアミノ酸D、S、TまたはNであり; X2はアミノ酸Y、LまたはWであり; X3はアミノ酸IまたはMであり; X4はアミノ酸Y、H、EまたはNであり; X5はアミノ酸Y、M、VまたはWであり; X6はアミノ酸D、N、HまたはFであり; X7はアミノ酸Y、GまたはSであり; X8はアミノ酸N、S、TまたはDであり; X9はアミノ酸G、SまたはDであり; X10はアミノ酸G、D、EまたはIであり; X11はアミノ酸TまたはSであり; X12はアミノ酸KまたはRであり; X13はアミノ酸YまたはLであり; X14はアミノ酸QまたはEであり; X15はアミノ酸KまたはNであり; X16はアミノ酸K、IまたはRであり; X17はアミノ酸G、AまたはDであり; X18はアミノ酸DまたはNであり; X19はアミノ酸RまたはYであり; X20はアミノ酸E、TまたはGであり; X21はアミノ酸D、SまたはNであり; X22はアミノ酸YまたはGであり; X23はアミノ酸G、SまたはVであり; X24はアミノ酸I、SまたはWであり; X25はアミノ酸S、WまたはAであり; X26はアミノ酸T、FまたはMであり; X27はアミノ酸Y、PまたはDであり; X28はアミノ酸SまたはYであり;
さらにここで、X'1はアミノ酸RまたはGであり; X'2はアミノ酸MまたはIであり; X'3はアミノ酸KまたはRであり; X'4はアミノ酸VまたはAであり; X'5はアミノ酸M、LまたはIであり; X'6はアミノ酸VまたはRであり; X'7はアミノ酸TまたはKであり; X'8はアミノ酸A、IまたはTであり; X'9はアミノ酸VまたはAであり; X'10はアミノ酸RまたはSであり; そしてX'11はアミノ酸DまたはEである]
からなる群より選択されるアミノ酸配列を含む、請求項1に記載の抗原結合性ポリペプチド。 - ヒト化抗体重鎖可変領域が、以下のアミノ酸配列:
(a)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQRLEWMGWIFPGSDITKYNEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCAREDYGISTYSAMDFWGQGTLVTVSS (配列番号4);
(b)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYIYWVRQAPGQGLEWIGYIDPYNGGTKYNQKFKDRVTMTRDTSISTAYMELSRLRSDDTAVYYCARTSGSSWFPYWGQGTLVTVSS (配列番号5);
(c)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYYIYWVRQAPGQGLEWIGYIDPYNGGTKYNQKFKDKATLTVDKSTSTAYMELSSLRSEDTAVYYCARTSGSSWFPYWGQGTLVTVSS (配列番号6);
(d)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYLIEWVRQAPGQGLEWMGVINPGTGETKYNENFRARVTMTRDTSISTAYMELSRLRSDDTAVYYCARWDRWGQGTLVTVSS (配列番号7); および
(e)
QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYWMNWVRQAPGQGLEWMGMIHPSDSESRLNQKFIDRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGNYVWAMDYWGQGTLVTVSS (配列番号8)
からなる群より選択されるアミノ酸配列を含む、請求項9に記載の抗原結合性ポリペプチド。 - ヒト化抗体軽鎖可変領域が、以下のアミノ酸配列:
(1)
X'12X'13X'14X'15TQX'16PX'17X'18X'19X'20X'21X'22X'23X'24X'25X'26X'27X'28X'29X'30CX29X30SX31X32X33X34X35X36X37X38WX'31X'32QX'33PX'34X'35X'36PX'37X'38LIX'39X43X44X45X46X47X48X49GX'40PX'41RFSGSGSGTX'42FTLX'43IX'44X'45X'46X'47X'48EDX'49X'50X'51YYCX50X51X52X53 X54X55PX56TFGQGTX'52VEIKR (配列番号9);
(2)
X'12X'13X'14X'15TQX'16PX'17X'18X'19X'20X'21X'22X'23X'24X'25X'26X'27X'28X'29X'30CX29X30SX31X32X33X34X35X36X37X38X39X40X41X42WX'31X'32QX'33PX'34X'35X'36X'37X'38LIX'39X43X44X45X46X47X48X49GX'40PX'41RFSGSGSGTX'42FTLX'43IX'44X'45X'46X'47X'48ED X'49X'50X'51YYCX50X51X52X53X54X55PX56TFGQGTX'52VEIKR (配列番号10); および
(3)
X'12X'13X'14X'15TQX'16PX'17X'18X'19X'20X'21X'22X'23X'24X'25X'26X'27X'28X'29X'30CX29X30SX31X32X33X34X35X36X37X38X39X40X41X42HWX'31X'32QX'33PX'34X'35X'36X'37X'38LIX'39X43X44X45X46X47X48X49GX'40PX'41RFSGSGSGTX'42FTLX'43IX'44X'45X'46X'47X'48EDX'49X'50X'51YYCX50X51X52X53X54X55PX56TFGQGTX'52VEIKR (配列番号11)
[ここで、X29はアミノ酸KまたはRであり; X30はアミノ酸AまたはSであり; X31はアミノ酸QまたはKであり; X32はアミノ酸D、SまたはNであり; X33はアミノ酸V、IまたはLであり; X34はアミノ酸G、S、VまたはLであり; X35はアミノ酸T、NまたはHであり; X36はアミノ酸A、NまたはSであり; X37はアミノ酸V、L、NまたはGであり; X38はアミノ酸A、H、GまたはYであり; X39はアミノ酸NまたはTであり; X40はアミノ酸TまたはYであり; X41はアミノ酸YまたはMであり; X42はアミノ酸FまたはHであり; X43はアミノ酸W、Y、KまたはIであり; X44はアミノ酸A、TまたはVであり; X45はアミノ酸SまたはYであり; X46はアミノ酸T、QまたはNであり; X47はアミノ酸R、SまたはLであり; X48はアミノ酸H、I、FまたはEであり; X49はアミノ酸TまたはSであり; X50はアミノ酸QまたはSであり; X51はアミノ酸QまたはHであり; X52はアミノ酸SまたはYであり; X53はアミノ酸S、N、TまたはRであり; X54はアミノ酸S、R、HまたはEであり; X55はアミノ酸Y、W、VまたはLであり; X56はアミノ酸LまたはYであり;
さらにここで、X'12はアミノ酸DまたはEであり; X'13はアミノ酸IまたはVであり; X'14はアミノ酸VまたはQであり; X'15はアミノ酸MまたはLであり; X'16はアミノ酸SまたはTであり; X'17はアミノ酸S、D、AまたはLであり; X'18はアミノ酸S、TまたはFであり; X'19はアミノ酸LまたはQであり; X'20はアミノ酸A、SまたはPであり; X'21はアミノ酸VまたはAであり; X'22はアミノ酸SまたはTであり; X'23はアミノ酸P、LまたはVであり; X'24はアミノ酸GまたはKであり; X'25はアミノ酸E、QまたはDであり; X'26はアミノ酸R、KまたはPであり; X'27はアミノ酸AまたはVであり; X'28はアミノ酸TまたはSであり; X'29はアミノ酸IまたはLであり; X'30はアミノ酸S、TまたはNであり; X'31はアミノ酸FまたはYであり; X'32はアミノ酸QまたはLであり; X'33はアミノ酸KまたはRであり; X'34はアミノ酸GまたはDであり; X'35はアミノ酸QまたはKであり; X'36はアミノ酸A、SまたはPであり; X'37はアミノ酸K、RまたはQであり; X'38はアミノ酸LまたはRであり; X'39はアミノ酸YまたはKであり; X'40はアミノ酸VまたはIであり; X'41はアミノ酸S、AまたはDであり; X'42はアミノ酸DまたはEであり; X'43はアミノ酸KまたはTであり; X'44はアミノ酸SまたはNであり; X'45はアミノ酸SまたはRであり; X'46はアミノ酸VまたはLであり; X'47はアミノ酸QまたはEであり; X'48はアミノ酸P、AまたはSであり; X'49はアミノ酸F、AまたはVであり; X'50はアミノ酸AまたはGであり; X'51はアミノ酸TまたはVであり; そしてX'52はアミノ酸RまたはKである]
からなる群より選択されるアミノ酸配列を含む、請求項2に記載のポリペプチド。 - ヒト化抗体軽鎖可変領域が、以下のアミノ酸配列:
(a)
DIQLTQSPSFLSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYSSYPLTFGQGTKVEIKR (配列番号12);
(b)
EIVLTQSPDFQSVTPKEKVTITCRASQSISNNLHWYQQKPDQSPKLLIKYTYQSISGVPSRFSGSGSGTDFTLTINSLEAEDAATYYCQQSNRWPLTFGQGTKVEIKR (配列番号13);
(c)
EIVMTQSPATLSVSPGEKATLSCRASQSISNNLHWYQQKPGQAPRLLIYYTYQSISGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQSNRWPLTFGQGTRVEIKR (配列番号14);
(d)
DVVMTQSPLSLPVTLGQPASISCRSSQNLVHSNGNTYFHWFQQRPGQSPRRLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPYTFGQGTKVEIKR (配列番号15);
(e)
DIVMTQTPLSLSVTPGQPASISCRSSQNLVHSNGNTYFHWYLQKPGQSPQLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCSQSTHVPYTFGQGTKVEIKR (配列番号16); および
(f)
DIVMTQSPDSLAVSLGERATINCRASKSVSTSGYTYMHWYQQKPGQPPKLLIYITSNLESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQHSRELPYTFGQGTKVEIKR (配列番号17)
からなる群より選択されるアミノ酸配列を含む、請求項11に記載の抗原結合性ポリペプチド。 - 請求項9〜10のいずれか一項に記載のヒト化重鎖と請求項11〜12のいずれか一項に記載のヒト化軽鎖を含む、LIGHTと特異的に結合する抗原結合性ポリペプチド。
- 抗原結合性ポリペプチドが抗体分子、Fabフラグメント、Fab'フラグメント、F(ab')2フラグメント、およびscFv分子からなる群より選択される、請求項1〜13のいずれか一項に記載の抗原結合性ポリペプチド。
- (a)アミノ酸配列:
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYIHWVRQAPGQRLEWMGWIFPGSDITKYNEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCAREDYGISTYSAMDFWGQGTLVTVSS (配列番号4)
を含む重鎖可変領域と;
(b)アミノ酸配列:
DIQLTQSPSFLSASVGDRVTITCKASQDVGTAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQYSSYPLTFGQGTKVEIKR (配列番号12)
を含む軽鎖可変領域と
を含む、請求項14に記載のポリペプチド。 - 前記抗体分子がヒト重鎖定常領域とヒト軽鎖定常領域を含む、請求項15に記載の抗原結合性ポリペプチド。
- 前記抗体分子がIgG分子である、請求項15〜16のいずれか一項に記載の抗原結合性ポリペプチド。
- (a) 抗原結合性ポリペプチドがscFv分子である; または
(b) 抗原結合性ポリペプチドがscFv HSA融合分子である; または
(c) 抗原結合性ポリペプチドがFab HSA融合分子である、
請求項14に記載の抗原結合性ポリペプチド。 - (a) 請求項18(a)のscFv分子が、(i) NH2-L-VH-X-VK-COOH および(ii) NH2-L-VK-X-VH-COOH[ここで、Lはリーダー配列であり、VHはヒト化抗体重鎖可変領域であり、Xは連結ポリペプチドであり、そしてVKはヒト化抗体軽鎖可変領域である]からなる群より選択される式を有するポリペプチドを含む;
(b) 請求項18(b)のscFv HSA融合分子のscFv部分がHSAのN末端に発現され、そのポリペプチドが、(i) NH2-L-VH-X-VK-HSA-COOH および(ii) NH2-L-VK-X-VH-HSA-COOH[ここで、Lはリーダー配列であり、VHはヒト化抗体重鎖可変領域であり、Xは連結ポリペプチドであり、HSAはヒト血清アルブミンであり、そしてVKはヒト化抗体軽鎖可変領域である]からなる群より選択される式を有する;
(c) 請求項18(b)のscFv HSA融合分子のscFv部分がHSAのC末端に発現され、そのポリペプチドが、(i) NH2-HSA-VH-X-VK-COOH および(ii) NH2-HSA-VK-X-VH-COOH[ここで、Lはリーダー配列であり、VHはヒト化抗体重鎖可変領域であり、Xは連結ポリペプチドであり、HSAはヒト血清アルブミンであり、そしてVKはヒト化抗体軽鎖可変領域である]からなる群より選択される式を有する;
(d) 請求項18(c)の抗原結合性ポリペプチドにおいて、Fab HSA融合分子の重鎖部分がHSAのNまたはC末端に発現され、そのポリペプチドが、(i) NH2-VH-CH1-HSA-COOH および(ii) NH2-HSA-VH-CH1-COOH[ここで、VHはヒト化抗体重鎖可変領域であり、CH1は重鎖定常ドメイン1であり、そしてHSAはヒト血清アルブミンである]からなる群より選択される式を有する;または
(e) 請求項18(c)の抗原結合性ポリペプチドにおいて、Fab HSA融合分子の軽鎖部分がHSAのNまたはC末端に発現され、そのポリペプチドが、(i) NH2-VK-CK-HSA-COOH および(ii) NH2-HSA-VK-CK-COOH[ここで、VKはヒト化抗体軽鎖可変領域であり、CKは軽鎖定常ドメインであり、そしてHSAはヒト血清アルブミンである]からなる群より選択される式を有する;
請求項18に記載の抗原結合性ポリペプチド。 - 治療薬または診断薬にコンジュゲートされた、請求項1〜19のいずれか一項に記載の抗原結合性ポリペプチド。
- (a) 治療薬が細胞毒性薬、放射性標識、免疫調節剤、ホルモン、酵素、オリゴヌクレオチド、光活性治療薬、およびこれらの組合せからなる群より選択される;または
(b) 診断薬が放射性標識、光活性診断薬、超音波増強剤、および非放射性標識からなる群より選択される;
請求項20に記載の抗原結合性ポリペプチド。 - (a) 前記ポリペプチドがLIGHTのアンタゴニストである;または
(b) 前記ポリペプチドがLIGHTのアゴニストではない;
請求項1〜21のいずれか一項に記載の抗原結合性ポリペプチド。 - 前記ポリペプチドが、好ましくは約108M-1〜約1010M-1のKdでLIGHTと結合する、請求項1〜22のいずれか一項に記載の抗原結合性ポリペプチド。
- 請求項1〜23のいずれか一項に記載の抗原結合性ポリペプチドおよび担体を含有する医薬組成物。
- 別の治療薬または診断薬をさらに含む、請求項24に記載の医薬組成物。
- 請求項24または25に記載の組成物を、それを必要とする患者に投与することを含む、疾患または症状を治療または診断する方法であって、前記疾患または症状が、炎症性疾患もしくは症状、免疫性疾患もしくは症状、悪性疾患もしくは症状、自己免疫疾患、炎症性腸疾患(IBD)、慢性閉塞性肺疾患(COPD)、関節炎、関節リウマチ、多発性硬化症、移植拒絶反応、移植片対宿主病(GVHD)、中枢神経系損傷、Th1介在性腸疾患、クローン病、乾癬、白血病、リンパ腫、慢性リンパ球性白血病、アテローム性動脈硬化症、肺癌、大腸癌、および肝炎からなる群より選択される、上記方法。
- 請求項1〜23のいずれか一項に記載の抗原結合性ポリペプチドのいずれか1つをコードする、単離されたポリヌクレオチド。
- 請求項27に記載のポリヌクレオチドに機能的に連結されたプロモーター配列を含む、単離されたポリヌクレオチド。
- 請求項27または28に記載のポリヌクレオチドで形質転換されている、単離された細胞。
- 請求項27または28に記載のポリヌクレオチドによりコードされた抗原結合性ポリペプチドを生産する方法であって、
a) 前記ポリヌクレオチドで形質転換された細胞を培養して、コードされた抗原結合性ポリペプチドを発現させること;および
b) そのように発現させた抗原結合性ポリペプチドを回収すること
を含む、上記方法。
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PCT/US2010/028144 WO2010111180A1 (en) | 2009-03-24 | 2010-03-22 | Humanized antibodies against light and uses thereof |
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US (2) | US8524869B2 (ja) |
EP (1) | EP2411412B1 (ja) |
JP (1) | JP2012521216A (ja) |
CN (1) | CN102428103B (ja) |
AU (1) | AU2010228990A1 (ja) |
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US8524869B2 (en) | 2013-09-03 |
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AU2010228990A1 (en) | 2011-10-27 |
CN102428103A (zh) | 2012-04-25 |
EP2411412A1 (en) | 2012-02-01 |
WO2010111180A1 (en) | 2010-09-30 |
RU2542394C2 (ru) | 2015-02-20 |
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