JP6345800B2 - 抗体−フィノマー複合体 - Google Patents
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- JP6345800B2 JP6345800B2 JP2016558161A JP2016558161A JP6345800B2 JP 6345800 B2 JP6345800 B2 JP 6345800B2 JP 2016558161 A JP2016558161 A JP 2016558161A JP 2016558161 A JP2016558161 A JP 2016558161A JP 6345800 B2 JP6345800 B2 JP 6345800B2
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- 229910052713 technetium Inorganic materials 0.000 description 1
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- AYEKOFBPNLCAJY-UHFFFAOYSA-O thiamine pyrophosphate Chemical compound CC1=C(CCOP(O)(=O)OP(O)(O)=O)SC=[N+]1CC1=CN=C(C)N=C1N AYEKOFBPNLCAJY-UHFFFAOYSA-O 0.000 description 1
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- 241001430294 unidentified retrovirus Species 0.000 description 1
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Description
本願は、2014年3月16日に出願された米国仮出願番号第61/954,437号に基づいて優先権を主張する。この仮出願の内容全体は、引用により本明細書に包含させる。
GVTLFVALYDYKQKGHLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(aka 11L0−C6)(配列番号2);
GVTLFVALYDYSARGQLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(aka 11L5−B06)(配列番号3);
GVTLFVALYDYESVSWSDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(aka 11L9−C09)(配列番号5);
GVTLFVALYDYSSRGVLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(aka 11L10−A05)(配列番号6);
GVTLFVALYDYANHGNRDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(aka 1L3−B9)(配列番号1);
GVTLFVALYDYDKLSALDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(aka 11L6−F03)(配列番号4);および、
GVTLFVALYDYSRKSNLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(aka 11L11−A09)(配列番号7)。
GVTLFVALYDYKQKGHLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号2);
GVTLFVALYDYSARGQLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号3);
GVTLFVALYDYESVSWSDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号5);
GVTLFVALYDYSSRGVLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号6);
GVTLFVALYDYANHGNRDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号1); GVTLFVALYDYDKLSALDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号4);および、
GVTLFVALYDYSRKSNLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号7)、または1−2、2−3、3−4、5−6、6−7、7−8、8−9、9−10、10−15、15−20、20−25もしくは25−30個の保存的、非保存的、または保存的および非保存的アミノ酸置換を有する上記の配列のいずれか、または1−2、2−3、3−4、5−6、6−7、7−8、8−9、9−10、10−15、15−20、20−25もしくは25−30個のアミノ酸欠失もしくは挿入を有する上記の配列のいずれか。
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号12);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号13)。
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号12);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号13)、または上記の重鎖(HC)または軽鎖(LC)配列のいずれかの可変鎖配列内もしくは外に、1−2、2−3、3−4、5−6、6−7、7−8、8−9、9−10、10−15、15−20、20−25、25−30個の保存的、非保存的、または保存的および非保存的アミノ酸置換、またはアミノ酸挿入もしくは欠失を有する配列。
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号15)(aka COVA 801);
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号16);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSGVTLFVALYDYKQKGHLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号17)(aka COVA 802);
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGVTLFVALYDYSARGQLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号18);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号19)(aka COVA 803);
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号20);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSGVTLFVALYDYSARGQLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号21)(aka COVA 804);
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGVTLFVALYDYESVSWSDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号22);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号23)(aka COVA 805);
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号24);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSGVTLFVALYDYESVSWSDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号25)(aka COVA 806);
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGVTLFVALYDYSSRGVLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号26);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号27)(aka COVA 807);
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号28);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSGVTLFVALYDYSSRGVLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号29)(aka COVA 808)、または上記の重鎖(HC)または軽鎖(LC)配列のいずれかの可変鎖配列内もしくは外に、1−2、2−3、3−4、5−6、6−7、7−8、8−9、9−10、10−15、15−20、20−25、25−30個の保存的、非保存的、または保存的および非保存的アミノ酸置換、またはアミノ酸挿入もしくは欠失を有する配列。
用語“フィノマー”は、ヒトFynキナーゼSH3ドメインに基づく、またはそれに由来する、後にモデル化された非免疫グロブリン由来結合(ポリ)ペプチドを意味し、Gebauer and Skerra (2009) Curr Opinion in Chemical Biology 13:245−255に記載されたいわゆる足場(scaffold)である。ヒトFynキナーゼのSH3ドメインは、タンパク質などの異なる標的に対して高い親和性および特異性で結合するタンパク質(フィノマーと称する)を操作するための足場として使用され得る(WO2008/022759、WO2011/023685、Grabulovski D. et al., (2007) J Biol Chem 282, p. 3196−3204, Bertschinger J. et al. (2007) Protein Eng Des Sel, 20, p.57−68および、Schlatter et al. (2012) mAbs, 4(4) p. 497−50)。RTループ(EARTED)領域およびsrcループ(NSSE)領域にそれぞれ下線を付したFyn3配列の配列:
RTループ srcループ
配列番号1:GVTLFVALYDYANHGNRDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ;
配列番号2:GVTLFVALYDYKQKGHLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ;
配列番号3:GVTLFVALYDYSARGQLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ;
配列番号4:GVTLFVALYDYDKLSALDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ;
配列番号5:GVTLFVALYDYESVSWSDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ;
配列番号6:GVTLFVALYDYSSRGVLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ;および、
配列番号7:GVTLFVALYDYSRKSNLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ。
トシリズマブ重鎖配列(配列番号8)、CDRに下線を付す。
トシリズマブ軽鎖配列(配列番号9)、CDRに下線を付す。
MTPGKTSLVSLLLLLSLEAIVKAGITIPRNPGCPNSEDKNFPRTVMVNLNIHNRNTNTNPKRSSDYYNRSTSPWNLHRNEDPERYPSVIWEAKCRHLGCINADGNVDYHMNSVPIQQEILVLRREPPHCPNSFRLEKILVSVGCTCVTPIVHHVA
である。
MLAVGCALLAALLAAPGAALAPRRCPAQEVARGVLTSLPGDSVTLTCPGVEPEDNATVHWVLRKPAAGSHPSRWAGMGRRLLLRSVQLHDSGNYSCYRAGRPAGTVHLLVDVPPEEPQLSCFRKSPLSNVVCEWGPRSTPSLTTKAVLLVRKFQNSPAEDFQEPCQYSQESQKFSCQLAVPEGDSSFYIVSMCVASSVGSKFSKTQTFQGCGILQPDPPANITVTAVARNPRWLSVTWQDPHSWNSSFYRLRFELRYRAERSKTFTTWMVKDLQHHCVIHDAWSGLRHVVQLRAQEEFGQGEWSEWSPEAMGTPWTESRSPPAENEVSTPMQLTTNKDDDNILFRDSANATSLPVQDSSSVPLPTFLVAGGSLAFGTLLCIAIVLRFKKTWKLRALKEGKTSMHPPYSLGQLVPERPRPTPVLVPLISPPVSPSSLGSDNTSSHNRPDARDPRSPYDISNTDYFFPR
である。
本発明のFyn SH3由来ポリペプチドは、モノクローナル溶解物ELISAによって決定されるように、IL−17Aに結合する。
IL−17aに結合するフィノマーの製造方法は、PCT/EP2013/069481に記載されている。要約すれば、IL−17Aに特異的なFyn−SH3由来結合タンパク質を、組み換えIL−17A(R&D Systems)を抗原として用い、標準的ファージディスプレイを選択技術(Grabulovski D. et al., (2007) J Biol Chem 282, p. 3196−3204, Viti, F. et al. (2000) Methods Enzymol. 326, 480−505)として用いて単離した。本発明のFyn SH3由来ポリペプチドである、n−src−ループ配列“STHEYE”を含む1L3−B09は、選択プロセス中に富化した。1L3−B09はIL−17Aに結合し、グリコシル化IL−17Aを非グリコシル化IL−17Aと同様によく阻害することが見出された。より高い親和性を有するFyn SH3由来IL−17A結合剤を得るために、1L3−B09を、親和性成熟のためのテンプレートとして用いた。n−src−ループ配列“STHEYE”は、一定に保たれ、無作為化RT−ループレパートリー((X1)(X2)(X3)(X4)(X5)(X6)として示される6個のアミノ酸残基)と組み合わされた。親和性成熟ライブラリ作製のプロセスは、無作為化RT−ループを有する天然のライブラリのクローニングについて記載したものと本質的に同じであった(Schlatterら、(2012) mAbs, 4(4) p. 497−50中の“library 0”)。
7つの代表的なIL−17A結合フィノマー配列(配列番号1−7)の配列は以下の通りである:
配列番号1(1L3−B9):GVTLFVALYDYANHGNRDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ;
配列番号2(11L0−C06):
GVTLFVALYDYKQKGHLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ;
配列番号3(11L5−B06):GVTLFVALYDYSARGQLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ;
配列番号4(11L6−F03):GVTLFVALYDYDKLSALDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ;
配列番号5(11L9−C09):GVTLFVALYDYESVSWSDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ;
配列番号6(11L10−A05):GVTLFVALYDYSSRGVLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ;および
配列番号7(11L11−A09):GVTLFVALYDYSRKSNLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ。
タンパク質発現および精製
FynomAbの4つの別個のロットを調製し、以下に記載の試験にて評価した。材料の2つのロットは、一過性トランスフェクトしたCHO細胞に由来した。実験室で作製した材料のロットは、以下に記載の通り、ロンザ発現ベクターを用いる安定なCHOプールに由来した。
Actemra(トシリズマブ)重鎖配列(配列番号8)(CDRを太字で示す)
Actemra(トシリズマブ)軽鎖配列(配列番号9)(CDRを太字で示す)
SDS−PAGE分析
SDS−PAGE分析を、各FynomAbおよびトシリズマブの3つの別個のロットで行った。5μgの各タンパク質を、トリス−グリシンSDSサンプルおよび泳動バッファーを用いて4−20%トリス−グリシン勾配ゲル上で、還元および非還元の両方の条件下で、電気泳動した。ゲルを、クマシーブリリアントブルー(SimplyBlue SafeStain, Invitrogen)で一晩染色し、蒸留水で十分に透明になるまで脱染色した。結果を図1(一過性のCHO生成物のSDS−PAGE分析)、図2および3(マウスPK試験のために作製された安定なCHO生成物のSDS−PAGE分析)に示す。
HPLC−SEC分析
3つの別個のロットのFynomAbを、HPLC−SEC分析法により評価した。1ロットの一過性のCHO生成物、および他の2つのロットを、安定にトランスフェクトされたCHO細胞株から内生的に産生した。10μgの各FynomAbタンパク質を、1mL/分の流速で移動相としてPBSを用いて、Zenix−C SEC−300カラム(Sepax Technologies)上に、注入した。A280での吸光度をモニターした。フィノマーの存在は、おそらく、固相とフィノマーとの間の二次的相互作用により、Actemraと比べて種々の程度にFynomAbの溶出を遅らせた。可溶性の凝集が、FynomAbの主ピークの前に溶出するピークとして観察され、重鎖融合コンストラクトCOVA801、COVA803、COVA805およびCOVA807において最も明白である。
ヒトIL−17AおよびヒトIL−6Rに対する親和性測定
ヒトIL−17AおよびヒトIL−6RへのFynomAb結合の親和性および動態パラメーターを決定するために、抗ヒト抗体を、アミンカップリングでGLMチップ上に結合させた。その後、COVA801−808 FynomAbまたは対照抗体は、リガンドとして捕捉され、IL−17AまたはIL−6Rのいずれかを分析物として流した。PBSTを移動相として使用し、再生を100mM HClの15秒間注入によって達成した。セクキヌマブをIL−17A結合の陽性対照として、およびIL−6R結合の陰性対照として用いた。トシリズマブおよび/またはアクテムラを、IL−6R結合の陽性対照として、およびIL−17−A結合の陰性対照として用いた。
可変軽鎖(配列番号33)
シグナル配列(下線)、可変ドメイン(kappa)(太字)
可変重鎖(配列番号34)
シグナル配列(下線)、可変ドメイン(kappa)(太字)
トシリズマブおよび/またはアクテムラを、IL−6R結合の陽性対照として、およびIL−17−A結合の陰性対照として用いた。
COVA801−808 FynomAbによるIL−17A結合ならびにセクキヌマブ(陽性対照および対照)およびトシリズマブまたはアクテムラ(陰性対照)についての代表的センサーグラムを図4に示す。各FynomAbおよびセクキヌマブの複数ロットについての複数の試験からの動態結合データの概要を表4にまとめた。示したセンサーグラムは、COVA801−808、別個のロットのトシリズマブ(toc)、市販のActemra、およびセクキヌマブ(sec)のものである。
COVA801−808FynomAbによるIL−6R結合、ならびにトシリズマブおよびアクテムラ(陽性対照および対照)およびセクキヌマブ(陰性対照)についての代表的センサーグラムを図6に示す。SPRによるFynomAb/IL6R相互作用の評価は、顕著に再現性があり、該相互作用を、図6に示す古典的ラングミュアフィッティングを用いて容易にモデル化することができる。示されるセンサーグラムはCOVA801−808、トシリズマブ(toc)の別個のロット、市販のActemra、およびセクキヌマブ(sec)についてのものである。各FynomAbの複数ロットおよびトシリズマブについての複数試験からの動態結合データのまとめを、表5にまとめる。これらのデータは、軽鎖または重鎖のいずれかのC末端におけるフィノマーの存在が、親抗体へのIL−6Rの結合に影響を及ぼさないことを示す。すべてのFynomAbは、互いに、および親抗体トシリズマブと顕著に類似した結合動態を示す。
HT−29 IL−17A阻害アッセイ
ヒトIL−17Aに対するCOVA801−808FynomAbの生物活性を評価するために、HT−29細胞(ATCC、#HTB−38)を、100nM〜6pMの範囲の種々の濃度の各FynomAbの存在下IL−17A(1.9nM)で刺激した。セクキヌマブを、IL−17A機能の遮断についての陽性対照として用いた。各条件について、20,000個の生細胞を添加し、37℃、5%CO2にて、48時間、平底96ウェルプレート中でインキュベートした。各条件はデュプリケートで試験した。
HEK−Blue(商標)IL−6R阻害アッセイ
COVA801−808構築物において抗IL−6R部分の生物活性を評価するために、HEK Blue IL−6細胞(Invivogen、hkb−il6)を、500nM〜0.2nMの範囲の種々の濃度のFynomAbの存在下、IL−6(15pM)で刺激した。阻害剤を、IL−6の添加前に30分間、細胞と共に予めインキュベートした。対照として、培地のみ、またはIL−6(15pM)を含む培地を使用した。また、トシリズマブまたはアクテムラを、IL−6R遮断についての陽性対照として用いた。各サンプルについて、50,000個の生細胞を添加し、37℃、5%CO2にて、96ウェルプレートのウェル中で20−24時間インキュベートした。各条件をトリプリケートで試験した。
血清安定性アッセイ
ヒト血清中の各FynomAbの安定性を評価するために、COVA801−808FynomAbをそれぞれ、90%ヒト血清(Sigma #H4522)中で、6日間、37℃にて、10μg/mlの濃度でインキュベートし、その後、サンドイッチELISAにより、FynomAbが、IL−17AおよびIL−6Rの両方への結合能を保持しているかどうかを評価した。サンドイッチELISAを用いて、PBSまたはヒト血清中でのインキュベーション後のFynomAbの同時結合を評価した。サンドイッチELISAのセットアップを図13に示す。
IL−6RおよびIL−17Aの同時結合
データは、COVA801−808 FynomAbのすべてが、同時にヒトIL−17AおよびヒトIL−6Rに結合可能であったことを示した。
IL−17AおよびIL−6Rの両方の存在下での二重特異性FynomAbの機能的活性
図15および16のデータは、FynomAbがヒトIL−17AおよびヒトIL−6Rに同時に結合し得ることを示す。しかしながら、FynomAbのmAb部分によるIL−6Rの結合が、そのリガンドであるIL−17Aを結合し、阻害するフィノマーの能力に影響を与えるかどうかは明らかではない。この問題を解くために、本発明者らは、可溶性IL−6Rの存在下でHT−29 IL−17A 機能的アッセイを行い、FynomAbによるIL−6Rの結合が、IL−17Aに対するそれらの結合および機能的活性を低減するかどうかを確認した。HT−29 IL−17A アッセイを、過剰量の可溶性IL−6Rの存在下および非存在下の両方で行ったこと以外は、上記のとおりに正確に行った。要約すれば、滴定量のCOVA804またはCOVA806を、過剰量の可溶性IL−6R(20nM)の存在下または非存在下で、IL−17A(1.9nM)と混合し、その後、これらの混合物をIL−17A応答性細胞株HT−29に添加した。その後、48時間後に、GROαの放出を、上記のとおりELISAにより測定した。セクキヌマブを、IL−17A遮断のための陽性対照として用いた。
フィノマーポリペプチドは、グリコシル化ヒトIL−17Aに高親和性を有して結合する
本実施例は、IL−17A結合フィノマーポリペプチドの発現収量ならびにサイズ排除クロマトグラフィーおよび表面プラズモン共鳴試験によるこれらのポリペプチドの特徴付けを示す。
親和性測定を、BIAcore T200計器(GE Healthcare)を用いて行った。グリコシル化IL−17A(HEK EBNA細胞内で所内で製造)と単量体IL−17A結合フィノマーポリペプチドとの相互作用分析のために、シリーズS CM5チップ(GE Healthcare)を、アミンカップリングキット(GE healthcare)を用いて固定化された2000RU IL−17Aと共に用いた。泳動バッファーは、0.05%トゥイーン20を含むPBSであった。相互作用を、30μl/分の流速および異なる濃度のIL−17A結合フィノマーポリペプチドの注入で測定した。相互作用の全ての動態データを、BIAcore T200評価ソフトウェアを用いて評価した。
結合特性を、選択されたIL−17A結合フィノマーポリペプチドについての以下の解離定数(KD)を明らかにするBIAcoreチップ上のリアルタイム相互作用分析によって分析した。
フィノマーポリペプチドは、グリコシル化IL−17Aを阻害する。
クローン1L3−B09(配列番号1)およびIL−17Aに最も高い結合親和性を有する5つのフィノマーポリペプチド(11L0−C06、11L5−B06、11L6−F03、11L9−C09、11L10−A05、配列番号2−6)を、それらのIL−17A阻害能力について試験した。示したIL−17A結合フィノマーポリペプチドの阻害活性を、種々の濃度のIL−17A結合フィノマーポリペプチドの存在下または非存在下で、ヒト皮膚線維芽細胞を組み換えグリコシル化IL−17A(HEK EBNA細胞内で所内で製造)および組み換えTNFα(Thermo Fisher Scientific)で刺激することにより試験した。細胞培養上清を、刺激の24時間後に採取し、該上清中のIL−6濃度をELISAにより決定した。結果は、IL−17A結合フィノマーポリペプチドがグリコシル化IL−17Aを特異的に阻害できたことを示している。
エンドトキシン除去のために、タンパク質溶液をアクロディスクのムスタングEメンブレン(VWR)で3回濾過した。濾過後、タ阻害剤IL−17A結合フィノマーポリペプチドを含むンパク質溶液のエンドトキシンレベルは、Limulus amebocyte lysate(LAL)テスト(PYROGENT Single test Gel Clot LAL アッセイ(Lonza))によって決定される通り、0.1EU/ml未満であった。約3900個の正常ヒト皮膚線維芽細胞 (PromoCell、NHDF−c、C12300)を含む100μlの細胞懸濁液を、1ウェル当たりに入れ(96ウェルプレート、TPPまたはコーニング)、37℃にて24時間培養した(培地:線維芽細胞増殖培地C−23010、PromoCell)。上清を吸引して除き、異なる濃度のIL−17A結合フィノマーポリペプチドとIL−17AおよびTNFαを含む培地(それぞれ終濃度1ng/mlおよび50pg/ml)とを混合後、1ウェル当たりに100μlの対応する溶液を添加した。対照として、PBSをIL−17A/TNFαを含む培地(陽性対照=“阻害剤なし”)および単一のサイトカインIL−17AまたはTNFαのみを含む培地(後者は、“TNFα対照”ウェル)と混合した。陰性対照として、PBSを培地のみと混合した。比較のために、アッセイを非グリコシル化IL−17A(R&D Systems)を同じ条件で用いて行った。37℃にて24時間インキュベーション後、上清をELISAに入れ、IL−6濃度を決定するために、IL−6ELISAキットを製造者の取扱説明書に従って用いて決定した(IL−6 ELISA kit、R&D Systems)。阻害割合をプロットし、IC50値をPrism 5ソフトウェアを用いて計算した。IL−17A阻害の割合を以下の式で求めた:
正常ヒト皮膚線維芽細胞を、IL−17A/TNFαおよび異なる濃度の示したIL−17A結合 フィノマーポリペプチドと共にインキュベートした。フィノマーポリペプチドは、グリコシル化IL−17Aを阻害することが明らかとなった。IC50値を表11に示す。
実施例13におけるデータは、WO2014/044758(PCT/EP2013/069481)に記載されている。
方法
フィノマー11L11−A09を、IL−17Aを阻害する能力について試験した。試験の条件は、他のフィノマーポリペプチドについて上記のものと同じであった。
正常ヒト皮膚線維芽細胞をIL−17A/TNFαおよび異なる濃度のフィノマーポリペプチド11L11−A09と共にインキュベートした。11L11−A09は、グリコシル化IL−17Aを66nMのIC50値で阻害することが明らかとなった(表12)。
C57BL/6マウスにおける薬物動態学的試験
COVA801−808 FynomAbのランク付けをするために、8つすべてのFynomAbの薬物動態学プロファイルをC57BL/6マウスにおいて評価した。
COVA801、COVA802、COVA803、COVA804、COVA805、COVA806、COVA807、COVA808で示されるFynomAbおよびトシリズマブの薬物動態特性の決定を、単回の眼窩後部注射後の異なる時点で採取されたマウスの血清中の濃度をELISAにより測定することにより行った。6週齢から8週齢の雌のC56BL/6マウス(Charles River、USA)に、個々の重量に基づいて10mg/kgの用量で静脈内注射した。各群は5匹のマウスから構成された。血液を、眼窩後部注射後30分、6時間、24時間、48時間、96時間、144時間、192時間、240時間、および288時間後に、静脈(尾静脈)から採取した。血液をclotting activator microvettes血液チューブ(CB300、Sarstedt)に集め、血清を10,000rpmで10分間遠心して調製した。血清を分析まで−20℃で貯蔵した。
試験したFynomAbおよびトシリズマブの血清濃度を、固定化されたヒトIL−17アルファ(Cell signaling Technologies、8928BF)および組み換えヒトIL−6Rアルファ(R&D Systems、Inc。227−SR/CF)を用いてそれぞれ高結合Nunc ELISAプレート(Thermo Scientific、456537)上でELISAにより決定した。両方とも、PBS中で一晩、4℃にて、5mg/mlでコーティングされた。プレートをPBS+0.05%トゥイーン(PBST)で洗浄し、PBST中で1%に希釈したBSA(Fischer Scientific、37525)で2時間ブロッキングした。各マウスおよび時間点について、血清の800倍、4,000倍および20,000倍希釈液を、ブロッカー希釈液(blocker diluent)に調製した。各FynomAbの対応する標準液を、2倍滴定値(4nM−0.03125nM)の4nMから開始するブロッカー希釈液での連続希釈液を作成して調製した。50μlの標準液(デュプリケート)および血清希釈液(トリプリケート)をプレートに添加し、RTにて1時間インキュベートした。プレートをPBSTで3回洗浄し、50μlの、1:5,000に希釈したペルオキシダーゼ−AffiniPureヤギ抗ヒトIgG(H+L)(Jackson ImmunoResearch、109−035−003)と共にRTにて1時間インキュベートした。プレートをPBSTで3回洗浄した。50μlのTMB液体基質(Sigma−Aldrich Inc.、T0440−1L)を全てのウェルに添加した。プレートを3分間インキュベートし、50μlの停止液で反応停止させた。吸光度を405nMで記録した(PHERAstar Plus)。
各マウスの血清濃度を、標準曲線および4パラメーターフィット分析(X値対数、Y値線形)を用いて計算した。各時間点およびマウスについて、トリプリケートの平均血清濃度(nM)に対応する希釈率を掛けて、ug/ml濃度に変換した。標準偏差(STDEV)および%CV(変動係数)を、各時間点および3つの希釈率について計算した。最低%CVおよび標準曲線の直線部分を示す最高値の1つの値を、各時間点の値として選択した。これらの値を薬物動態パラメーター分析に供した(Phoenix 64, WinNonlin 6.3)。半減期(時間)、曲線下面積(AUC;h*ug/ml)、分布容積(Vz;ml)およびクリアランス(Cl;ml/時)を、非コンパートメントPK分析、モデルタイプ:血漿(200−202)、計算方法:線形台形 線形補間式を用いて計算した。各マウスについて標準曲線は、均一な重量計算およびベストフィットラムダZ計算に基づき、回帰に少なくとも3データ点を必要とし、Cmaxは含まれなかった。
各FynomAbおよびトシリズマブの血清濃度および薬物動態パラメーターを、表13−21に示す。IL−6RおよびIL−17A ELISAの両方を、血清濃度およびPKパラメーターを計算するために用いたが、IL−6Rデータのみを本明細書に示す。しかしながら、同様の血清濃度およびPKパラメーターをIL−17A ELISAデータから決定した。したがって、2つの異なるELISA法についての血清濃度対時間曲線は、各FynomAbについて顕著によく似ている(図22−25参照)。このデータは、FynomAbがインビボで安定であり、そのIL−6RおよびIL−17Aの両方に結合する能力が保持されていることを示す。一般に、この薬物動態学試験の結果は、同じマウス系統における前のデータと一致している。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。同様の血清濃度およびPKパラメーターを、IL−17A ELISAから決定した。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。同様の血清濃度およびPKパラメーターを、IL−17A ELISAから決定した。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。同様の血清濃度およびPKパラメーターを、IL−17A ELISAから決定した。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。同様の血清濃度およびPKパラメーターを、IL−17A ELISAから決定した。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。同様の血清濃度およびPKパラメーターを、IL−17A ELISAから決定した。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。同様の血清濃度およびPKパラメーターを、IL−17A ELISAから決定した。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。同様の血清濃度およびPKパラメーターを、IL−17A ELISAから決定した。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。同様の血清濃度およびPKパラメーターを、IL−17A ELISAから決定した。
IL6RまたはIL−17A ELISAのいずれかにより決定されるように、平均血清濃度+/−標準偏差(STDEV)は、COVA801およびCOVA802とコンパレータとしてのトシリズマブ(IL−6R ELISA)について示す。
IL6RまたはIL−17A ELISAのいずれかにより決定されるように、平均血清濃度+/−標準偏差(STDEV)は、COVA803およびCOVA804とコンパレータとしてのトシリズマブ(IL−6R ELISA)について示す。
IL6RまたはIL−17A ELISAのいずれかにより決定されるように、平均血清濃度+/−標準偏差(STDEV)は、COVA805およびCOVA806とコンパレータとしてのトシリズマブ(IL−6R ELISA)について示す。
IL6RまたはIL−17A ELISAのいずれかにより決定されるように、平均血清濃度+/−標準偏差(STDEV)は、COVA807およびCOVA808とコンパレータとしてのトシリズマブ(IL−6R ELISA)について示す。
カニクイザルにおける薬物動態試験
投与、採血
COVA801、COVA802、COVA803、COVA804、COVA806、COVA808で示されるFynomAbおよびトシリズマブの薬物動態特性の決定を、単回の静脈内注射後の異なる時間点で採取した、カニクイザル血清中のELISAによる濃度測定により行った。オスおよびメスのサルに、個々の重量に基づいて、5mg/kg用量を静脈内注射した。各群は4匹のサルで構成された。静脈内注射後5分、30分、2時間、6時間、24時間、3日、4日、5日、7日、10日、13日、17日、22日および27日に採血した。血液を任意の抗凝固剤を含まないチューブに集め、血清を10,000rpmで1−2分間遠心することにより調製した。血清を分析まで−80℃にて貯蔵した。
試験FynomAbおよびトシリズマブの血清濃度を、マウスPK試験について上記のものと同じプロトコルにしたがってELISAにより決定した。
各サルの血清濃度を標準曲線および4パラメーターフィット分析(X値対数、Y値線形)を用いて計算した。各時間点およびサルについて、デュプリケートの平均血清濃度(nM)に対応する希釈率を掛けて、ug/ml濃度に変換した。STDEVおよび%CVを、各時間点および3つの希釈率について計算した。最低%CVおよび標準曲線の直線部分を示す最高値の1つの値を、各時間点の値として選択した。これらの値を薬物動態パラメーター分析に供した(Phoenix 64, WinNonlin 6.3)。半減期(時間)、曲線下面積(AUC;h*ug/ml)、分布容積(Vz;ml)およびクリアランス(Cl;ml/時)を、非コンパートメントPK分析、モデルタイプ:血漿(200−202)、計算方法:線形台形 線形補間式を用いて計算した。各サルについて標準曲線は、均一な重量計算およびベストフィットラムダZ計算に基づき、回帰に少なくとも3データ点を必要とし、Cmaxは含まれなかった。
各FynomAbおよびトシリズマブの血清濃度および薬物動態パラメーターを、表22−28に示す。IL−6RおよびIL−17A ELISAの両方を、血清濃度およびPKパラメーターを計算するために用いたが、IL−6Rデータのみを本明細書に示す。しかしながら、同様の血清濃度およびPKパラメーターをIL−17A ELISAデータから決定した。したがって、2つの異なるELISA法についての血清濃度対時間曲線は、各FynomAbについて顕著によく似ている(図26−29参照)。このデータは、FynomAbがインビボで安定であり、そのIL−6RおよびIL−17Aの両方に結合する能力が保持されていることを示す。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。同様の血清濃度およびPKパラメーターを、IL−17A ELISAから決定した。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。同様の血清濃度およびPKパラメーターを、IL−17A ELISAから決定した。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。同様の血清濃度およびPKパラメーターを、IL−17A ELISAから決定した。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。同様の血清濃度およびPKパラメーターを、IL−17A ELISAから決定した。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。同様の血清濃度およびPKパラメーターを、IL−17A ELISAから決定した。
A)ELISAにより決定された各時間点での血清濃度(IL−6R)を示す。平均値および標準偏差(STDEV)も示される。(B)半減期、分布容積(Vz)、クリアランス(Cl)および曲線下面積(AUC)などの、重要な薬物動態パラメーターのまとめ。パラメーターは、Aに示される血清濃度を用いて計算した。同様の血清濃度およびPKパラメーターを、IL−17A ELISAから決定した。
本明細書に記載されるデータは、8つ全てのFynomAbが結合して、機能的にIL−17AおよびIL−6Rの両方を遮断し得ることを示している。8つ全てのコンストラクトは、IL−17AおよびIL−6Rについて顕著に類似した親和性を有し、細胞ベースのアッセイにおいて類似の機能的活性を有し、そして軽鎖フィノマー融合体(FynomAbは、COVA802、COVA804、COVA806およびCOVA808として示す)は、良好なSECプロファイルを有し、かつ凝集する傾向が少なかった。
Claims (23)
- 以下の配列:GVTLFVALYDYKQKGHLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(aka 11L0−C6)(配列番号2);GVTLFVALYDYSARGQLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(aka 11L5−B06)(配列番号3);GVTLFVALYDYESVSWSDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(aka 11L9−C09)(配列番号5);GVTLFVALYDYSSRGVLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(aka 11L10−A05)(配列番号6);GVTLFVALYDYANHGNRDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(aka 1L3−B9)(配列番号1);GVTLFVALYDYDKLSALDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(aka 11L6−F03)(配列番号4);および、GVTLFVALYDYSRKSNLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(aka 11L11−A09)(配列番号7)
のいずれかの12位〜17位部分のモチーフ並びに31位〜36位のモチーフを維持し、かつ当該配列と少なくとも90%の同一性を有し、インターロイキン−17a(IL−17a)に結合するフィノマー配列が、インターロイキン−6受容体(IL−6R)に結合する抗体またはIL−6R結合能を有するその部分配列と複合体を形成している、
IL−17aおよびIL−6Rの両方に結合し、両方の活性を阻害する二重特異性融合ポリペプチド。 - フィノマー配列が、該配列のアミノ酸位置28−42のQILSTHEYEDWWEARモチーフを含む、請求項1に記載の融合ポリペプチド。
- グリコシル化IL−17aに結合して、IL−17受容体機能またはシグナル伝達を阻害する、請求項1または2に記載の融合ポリペプチド。
- フィノマー配列がグリコシル化IL−17aに対して1から200nMの結合親和性(Kd)を有する、請求項3記載の融合ポリペプチド。
- フィノマー配列が配列番号1のポリペプチドのグリコシル化IL−17aに対する結合親和性よりも高い、グリコシル化IL−17aに対する結合親和性(KdまたはKD)を有する、請求項1〜4のいずれかに記載の融合ポリペプチド。
- フィノマー配列が配列番号1〜7いずれかに記載の配列と少なくとも95%同一性を有する配列である、請求項1〜5いずれかに記載の融合ポリペプチド。
- フィノマー配列が配列番号1〜7いずれかに記載の配列を有する、請求項6に記載の融合ポリペプチド。
- フィノマー配列が、IL−6Rに結合する抗体の重鎖もしくは軽鎖配列またはIL−6R結合能を有するその部分配列と複合体を形成する、請求項1〜7いずれかに記載の融合ポリペプチド。
- フィノマー配列が、IL−6Rに結合する抗体の重鎖配列またはIL−6R結合能を有するその部分配列のアミノ末端またはカルボキシル末端と複合体を形成する、請求項8に記載の融合ポリペプチド。
- フィノマー配列が、IL−6Rに結合する抗体の軽鎖配列またはIL−6R結合能を有するその部分配列のアミノ末端またはカルボキシル末端と複合体を形成する、請求項8に記載の融合ポリペプチド。
- フィノマー配列がリンカーを介してIL−6Rに結合する抗体の重鎖もしくは軽鎖配列またはIL−6R結合能を有するその部分配列と複合体を形成する、請求項1〜10のいずれかに記載の融合ポリペプチド。
- 融合ポリペプチドが、同時にIL−17aおよびIL−6Rに結合する、請求項1〜11のいずれかに記載の融合ポリペプチド。
- IL−6Rに結合する抗体またはIL−6R結合能を有するその部分配列が、以下の可変領域CDR1−3を有する重鎖(HC):SDHAWS;YISYSGITTYNPSLKS;および、SLARTTAMDY、および以下の可変領域CDR1−3を有する軽鎖(LC):RASQDISSYLN;YTSRLHS;および、QQGNTLPYTを含む、請求項1〜12いずれかに記載の融合ポリペプチド。
- IL−6Rに結合する抗体が、以下の配列:
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号12);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号13)
それぞれの配列と少なくとも90%の同一性を有する重鎖(HC)および(LC)を含む、請求項13に記載の融合ポリペプチド。 - IL−6Rに結合する抗体が配列番号12および13に記載のアミノ酸配列を含む、請求項14記載の融合ポリペプチド。
- 以下の重鎖(HC)および軽鎖(LC)配列:
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGVTLFVALYDYKQKGHLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号14);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号15);
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号16);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSGVTLFVALYDYKQKGHLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号17);
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGVTLFVALYDYSARGQLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号18);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号19);
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号20);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSGVTLFVALYDYSARGQLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号21);
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGVTLFVALYDYESVSWSDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号22);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号23);
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号24);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSGVTLFVALYDYESVSWSDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号25);
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGGGGGSGGGGSGGGGSGVTLFVALYDYSSRGVLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号26);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号27);
(HC)QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTMLRDTSKNQFSLRLSSVTAADTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG(配列番号28);
(LC)DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGECGGGGSGGGGSGGGGSGVTLFVALYDYSSRGVLDLSFHKGEKFQILSTHEYEDWWEARSLTTGETGYIPSNYVAPVDSIQ(配列番号29)、
において、配列番号14と少なくとも90%の同一性を有する重鎖と配列番号15と少なくとも90%の同一性を有する軽鎖、
配列番号16と少なくとも90%の同一性を有する重鎖と配列番号17と少なくとも90%の同一性を有する軽鎖、
配列番号18と少なくとも90%の同一性を有する重鎖と配列番号19と少なくとも90%の同一性を有する軽鎖、
配列番号20と少なくとも90%の同一性を有する重鎖と配列番号21と少なくとも90%の同一性を有する軽鎖、
配列番号22と少なくとも90%の同一性を有する重鎖と配列番号23と少なくとも90%の同一性を有する軽鎖、
配列番号24と少なくとも90%の同一性を有する重鎖と配列番号25と少なくとも90%の同一性を有する軽鎖、
配列番号26と少なくとも90%の同一性を有する重鎖と配列番号27と少なくとも90%の同一性を有する軽鎖、
配列番号28と少なくとも90%の同一性を有する重鎖と配列番号29と少なくとも90%の同一性を有する軽鎖、
のいずれかの組み合わせを含む、請求項13記載の融合ポリペプチド。 - 配列番号14と15、配列番号16と17、配列番号18と19、配列番号20と21、配列番号22と23、配列番号24と25、配列番号26と27、および配列番号28と29のいずれかの組み合わせを含む、請求項16記載の融合ポリペプチド。
- 融合ポリペプチドが、ヒトのIL−17aまたはIL−6Rに結合する、請求項1〜17のいずれかに記載の融合ポリペプチド。
- ポリペプチドが単離または精製されている、請求項1〜18のいずれかに記載の融合ポリペプチド。
- 請求項1〜19のいずれかに記載の融合ポリペプチドを含む医薬組成物。
- 自己免疫疾患または障害の処置のための請求項20に記載の医薬組成物。
- 自己免疫疾患または障害が、筋肉、骨格、神経系、結合組織、内分泌系、皮膚、気道もしくは肺系、胃腸系、眼科系、または循環器系に影響を与えるものである、請求項21に記載の医薬組成物。
- 自己免疫疾患または障害が、関節炎、関節リウマチ、乾癬、およびブドウ膜炎からなる群より選択される、請求項21に記載の医薬組成物。
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