JP7166923B2 - 標的療法剤およびその使用 - Google Patents
標的療法剤およびその使用 Download PDFInfo
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- JP7166923B2 JP7166923B2 JP2018541289A JP2018541289A JP7166923B2 JP 7166923 B2 JP7166923 B2 JP 7166923B2 JP 2018541289 A JP2018541289 A JP 2018541289A JP 2018541289 A JP2018541289 A JP 2018541289A JP 7166923 B2 JP7166923 B2 JP 7166923B2
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Description
本出願は、そのすべての全内容が本明細書に援用される、2016年2月5日出願の米国仮特許出願第62/291,769号;2016年5月13日出願の第62/335,880号;2016年10月24日出願の第62/411,805号;2016年2月5日出願の第62/291,772号;2016年2月5日出願の第62/291,774号;2016年5月13日出願の第62/335,965号;2016年2月5日出願の第62/291,776号;2016年5月13日出願の第62/335,968号;2016年5月13日出願の第62/335,979号;2016年5月13日出願の第62/336,030号、2016年6月23日出願の第62/353,607号;および2016年2月5日出願の第62/291,779号の恩典を請求する。
本発明は、部分的に、標的療法剤および癌などの疾患の治療におけるその使用に関する。
本明細書と共に電子提出されたテキストファイルの内容は、その全体が本明細書に援用される:配列表のコンピュータ読み取り可能フォーマットコピー(ファイル名:ORN-021PC_Sequence_listing;記録日:2017年2月1日;ファイルサイズ:231KB)。
多様な態様において、本キメラタンパク質は、免疫チェックポイントタンパク質に対して向けられる1つの標的化部分を有する。多様な態様において、免疫チェックポイントタンパク質は、プログラム細胞死タンパク質1(PD-1)、PD-1リガンド1(PD-L1;B7-H1およびCD274としても公知である)、およびPD-1リガンド2(PD-L2;B7-DCおよびCD273としても公知である)より選択される。
QVQLVQSGVEVKKPGASVKVSCKASGYTFTNYYMYWVRQAPGQGLEWMGGINPSNGGTNF NEKFKNRVTLTTDSSTTTAYMELKSLQFDDTAVYYCARRDYRFDMGFDYWGQGTTVTVSS ASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSV FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTY RVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTK NQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEG NVFSCSVMHEALHNHYTQKSLSLSLGK (配列番号1)
のアミノ酸配列を含む重鎖;および/または:
EIVLTQSPATLSLSPGERATLSCRASKGVSTSGYSYLHWYQQKPGQAPRLLIYLASYLES GVPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSRDLPLTFGGGTKVEIKRTVAAPSVF IFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLS STLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (配列番号2)
のアミノ酸配列を含む軽鎖を含む。
QVQLVESGGG VVQPGRSLRL DCKASGITFS NSGMHWVRQA PGKGLEWVAV IWYDGSKRYY
ADSVKGRFTI SRDNSKNTLF LQMNSLRAED TAVYYCATND DYWGQGTLVT VSSASTKGPS
VFPLAPCSRS TSESTAALGC LVKDYFPEPV TVSWNSGALT SGVHTFPAVL QSSGLYSLSS
VVTVPSSSLG TKTYTCNVDH KPSNTKVDKR VESKYGPPCP PCPAPEFLGG PSVFLFPPKP
KDTLMISRTP EVTCVVVDVS QEDPEVQFNW YVDGVEVHNA KTKPREEQFN STYRVVSVLT
VLHQDWLNGK EYKCKVSNKG LPSSIEKTIS KAKGQPREPQ VYTLPPSQEE MTKNQVSLTC
LVKGFYPSDI AVEWESNGQP ENNYKTTPPV LDSDGSFFLY SRLTVDKSRW QEGNVFSCSV
MHEALHNHYT QKSLSLSLGK (配列番号3)
のアミノ酸配列を含む重鎖;および/または:
EIVLTQSPAT LSLSPGERAT LSCRASQSVS SYLAWYQQKP GQAPRLLIYD ASNRATGIPA
RFSGSGSGTD FTLTISSLEP EDFAVYYCQQ SSNWPRTFGQ GTKVEIKRTV AAPSVFIFPP
SDEQLKSGTA SVVCLLNNFY PREAKVQWKV DNALQSGNSQ ESVTEQDSKD STYSLSSTLT
LSKADYEKHK VYACEVTHQG LSSPVTKSFN RGEC (配列番号4)
のアミノ酸配列を含む軽鎖を含む。
US 2008/0025980の配列番号15(配列番号5):
EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWYQQKPGKAPKLLIYRTSNLASGVPSRFSGSGSGTDFTLTINSLQPEDFATYYCQQRSSFPLTFGGGTKLEIK;
US 2008/0025980の配列番号16(配列番号6):
EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWFQQKPGKAPKLWIYRTSNLASGVPSRFSGSGSGTDYTLTINSLQPEDFATYYCQQRSSFPLTFGGGTKLEIK;
US 2008/0025980の配列番号17(配列番号7):
EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWFQQKPGKAPKLWIYRTSNLASGVPSRFSGSGSGTDYCLTINSLQPEDFATYYCQQRSSFPLTFGGGTKLEIK;
US 2008/0025980の配列番号18(配列番号8):
EIVLTQSPSSLSASVGDRVTITCSARSSVSYMHWFQQKPGKAPKLWIYRTSNLASGVPSRFSGSGSGTSYCLTINSLQPEDFATYYCQQRSSFPLTFGGGTKLEIK;
および/またはUS 2008/0025980の配列番号20~24より選択されるアミノ酸配列を含む重鎖:
US 2008/0025980の配列番号20(配列番号9):
QVQLVQSGSELKKPGASVKISCKASGYSFSNYGMNWVRQAPGQGLQWMGWINTDSGESTYAEEFKGRFVFSLDTSVSTAYLQITSLTAEDTGMYFCAKVGYDALDYWGQGTLVTVSS;
US 2008/0025980の配列番号21(配列番号10):
QVQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVRQAPGQGLQWMGWINTDSGESTYAEEFKGRFVFSLDTSVSTAYLQITSLTAEDTGMYFCAKVGYDALDYWGQGTLVTVSS;
US 2008/0025980の配列番号22(配列番号11):
QVQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVRQAPGQGLQWMGWINTDSGESTYAEEFKGRFVFSLDTSVNTAYLQITSLTAEDTGMYFCVRVGYDALDYWGQGTLVTVSS;
US 2008/0025980の配列番号23(配列番号12):
QIQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVRQAPGQGLQWMGWINTDSGESTYAEEFKGRFVFSLDTSVNTAYLQITSLTAEDTGMYFCVRVGYDALDYWGQGTLVTVSS;
US 2008/0025980の配列番号24(配列番号13):
QIQLVQSGSELKKPGASVKISCKASGYTFTNYGMNWVKQAPGQGLKWMGWINTDSGESTYAEEFKGRFAFSLDTSVNTAYLQITSLNAEDTGMYFCVRVGYDALDYWGQGTLVTVSS
を含む。
LFTVTVPKELYIIEHGSNVTLECNFDTGSHVNLGAITASLQKVENDTSPHRERATLLEEQLPLGKASFHIPQVQVRDEGQYQCIIIYGVAWDYKYLTLKVKASYRKINTHILKVPETDEVELTCQATGYPLAEVSWPNVSVPANTSHSRTPEGLYQVTSVLRLKPPPGRNFSCVFWNTHVRELTLASIDLQSQMEPRTHPTWLLHIFIPFCIIAFIFIATVIALRKQLCQKLYSSKDTTK
RPVTTTKREVNSAI(配列番号14)
および/またはWO2010/027827の配列番号83を含むB7-DC融合タンパク質:
MIFLLLMLSLELQLHQIAALFTVTVPKELYIIEHGSNVTLECNFDTGSHVNLGAITASLQKVENDTSPHRERATLLEEQLPLGKASFHIPQVQVRDEGQYQCIIIYGVAWDYKYLTLKVKASYRKINTHILKVPETDEVELTCQATGYPLAEVSWPNVSVPANTSHSRTPEGLYQVTSVLRLKPPPGRNFSCVFWNTHVRELTLASIDLQSQMEPRTHPTWEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号15)
を含んでよい。
SNTSESFK(SNTSESF)FRVTQLAPKAQIKE-NH2(配列番号16)
EVQLQQSGPV LVKPGASVKM SCKASGYTFT DYYMNWVKQS HGKSLEWIGN
INPYNGGTTY NQKFKGKATL TVDKSSRTAY MEINSLTSED SAVYYCARGR
IYDGSLDYWG QGTALTVSS (配列番号17)
のアミノ酸配列を含む重鎖可変領域;および/または:
DIQMTQFPSS LCASQGGKVT VTCKASQDIN NYMAWYQHKP GKGPRLLIHY
TSTLLSGIPS RFSGSGSGRD YSFSISNLEP EDIATYYCLQ YDNLWTFGGG
TKLEIK (配列番号18)
のアミノ酸配列を含む軽鎖可変領域を含む。
QVQLQQSGAE LAKPGASVRL SCKASGYTFT NYWMHWVKQR PGQGLEWIGH
INPSSGFTTY NQNFKDKATL TADKSSNTAY MQLSSLTYED SAVYFCARED
YDVDYWGQGT TLTVSS (配列番号19)
のアミノ酸配列を含む重鎖可変領域;および/または:
DIVMTQSQKF MSTSVGDRVS VTCKASQSVD TNVAWYQQKP GQSPKALIFS
ASYRYSGVPD RFTGSGSGTD FTLTINSVQS EDLAEYFCQQ YNSYPYTFGS
GTKLEIK (配列番号20)
のアミノ酸配列を含む軽鎖可変領域を含む。
EVQLVESGGG LVKPGGSLKL SCAASGFTFS DYGMHWVRQA PEKGLEWVAY
ISSGSYTIYY TDTVKGRFTI SRDNAKNTLF LQMTSLRSED TAMYYCARRG
YGSFYEYYFD YWGQGTTLTV SS (配列番号21)
のアミノ酸配列を含む重鎖可変領域;および/または:
QIVLTQSPAL MSASPGEKVT MTCSASSSVS YMYWYQQKPR SSPKPWIYLT
SNLASGVPAR FSGSGSGTSY SLTISSMEAE DAATYYCQQW SSNPFTFGSG
TKLEIK (配列番号22)
のアミノ酸配列を含む軽鎖可変領域を含む。
US 8,907,065の配列番号347(配列番号23):
EVQLVESGGGLVQAGKSLRLSCAASGSIFSIHAMGWFRQAPGKEREFVAAITWSGGITYYEDSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAADRAESSWYDYWGQGTQVTVSS;
US 8,907,065の配列番号348(配列番号24):
EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAGDKHQSSWYDYWGQGTQVTVSS;
US 8,907,065の配列番号349(配列番号25):
EVQLVESGGGLVQAGGSLRLSCAASGSISSIHAMGWFRQAPGKEREFVAAITWSGGITYYADSLKGRFTISRDNAKNTGYLQMNSLKPEDTAIYYCAADRAQSSWYDYWGQGTQVTVSS;
US 8,907,065の配列番号350(配列番号26):
EVQLVESGGGLVQAGGSLGLSCAASGSIFSINAMAWFRQAPGKEREFVALISWSGGSTYYEDSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAADRVDSNWYDYWGQGTQVTVSS;
US 8,907,065の配列番号351(配列番号27):
EVQLVESGGGLVQAGGSLRLSCAASGRAFSSGTMGWFRRAPGKEREFVASIPWSGGRIYYADSVKGRFTISRDNAQNTVYLQMNSLKPEDTAVYYCAVKERSTGWDFASWGQCTQVTVSS
を含む。
US2011/0271358の配列番号25(配列番号28):
QVQLVQSGAELKQPGASVKMSCKASGYSFTSSWIHWVKQAPGQGLEWIGYIYPSTGFTEYNQKFKDRATLTADKSTSTAYMELSSLRSEDSAVYYCARWRDSSGYHAMDYWGQGTSVTVS
S;
US2011/0271358の配列番号26(配列番号29):
QVQLVQSGAEVKQPGASVKMSCKASGYSFTSSWIHWVKQAPGQGLEWIGYIYPSTGFTEYNQKFKDRATLTADKSTSTAYMELSSLRSEDTAVYY3/d10CARWRDSSGYHAMDYWGQGTSVTVSS;
US2011/0271358の配列番号27(配列番号30):
QVQLVQSGHEVKQPGASVKMSCKASGYSFTSSWIHWVKQAPGQGLEWIGYIYPSTGFTEYNQKFKDRATLTADKSTSTAYMELSSLRSEDTAVYYCARWRDSSGYHAMDYWGQGTLVTVSS;
US2011/0271358の配列番号28(配列番号31):
QVQLVQSGHEVKQPGASVKMSCKASGYSFTSSWIHWVRQAPGQGLEWIGYIYPSTGFTEYNQKFKDRATLTADKSTSTAYMELSSLRSEDTAVYYCARWRDSSGYHAMDYWGQGTLVTVSS;
US2011/0271358の配列番号29(配列番号32):
QVQLVQSGHEVKQPGASVKVSCKASGYSFTSSWIHWVRQAPGQGLEWIGYIYPSTGFTEYNQKFKDRATITADKSTSTAYMELSSLRSEDTAVYYCARWRDSSGYHAMDYWGQGTLVTVSS
より選択されるアミノ酸配列を含む重鎖;および/またはUS2011/0271358の配列番号30~33:
US2011/0271358の配列番号30(配列番号33):
DIVLTQSPASLTLSPGQRLTISCRASQSVSTSGYSYMHWYQQKPDQSPKLLIKFGSNLESGIPARFSGSGSGTDFTLTISSLEEEDFATYYCQHSWEIPYTFGQGTKLEIK;
US2011/0271358の配列番号31(配列番号34):
DIVLTQSPATLSLSPGQRLTISCRASQSVSTSGYSYMHWYQQKPDQSPKLLIKFGSNLESGIPARFSGSGSGTDFTLTISSLEPEDFATYYCQHSWEIPYTFGQGTKLEIK;
US2011/0271358の配列番号32(配列番号35):
EIVLTQSPATLSLSPGQRLTISCRASQSVSTSGYSYMHWYQQKPDQSPKLLIKFGSNLESGIPARFSGSGSGTDFTLTISSLEPEDFATYYCQHSWEIPYTFGQGTKLEIK;
US2011/0271358の配列番号33(配列番号36):
DIVLTQSPATLSLSPGQRLTISCRASQSVSTSGYSYMHWYQQKPDQSPKLLIKFGSNLESGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQHSWEIPYTFGQGTKLEIK
より選択されるアミノ酸配列を含む軽鎖を含む。
EVQLVESGGG LVQPGGSLRL SCAASGFTFS RYWMSWVRQA PGKGLEWVAN
IKQDGSEKYY VDSVKGRFTI SRDNAKNSLY LQMNSLRAED TAVYYCAREG
GWFGELAFDY WGQGTLVTVS SASTKGPSVF PLAPSSKSTS GGTAALGCLV
KDYFPEPVTV SWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSSLGTQ
TYICNVNHKP SNTKVDKRVE PKSCDKTHTC PPCPAPEFEG GPSVFLFPPK
PKDTLMISRT PEVTCVVVDV SHEDPEVKFN WYVDGVEVHN AKTKPREEQY
NSTYRVVSVL TVLHQDWLNG KEYKCKVSNK ALPASIEKTI SKAKGQPREP
QVYTLPPSRE EMTKNQVSLT CLVKGFYPSD IAVEWESNGQ PENNYKTTPP
VLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHEALHNHY TQKSLSLSPG
K (配列番号37)
のアミノ酸配列を含む重鎖;および/または:
EIVLTQSPGT LSLSPGERAT LSCRASQRVS SSYLAWYQQK PGQAPRLLIY
DASSRATGIP DRFSGSGSGT DFTLTISRLE PEDFAVYYCQ QYGSLPWTFG
QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK
VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKH KVYACEVTHQ
GLSSPVTKSF NRGEC (配列番号38)
のアミノ酸配列を含む軽鎖を含む。
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSS(配列番号39)
を含む重鎖可変領域;および/またはWO/2016/06272の配列番号3のアミノ酸配列:
EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK(配列番号40)
を含む軽鎖可変領域を含む。
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号41)
のアミノ酸配列を含む重鎖;および/または:
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号42)
のアミノ酸配列を含む軽鎖を含む。
EVQLLESGGG LVQPGGSLRL SCAASGFTFS SYIMMWVRQA PGKGLEWVSS
IYPSGGITFY ADTVKGRFTI SRDNSKNTLY LQMNSLRAED TAVYYCARIK
LGTVTTVDYW GQGTLVTVSS ASTKGPSVFP LAPSSKSTSG GTAALGCLVK
DYFPEPVTVS WNSGALTSGV HTFPAVLQSS GLYSLSSVVT VPSSSLGTQT
YICNVNHKPS NTKVDKKVEP KSCDKTHTCP PCPAPELLGG PSVFLFPPKP
KDTLMISRTP EVTCVVVDVS HEDPEVKFNW YVDGVEVHNA KTKPREEQYN
STYRVVSVLT VLHQDWLNGK EYKCKVSNKA LPAPIEKTIS KAKGQPREPQ
VYTLPPSRDE LTKNQVSLTC LVKGFYPSDI AVEWESNGQP ENNYKTTPPV
LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV MHEALHNHYT QKSLSLSPGK
(配列番号43)
のアミノ酸配列を含む重鎖;および/または:
QSALTQPASV SGSPGQSITI SCTGTSSDVG GYNYVSWYQQ HPGKAPKLMI
YDVSNRPSGV SNRFSGSKSG NTASLTISGL QAEDEADYYC SSYTSSSTRV
FGTGTKVTVL GQPKANPTVT LFPPSSEELQ ANKATLVCLI SDFYPGAVTV
AWKADGSPVK AGVETTKPSK QSNNKYAASS YLSLTPEQWK SHRSYSCQVT
HEGSTVEKTV APTECS (配列番号44)
のアミノ酸配列を含む軽鎖を含む。
QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSTYAISWVRQAPGQGLEWMGGIIPIFGKAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARKFHFVSGSPFGMDVWGQGTTVTVSS(配列番号45)
のアミノ酸配列を含む重鎖可変領域;および/または:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTKVEIK(配列番号46)
のアミノ酸配列を含む軽鎖可変領域を含む。
QVQLVQSGAEVKKPGASVKVSCKASGYTFTDYGFSWVRQAPGQGLEWMGWITAYNGNTNYAQKLQGRVTMTTDTSTSTVYMELRSLRSDDTAVYYCARDYFYGMDVWGQGTTVTVSS(配列番号47)
のアミノ酸配列を含む重鎖可変領域;および/または:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLVWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPRTFGQGTKVEIK(配列番号48)
のアミノ酸配列を含む軽鎖可変領域を含む。
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYDVHWVRQAPGQRLEWMGWLHADTGITKFSQKFQGRVTITRDTSASTAYMELSSLRSEDTAVYYCARERIQLWFDYWGQGTLVTVSS(配列番号49)
のアミノ酸配列を含む重鎖可変領域;および/または:
DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPYTFGQGTKLEIK(配列番号50)
のアミノ酸配列を含む軽鎖可変領域を含む。
QVQLVQSGAEVKKPGSSVKVSCKVSGGIFSTYAINWVRQAPGQGLEWMGGIIPIFGTANHAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYYCARDQGIAAALFDYWGQGTLVTVSS(配列番号51)
のアミノ酸配列を含む重鎖可変領域;および/または:
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPWTFGQGTKVEIK(配列番号52)
のアミノ酸配列を含む軽鎖可変領域を含む。
EVQLVESGGGLVQPGRSLRLSCAVSGFTFDDYVVHWVRQAPGKGLEWVSGISGNSGNIGYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAVPFDYWGQGTLVTVSS(配列番号53)
のアミノ酸配列を含む重鎖可変領域;および/または:
DIQMTQSPSSLSASVGDRVTITCRASQGISSWLAWYQQKPEKAPKSLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPYTFGQGTKLEIK(配列番号54)
のアミノ酸配列を含む軽鎖可変領域を含む。
QVQLVQSGAEVKKPGSSVKVSCKTSGDTFSSYAISWVRQAPGQGLEWMGGIIPIFGRAHYAQKFQGRVTITADESTSTAYMELSSLRSEDTAVYFCARKFHFVSGSPFGMDVWGQGTTVTVSS(配列番号55)
のアミノ酸配列を含む重鎖可変領域;および/または:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTKVEIK(配列番号56)
のアミノ酸配列を含む軽鎖可変領域を含む。
QVQLVQSGAEVKKPGSSVKVSCKTSGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGKAHYAQKFQGRVTITADESTTTAYMELSSLRSEDTAVYYCARKYDYVSGSPFGMDVWGQGTTVTVSS(配列番号57)
のアミノ酸配列を含む重鎖可変領域;および/または:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTKVEIK(配列番号58)
のアミノ酸配列を含む軽鎖可変領域を含む。
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAINWVRQAPGQGLEWMGGIIPIFGSANYAQKFQDRVTITADESTSAAYMELSSLRSEDTAVYYCARDSSGWSRYYMDVWGQGTTVTVSS(配列番号59)
のアミノ酸配列を含む重鎖可変領域;および/または:
EIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSPFGGGTKVEIK(配列番号60)
のアミノ酸配列を含む軽鎖可変領域を含む。
QVQLVQSGAEVKEPGSSVKVSCKASGGTFNSYAISWVRQAPGQGLEWMGGIIPLFGIAHYAQKFQGRVTITADESTNTAYMDLSSLRSEDTAVYYCARKYSYVSGSPFGMDVWGQGTTVT
VSS(配列番号61)
のアミノ酸配列を含む重鎖可変領域;および/または:
EIVLTQSPATLSLSPGERATLSCRASQSVSSYLAWYQQKPGQAPRLLIYDASNRATGIPARFSGSGSGTDFTLTISSLEPEDFAVYYCQQRSNWPTFGQGTRLEIK(配列番号62)
のアミノ酸配列を含む軽鎖可変領域を含む。
EVQLVESGGGLVQPGRSLRLSCAASGITFDDYGMHWVRQAPGKGLEWVSGISWNRGRIEYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTALYYCAKGRFRYFDWFLDYWGQGTLVTVSS (配列番号63)
のアミノ酸配列を含む重鎖可変領域;および/または:
AIQLTQSPSSLSASVGDRVTITCRASQGISSALAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQFNSYPFTFGPGTKVDIK(配列番号64)
のアミノ酸配列を含む軽鎖可変領域を含む。
EVKLQESGPS LVKPSQTLSL TCSVTGYSIT SDYWNWIRKF PGNKLEYVGY
ISYTGSTYYN PSLKSRISIT RDTSKNQYYL QLNSVTSEDT ATYYCARYGG
WLSPFDYWGQ GTTLTVSS (配列番号65)
のアミノ酸配列を含む重鎖可変領域;および/または:
DIVMTQSHKL MSTSVGDRVS ITCKASQDVG TAVAWYQQKP GQSPKLLIYW
ASTRHTGVPD RFTGSGSGTD FTLTISNVQS EDLADYFCQQ DSSYPLTFGA
GTKVELK (配列番号66)
のアミノ酸配列を含む軽鎖可変領域を含む。
EVQLQESGPG LVAPSQSLSI TCTVSGFSLT TYSINWIRQP PGKGLEWLGV
MWAGGGTNSN SVLKSRLIIS KDNSKSQVFL KMNSLQTDDT ARYYCARYYG
NSPYYAIDYW GQGTSVTVSS (配列番号67)
のアミノ酸配列を含む重鎖可変領域;および/または:
DIVTTQSHKL MSTSVGDRVS ITCKASQDVG TAVAWYQQKP GQSPKLLIYW
ASTRHTGVPD RFTGSGSGTD FTLTISNVQS EDLADYFCQQ DSSYPLTFGA
GTKVELK (配列番号68)
のアミノ酸配列を含む軽鎖可変領域を含む。
EVKLQESGPS LVKPSQTLSL TCSVTGYSII SDYWNWIRKF PGNKLEYLGY
ISYTGSTYYN PSLKSRISIT RDTSKNQYYL QLNSVTTEDT ATYYCARRGG
WLLPFDYWGQ GTTLTVSS (配列番号69)
のアミノ酸配列を含む重鎖可変領域;および/または:
DIVMTQSPSS LAVSVGEKVS MGCKSSQSLL YSSNQKNSLA WYQQKPGQSP
KLLIDWASTR ESGVPDRFTG SGSGTDFTLT ISSVKAEDLA VYYCQQYYGY
PLTFGAGTKL ELK (配列番号70)
のアミノ酸配列を含む軽鎖可変領域を含む。
EVKLQESGPS LVKPGASVKL SCKASGYTFT SYDINWVKQR PGQGLEWIGW
IFPRDNNTKY NENFKGKATL TVDTSSTTAY MELHSLTSED SAVYFCTKEN
WVGDFDYWGQ GTTLTLSS (配列番号71)
のアミノ酸配列を含む重鎖可変領域;および/または:
DIVMTQSPAI MSASPGEKVT MTCSASSSIR YMHWYQQKPG TSPKRWISDT
SKLTSGVPAR FSGSGSGTSY ALTISSMEAE DAATYYCHQR SSYPWTFGGG
TKLEIK (配列番号72)
のアミノ酸配列を含む軽鎖可変領域を含む。
EVQLQQSGPD LVTPGASVRI SCQASGYTFP DYYMNWVKQS HGKSLEWIGD
IDPNYGGTTY NQKFKGKAIL TVDRSSSTAY MELRSLTSED SAVYYCARGA
LTDWGQGTSL TVSS (配列番号73)
のアミノ酸配列を含む重鎖可変領域;および/または:
QIVLSQSPAI LSASPGEKVT MTCRASSSVS YIYWFQQKPG SSPKPWIYAT
FNLASGVPAR FSGSGSGTSY SLTISRVETE DAATYYCQQW SNNPLTFGAG
TKLELK (配列番号74)
のアミノ酸配列を含む軽鎖可変領域を含む。
US2011/0271358の配列番号34(配列番号75):
EVQLVQSGPELKKPGASVKMSCKASGYTFTSYVMHWVKQAPGQRLEWIGYVNPFNDGTKYNEMFKGRATLTSDKSTSTAYMELSSLRSEDSAVYYCARQAWGYPWGQGTLVTVSS;
US2011/0271358の配列番号35(配列番号76):
EVQLVQSGAEVKKPGASVKMSCKASGYTFTSYVMHWVKQAPGQRLEWIGYVNPFNDGTKYNEMFKGRATLTSDKSTSTAYMELSSLRSEDTAVYYCARQAWGYPWGQGTLVTVSS;
US2011/0271358の配列番号36(配列番号77):
EVQLVQSGAEVKKPGASVKMSCKASGYTFTSYVMHWVRQAPGQRLEWIGYVNPFNDGTKYNEMFKGRATLTSDKSTSTAYMELSSLRSEDTAVYYCARQAWGYPWGQGTLVTVSS;
US2011/0271358の配列番号37(配列番号78):
EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVMHWVRQAPGQRLEWIGYVNPFNDGTKYNEMFKGRATLTSDKSTSTAYMELSSLRSEDTAVYYCARQAWGYPWGQGTLVTVSS;
US2011/0271358の配列番号38(配列番号79):
EVQLVQSGAEVKKPGASVKVSCKASGYTFTSYVMHWVRQAPGQRLEWIGYVNPFNDGTKYNEMFKGRATITSDKSTSTAYMELSSLRSEDTAVYYCARQAWGYPWGQGTLVTVSS;
より選択されるアミノ酸配列を含む重鎖および/またはUS2011/0271358の配列番号39~42:
US2011/0271358の配列番号39(配列番号80):
DIVLTQSPASLALSPGERATLSCRATESVEYYGTSLVQWYQQKPGQPPKLLIYAASSVDSGVPSRFSGSGSGTDFTLTINSLEEEDAAMYFCQQSRRVPYTFGQGTKLEIK;
US2011/0271358の配列番号40(配列番号81):
DIVLTQSPATLSLSPGERATLSCRATESVEYYGTSLVQWYQQKPGQPPKLLIYAASSVDSGVPSRFSGSGSGTDFTLTINSLEAEDAAMYFCQQSRRVPYTFGQGTKLEIK;
US2011/0271358の配列番号41(配列番号82):
EIVLTQSPATLSLSPGERATLSCRATESVEYYGTSLVQWYQQKPGQPPKLLIYAASSVDSGVPSRFSGSGSGTDFTLTINSLEAEDAAMYFCQQSRRVPYTFGQGTKLEIK;
US2011/0271358の配列番号42(配列番号83):
DIVLTQSPATLSLSPGERATLSCRATESVEYYGTSLVQWYQQKPGQPPKLLIYAASSVDSGVPSRFSGSGSGTDFTLTINSLEAEDAATYFCQQSRRVPYTFGQGTKLEIK
より選択されるアミノ酸配列を含む軽鎖を含む。
WO 2011/066389の配列番号2(配列番号84):
EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYSMNWVRQAPGKGLEWVSSISSSGDYIYYADSVKGRFTISRDNAKNSLFLQMNSLKAEDTAVYYCARDLVTSMVAFDYWGQGTLVTVSS
のアミノ酸配列を含む重鎖可変領域;および/または:
WO 2011/066389の配列番号7(配列番号85):
SYELTQPPSVSVSPGQAARITCSGDALPQKYVFWYQQKSGQAPVLVIYEDSKRPSGIPERFSGSSSGTMATLTISGAQVEDEADYYCYSTDRSGNHRVFGGGTRLTVL
のアミノ酸配列を含む軽鎖可変領域を含む。
WO 2011/066389の配列番号12(配列番号86):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQDGGEQYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDWNYGYYDMDVWGQGTTVTVSS
のアミノ酸配列を含む重鎖可変領域;および/または:
WO 2011/066389の配列番号17(配列番号87):
EIVLTQSPGTLSLSPGERATLSCRASQSVSSNYLAWFQQKPGQAPRLLIFGTSSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSSIFTFGPGTKVDIK
のアミノ酸配列を含む軽鎖可変領域を含む。
WO 2011/066389の配列番号22(配列番号88):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVS
S
のアミノ酸配列を含む重鎖可変領域;および/または:
WO 2011/066389の配列番号27(配列番号89):
EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTEVEIK
のアミノ酸配列を含む軽鎖可変領域を含む。
WO 2011/066389の配列番号32(配列番号90):
EVQLLESGGGLVQPGGSLRLSCAASGFTFSNYAMSWVRQAPGKGLEWVSAIRGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDLHYDSSGYLDYWGQGTLVTVSS
のアミノ酸配列を含む重鎖可変領域;および/または:
WO 2011/066389の配列番号37(配列番号91):
DIQMTQSPSSVSASVGDRVTITCRASQGIRSWLAWYQQKPGKAPKLLIYAISRLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQANSFPLTFGGGTKVEIK
のアミノ酸配列を含む軽鎖可変領域を含む。
WO 2011/066389の配列番号42(配列番号92):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWVRQAPGKGLEWVANIKQDGGEKYYVDSVKGRFTISRDNAKNSLFLQMNSLRAEDTAVYYCARVQLYSDYFDYWGQGTLVTVSS
のアミノ酸配列を含む重鎖可変領域;および/または:
WO 2011/066389の配列番号47(配列番号93):
DIQMTQSPSSVSASVGDRVTITCRASQGISSWLAWYQQKSGKAPKLLIYAASGLQSGVPSRFSGSGSGTDFTLTISSLQPEDLATYYCQQSHSLPPTFGQGTKVEIK
のアミノ酸配列を含む軽鎖可変領域を含む。
WO 2011/066389の配列番号52(配列番号94):
EVQLLESGGDLVQPGGSLRLSCAASGFTFNSYAMSWVRQAPGKGLEWVSTISGSGGFTFSADSVKGRFTISRDNSKNTLFLQMNSLRVEDSAVYSCAKVLVGFNNGCWDYWGQGTLVTVSS
のアミノ酸配列を含む重鎖可変領域;および/または:
WO 2011/066389の配列番号57(配列番号95):
SYVLTQPPSVSVAPGQTARITCGGNNIGSKSVHWYQQKPGQAPVLVVYDDSDRPSGIPERFSGSNSGNTATLTISRVEAGDEADYYCQVWDSSNDHVVFGGGTKLTVL
のアミノ酸配列を含む軽鎖可変領域を含む。
WO 2011/066389の配列番号62(配列番号96):
EVQLVESGGGLVKPGGSLRLSCAASGFTFSTYSMNWVRQAPGKGLEWVSSISSSGDYIYYADSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCARDLVTSMVAFDYWGQGTLVTVSS
のアミノ酸配列を含む重鎖可変領域;および/または:
WO 2011/066389の配列番号67(配列番号97):
SYELTQPPSVSVSPGQTARITCSGDALPQKYVFWYQQKSGQAPVLVIYEDSKRPSGIPERFSGSSSGTMATLTISGAQVEDEADYYCYSTDRSGNHRVFGGGTKLTVL
のアミノ酸配列を含む軽鎖可変領域を含む。
WO 2011/066389の配列番号72(配列番号98):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSRYWMSWVRQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYYCAREGGWFGELAFDYWGQGTLVTVSS
のアミノ酸配列を含む重鎖可変領域;および/または:
WO 2011/066389の配列番号77(配列番号99):
EIVLTQSPGTLSLSPGERATLSCRASQRVSSSYLAWYQQKPGQAPRLLIYDASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQYGSLPWTFGQGTKVEIK
のアミノ酸配列を含む軽鎖可変領域を含む。
WO2016/061142の配列番号18(配列番号100):
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMYWVRQATGQGLEWMGRIDPNSGSTKYNEKFKNRFTISRDDSKNTAYLQMNSLKTEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS;
WO2016/061142の配列番号30(配列番号101):
EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQATGQGLEWMGRIDPNSGSTKYNEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS;
WO2016/061142の配列番号38(配列番号102):
EVQLVQSGAEVKKPGESLRISCKGSGYTFTSYWMYWVRQAPGQGLEWMGRIDPNSGSTKYNEKFKNRVTISVDTSKNQFSLKLSSVTAADTAVYYCARDYRKGLYAMDYWGQGTTVTVSS;
WO2016/061142の配列番号46(配列番号103):
EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWIRQSPSRGLEWLGRIDPNSGSTKYNEKFKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARDYRKGLYAMDYWGQGTTVTVSS;
WO2016/061142の配列番号50(配列番号104):
EVQLVQSGAEVKKPGESLRISCKGSGYTFTSYWMYWIRQPPGKGLEWIGRIDPNSGSTKYNEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS;
WO2016/061142の配列番号54(配列番号105):
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYWMYWIRQSPSRGLEWLGRIDPNSGSTKYNEKFKNRFTISRDDSKNTAYLQMNSLKTEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS;
WO2016/061142の配列番号62(配列番号106):
EVQLVQSGAEVKKPGESLRISCKGSGYTFTSYWMYWVRQARGQRLEWIGRIDPNSGSTKYNEKFKNRLTISKDTSKNQVVLTMTNMDPVDTATYYCARDYRKGLYAMDYWGQGTTVTVSS;
WO2016/061142の配列番号70(配列番号107):
QITLKESGPTLVKPTQTLTLTCTFSGYTFTSYWMYWVRQAPGKGLEWVSRIDPNSGSTKYNEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS;
WO2016/061142の配列番号78(配列番号108):
EVQLVQSGAEVKKPGATVKISCKVSGYTFTSYWMYWVRQARGQRLEWIGRIDPNSGSTKYNEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDYRKGLYAMDYWGQGTTVTVSS
より選択されるアミノ酸配列を含む重鎖;および/またはUS2016/061142の配列番号22、26、34、42、58、66、74、82、および86:
WO2016/061142の配列番号22(配列番号109):
DIVMTQTPLSLPVTPGEPASISCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQYNSYPLTFGQGTKVEIK;
WO2016/061142の配列番号26(配列番号110):
DIQMTQSPSSLSASVGDRVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYNSYPLTFGQGTKVEIK;
WO2016/061142の配列番号34(配列番号111):
EIVLTQSPDFQSVTPKEKVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQYNSYPLTFGQGTKVEIK;
WO2016/061142の配列番号42(配列番号112):
EIVLTQSPDFQSVTPKEKVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYNSYPLTFGQGTKVEIK.
WO2016/061142の配列番号58(配列番号113):
EIVLTQSPATLSLSPGERATLSCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQQYNSYPLTFGQGTKVEIK;
WO2016/061142の配列番号66(配列番号114):
DVVMTQSPLSLPVTLGQPASISCKASQDVGTAVAWYQQKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK;
WO2016/061142の配列番号74(配列番号115):
DIQMTQSPSSLSASVGDRVTITCKASQDVGTAVAWYQQKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQYNSYPLTFGQGTKVEIK;
WO2016/061142の配列番号82(配列番号116):
AIQLTQSPSSLSASVGDRVTITCKASQDVGTAVAWYLQKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQQYNSYPLTFGQGTKVEIK;
WO2016/061142の配列番号86(配列番号117):
EIVLTQSPDFQSVTPKEKVTITCKASQDVGTAVAWYQQKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK
より選択されるアミノ酸配列を含む軽鎖を含む。
WO2016/022630の配列番号2(配列番号118):
EVKLVESGGGLVKPGGSLKLSCAASGFIFRSYGMSWVRQTPEKRLEWVASISSGGSTYYPDSVKGRFTISRDNARNILYLQMSSLRSEDTAMYDCARGYDSGFAYWGQGTLVTVSE;
WO2016/022630の配列番号6(配列番号119):
EVKLVESGGGLVKPGGSLKLSCAASGFTFRSYGMSWVRQTPEKRLEWVASISSGGTTYYPDSVKGRFIISRDNARNILYLQMSSLRSEDTAMYYCAKGYDSGFAYWGQGTLVIVSA;
WO2016/022630の配列番号10(配列番号120):
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTTYGVHWVRQSPGKGLEWLGVIWRGVTTDYNAAFMSRLTITKDNSKSQVFFKMNSLQANDTAIYYCARLGFYAMDYWGQGTSVTVSS;
WO2016/022630の配列番号14(配列番号121):
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTSYGVHWVRQSPGKGLEWLGVIWSGGVTDYNAAFISRLSISKDNSKSQVFFKMNSLQANDTAIYYCARLGFYAMDYWGQGTSVTVSS;
WO2016/022630の配列番号18(配列番号122):
EVKLFESGGGLVQPGGSLKLSCVASGFDFSTYWMHWVRQAPGQGLEWIGQINPDSTTINYAPSLKDRFIISRDNAKNTLFLQMSKVRSEDTALYYCAKPGDYGYDFDCWGQGTTLTVSS;
WO2016/022630の配列番号22(配列番号123):
EVQLQESGPSLVKPSQTLSLTCSVTGDSITSGYWNWIRKFPGNKLEYMGYISYSGSTYYNPSLKSRISITRDTSKNQYYLQLNSVTTEDTATYYCARSLLWFSTGFAYWGQGTLVTVSA;
WO2016/022630の配列番号26(配列番号124):
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTSYGVHWVRQSPGKGLEWLGVIWSGGITDYNAAFKSRLSISKDNSKSQVFFKMNSLQANDTAIYFCARLGFYAMDYWGQGTSVTVSS;
WO2016/022630の配列番号30(配列番号125):
EVKLVESGGGLVKPGGSLKLSCAASGFTFRSYGMSWARQIPEKRLEWVASISSGGTTYYLGSVQGRFTISRDNARNILYLQMSSLRSEDTAMYYCARGYDAGFAYWGQGTLVSVSE;
WO2016/022630の配列番号34(配列番号126):
EVQLQESGPSLVKPSQTLSLTCSVTGDSITSGYWTWIRKFPGNKLEYMGYISYTGSTYYNPSLKSRISISRDTSKSQYYLQLNSVTTEDTATYYCARQRDWLGFAYWGQGTLVTVSA;
WO2016/022630の配列番号38(配列番号127):
EEKLVESGGGLVKPGGSLKLSCAASGFSFSSYGMSWVRQTPEKRLEWVASISSGGSIYYPDSVKGRFTISRDNARNILYLQMSSLRSEDTAMYYCARGYDAGFAFWGQGTLVTASA;
WO2016/022630の配列番号42(配列番号128):
QITLKESGPTLVKPTQTLTLTCTVSGFSLSTYGVHWIRQPPGKALEWLGVIWRGVTTDYNAAFMSRLTITKDNSKNQVVLTMNNMDPVDTATYYCARLGFYAMDYWGQGTLVTVSS;
WO2016/022630の配列番号46(配列番号129):
EVQLVESGGGLVKPGGSLRLSCAASGFIFRSYGMSWVRQAPGKGLEWVASISSGGSTYYPDSVKGRFTISRDNAKNSLYLQMNSLRAEDTAVYDCARGYDSGFAYWGQGTLVTVSS
より選択されるアミノ酸配列を含む重鎖;および/またはWO2016/022630の配列番号4、8、12、16、20、24、28、32、36、40、44、および48:
WO2016/022630の配列番号4(配列番号130):
DIVLTQSPASLAVSLGQRATISCRASQSVSTSSSSFMHWYQQKPGQPPKLLIKYASNLESGVPARFSGSGSGTDFTLNIHPVEEEDTATYYCQHSWEIPYTFGGGTKLEIKR;
WO2016/022630の配列番号8(配列番号131):
DIVLTQSPPSLAVSLGQRATISCRASQSVSTSSSSYMHWYQQKPGQPPKLLIKYASNLESGVPARFSGSGSGTDFTLNIHPVEEEDTATYYCQHSWEIPYTFGGGTKLEIK;
WO2016/022630の配列番号12(配列番号132):
SIVMTQTPKFLLVSAGDRVTITCKASQSVSNDVAWYQQKPGQSPKLLIYYAANRYTGVPDRFTGSGYGTDFTFTISIVQAEDLAVYFCQQDYTSPYTFGGGTKLEIK;
WO2016/022630の配列番号16(配列番号133):
SIVMTQTPKFLLVSAGDRVTITCKASQSVSNDVGWYQQKPGQSPKLLIYYASNRYSGVPDRFTGSGYGTDFTFTISTVQAEDLAVYFCQQDYTSPYTFGGGTKLEIK;
WO2016/022630の配列番号20(配列番号134):
DVLMTQTPLYLPVSLGDQASISCRSSQIIVHSNANTYLEWFLQKPGQSPKLLIYKVSNRFSGVPDRFSGSGSGTDFTLKISRVEAEDLGVYYCFQGSHVPYTFGGGTKLEIK;
WO2016/022630の配列番号24(配列番号135):
QIVLTQSPAIMSASPGEKVTLTCSASSSVSSSYLYWNQQKPGSSPKVWIYNTSNLASGVPARFSGSGSGTSYSLTISSMEAEDAASYFCHQWRSYPPTLGAGTKLELK;
WO2016/022630の配列番号28(配列番号136):
QIVLTQSPAIMSASPGEKVTMTCSANSSVSYMHWYQQKSGTSPKRWIYDTSKLASGVPARFSGSGSGTSYSLTISSMGAEDAATYYCQQWSSNPWTFGGGTKLEIK;
WO2016/022630の配列番号32(配列番号137):
DIVLTQSPASLAVSLGQRATISCRASQSVSTSSYSYMHWYQQKPGQPPKLLIKYASNLESGVPARFSGSGSGTDFTLNIHPVEEEDTATYYCQNSWEIPYTFGGGTKLEIK;
WO2016/022630の配列番号36(配列番号138):
DIVMTQTPSSLAVSLGEKVTMSCKSSQSLLYSSNQKNSLAWYQQKPGQSPKLLIYWASNRESGVPDRFTGSSSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK;
WO2016/022630の配列番号40(配列番号139):
DIVLTQSPASLAVSLGQRATISCRASQSVSTSSYSYVHWYQQKPGQPPKLLIKYASNLESGVPARFSGSGSGTDFTLNIHPVEEEDTATYYCQHSWEIPYTFGGGTKLEIK;
WO2016/022630の配列番号44(配列番号140):
DIQMTQSPSSLSASVGDRVTITCKASQSVSNDVAWYQQKPGKAPKLLIYYAANRYTGVPDRFSGSGYGTDFTFTISSLQPEDIATYFCQQDYTSPYTFGQGTKLEIK;
WO2016/022630の配列番号48(配列番号141):
DIVLTQSPASLAVSPGQRATITCRASQSVSTSSSSFMHWYQQKPGQPPKLLIKYASNLESGVPARFSGSGSGTDFTLTINPVEANDTANYYCQHSWEIPYTFGQGTKLEIK
より選択されるアミノ酸配列を含む軽鎖を含む。
WO2015/112900の配列番号38(配列番号142):
EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQATGQGLEWMGNIYPGTGGSNFDEKFKNRVTITADKSTSTAYMELSSLRSEDTAVYYCTRWTTGTGAYWGQGTTVTVSS;
WO 2015/112900の配列番号50(配列番号143):
EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSS;
WO 2015/112900の配列番号82(配列番号144):
QVQLVQSGAEVKKPGASVKVSCKASGYTFTTYWMHWIRQSPSRGLEWLGNIYPGTGGSNFDEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSS;
WO 2015/112900の配列番号86(配列番号145):
EVQLVQSGAEVKKPGESLRISCKGSGYTFTTYWMHWVRQAPGQGLEWMGNIYPGTGGSNFDEKFKNRFTISRDNSKNTLYLQMNSLRAEDTAVYYCTRWTTGTGAYWGQGTTVTVSS
より選択されるアミノ酸配列を含む重鎖;および/またはWO2015/112900の配列番号42、46、54、58、62、66、70、74、および78:
WO2015/112900の配列番号42(配列番号146):
EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQNDYSYPYTFGQGTKVEIK;
WO 2015/112900の配列番号46(配列番号147):
DIQMTQSPSSLSASVGDRVTITCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGIPPRFSGSGYGTDFTLTINNIESEDAAYYFCQNDYSYPYTFGQGTKVEIK;
WO 2015/112900の配列番号54(配列番号148):
EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQNDYSYPYTFGQGTKVEIK;
WO 2015/112900の配列番号58(配列番号149):
DIVMTQTPLSLPVTPGEPASISCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK;
WO 2015/112900の配列番号62(配列番号150):
EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK;
WO 2015/112900の配列番号66(配列番号151):
EIVLTQSPDFQSVTPKEKVTITCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK;
WO 2015/112900の配列番号70(配列番号152):
EIVLTQSPATLSLSPGERATLSCKSSQSLLDSGNQKNFLTWYQQKPGQAPRLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK;
WO 2015/112900の配列番号74(配列番号153):
DIQMTQSPSSLSASVGDRVTITCKSSQSLLDSGNQKNFLTWYLQKPGQSPQLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK;
WO 2015/112900の配列番号78(配列番号154):
DVVMTQSPLSLPVTLGQPASISCKSSQSLLDSGNQKNFLTWYQQKPGKAPKLLIYWASTRESGVPSRFSGSGSGTDFTFTISSLEAEDAATYYCQNDYSYPYTFGQGTKVEIK
より選択されるアミノ酸配列を含む軽鎖を含む。
WO 2010/077634の配列番号20(配列番号155):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSDSWIHWVRQAPGKGLEWVAWISPYGGSTYYADSVKGRFTISADTSKNTAYLQMNSLRAEDTAVYYCARRHWPGGFDYWGQGTLVTVSA
のアミノ酸配列を含む重鎖可変領域;および/または
WO 2010/077634の配列番号21(配列番号156):
DIQMTQSPSSLSASVGDRVTITCRASQDVSTAVAWYQQKPGKAPKLLIYSASFLYSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYLYHPATFGQGTKVEIKR
のアミノ酸配列を含む軽鎖可変領域を含む。
US 8,907,065の配列番号394(配列番号157):
EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYAIGWFRQAPGKEREWASSISSSDGSTYYADSVKGRFTISRDNAKNTVFLQMNSLKPEDTAVYSCAASQAPITIATMMKPFYDYWGQGTQVTVSS;
US 8,907,065の配列番号395(配列番号158):
EVQLVESGGGLVQPGGSLRLSCAASGFTLDYYAKCWFRQAPGKEREWVSCISSSDGSTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYFCAARHGGPLTVEYFFDYWGQGTQVTVSS;
US 8,907,065の配列番号396(配列番号159):
EVQLVESGGGLVQPGGSLRLSCAASGFTFDYYAIGWFRQAPGKAREGVSCISGGDNSTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCATGGWKYCSGYDPEYIYWGQGTQVTVSS;
US 8,907,065の配列番号397(配列番号160):
EVQLVESGGGLVQAGGSLRLSCAASGSTFSQYDVGWYRQAPGKQRELVAFSSSGGRTIYPDSVKGRFTFSRDNTKNTVYLQMTSLKPEDTAVYYCKIDWYLNSYWGQGTQVTVSS;
US 8,907,065の配列番号398(配列番号161):
EVQLVESGGGLVQAGGSLRLSCAASGVDASNSAMGWYRQAPGKQREWVARITGGGLIAYTDSVKGRFTISRDNAKSTVYLQMNSLEPEDTAVYYCNTINSRDGWGQGTQVTVSS;
US 8,907,065の配列番号399(配列番号162):
EVQLVESGGGLVQAGGSLTISCAASGITFSDSIVSWYRRARGKQREWVAGISNGGTTKYAESVLGRFTISRDNAKNNVYLQMNGLNPEDTAVYLCKVRQYWGQGTQVTVSS
を含む。
US 8,907,065の配列番号449(配列番号163):
EVQLVESGGGLVQAGGSLRLSCAASESTVLINAMGWYRQAPGKQRELVASISSGGSTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCNADVYPQDYGLGYVEGKVYYGHDYWGTGTLVTVSS;
US 8,907,065の配列番号450(配列番号164):
EVQLVESGGGLVQAGGSLRLSCAASGSTFSNYVSNYAMGWGRQAPGTQRELVASISNGDTTNYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCFEHQVAGLTWGQGTQVTVSS;
US 8,907,065の配列番号451(配列番号165):
EVQLVESGGGLVQAGGSLRLSCVASGXALKIXVMGWYRQAPGKQRELVAAITSGGRTNYSDSVKGRFTISGDNAXNTVYLQMNSLKSEDTAVYYCREWNSGYPPVDYWGQGTQVTVSS;
US 8,907,065の配列番号452(配列番号166):
EVQLVESGGGLVQAGGSLRLSCAASGRTFSSGTMGWFRRAPGKEREFVASIPWSGGRTYYADSVKDRFTISRDNAQNTVFLQMNSLKPEDTAVYYCAFKERSTGWDFASWGQGIQVTVSS;
US 8,907,065の配列番号453(配列番号167):
EVQLVESGGGLVQTGGSLRLSCAASGFTLDYYGIGWFRQAPGKEREGVSFISGSDGSTYYAESVKGRFTISRDKAKNTVYLQMNSLKPEDTAVYYCAADPWGPPSIATMTSYEYKHWGQGTQVTVSS;
US 8,907,065の配列番号454(配列番号168):
EVQLVESGGGLVQPGGSLRLSCAASGFTFSTYTMIWLRRAPGKGFEWVSTIDKDGNTNYVDSVKGRFAVSRDNTKNTLYLQMNSLKPEDTAMYYCTKHGSSARGQGTRVTVSS;
US 8,907,065の配列番号455(配列番号169):
EVQLVESGGGLVEPGGSLRLSCVASGFTFSSYDMSWVRQAPGKGLEWVSTINSGGGITYRGSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCENGGSSYRRGQGTQVTVSS
を含む。
US2011/0271358の配列番号43(配列番号170):
QVQLVQSGAELKKPGASVKMSCKASGYTFTGYTMHWVKQAPGQGLEWIGYINPRSGYTEYNQKFKDRTTLTADKSTSTAYMELSSLRSEDSAVYYCARPWFAYWGQGTLVTVSS;
US2011/0271358の配列番号44(配列番号171):
QVQLVQSGAEVKKPGASVKMSCKASGYTFTGYTMHWVKQAPGQGLEWIGYINPRSGYTEYNQKFKDRTTLTADKSTSTAYMELSSLRSEDTAVYYCARPWFAYWGQGTLVTVSS;
US2011/0271358の配列番号45(配列番号172):
QVQLVQSGAEVKKPGASVKMSCKASGYTFTGYTMHWVRQAPGQGLEWIGYINPRSGYTEYNQKFKDRTTLTADKSTSTAYMELSSLRSEDTAVYYCARPWFAYWGQGTLVTVSS;
US2011/0271358の配列番号46(配列番号173):
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYTMHWVRQAPGQGLEWIGYINPRSGYTEYNQKFKDRTTLTADKSTSTAYMELSSLRSEDTAVYYCARPWFAYWGQGTLVTVSS;
US2011/0271358の配列番号47(配列番号174):
QVQLVQSGAEVKKPGASVKVSCKASGYTFTGYTMHWVRQAPGQGLEWIGYINPRSGYTEYNQKFKDRTTITADKSTSTAYMELSSLRSEDTAVYYCARPWFAYWGQGTLVTVSS
より選択されるアミノ酸配列を含む重鎖;および/またはUS2011/0271358の配列番号48~51:
US2011/0271358の配列番号48(配列番号175):
DIVMTQSPASLTVTPGEKVTITCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKLEIK;
US2011/0271358の配列番号49(配列番号176):
DIVMTQSPASLSVTPGEKVTITCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKLEIK;
US2011/0271358の配列番号50(配列番号177):
DIVMTQSPAFLSVTPGEKVTITCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKLEIK;
US2011/0271358の配列番号51(配列番号178):
DIVMTQSPAFLSVTPGEKVTITCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQNDYSYPLTFGQGTKLEIK
より選択されるアミノ酸配列を含む軽鎖を含む。
1つの側面において、本発明は、シグナル伝達剤(例えば、免疫調節剤)を含むキメラタンパク質を提供する。多様な態様において、シグナル伝達剤は、減少した活性を有するように修飾される。いくつかの態様において、シグナル伝達剤は、1またはそれより多いその受容体に対する減少したアフィニティを有するように修飾され、これはキメラタンパク質の活性の減弱化を可能にし、かつ/または非特異的なシグナル伝達または望ましくない隔絶を防止する。多様な態様において、修飾シグナル伝達剤の活性は、特定の細胞タイプを標的とする標的化部分をさらに含むキメラタンパク質の背景で、回復される。特に、修飾シグナル伝達剤の活性は、標的細胞に対して回復されるが、非標的細胞に対しては回復されない。したがって、多様な態様において、本発明のキメラタンパク質は、標的細胞での増進した特異性および有効性、ならびにより低い全身毒性を含む減少した副作用などの療法的利点を提供する。
IFN-α2a(配列番号179):
CDLPQTHSLGSRRTLMLLAQMRKISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKEDSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMRSFSLSTNLQESLRSKE
のアミノ酸配列を有するアレル型IFN-α2aである。
IFN-α2b(配列番号180):
CDLPQTHSLGSRRTLMLLAQMRRISLFSCLKDRHDFGFPQEEFGNQFQKAETIPVLHEMIQQIFNLFSTKDSSAAWDETLLDKFYTELYQQLNDLEACVIQGVGVTETPLMKEDSILAVRKYFQRITLYLKEKKYSPCAWEVVRAEIMRSFSLSTNLQESLRSKE
のアミノ酸配列(アミノ酸23位でIFN-α2aと異なる)を有するアレル型IFN-α2bである。
TNF-α(配列番号181)
VRSSSRTPSDKPVAHVVANPQAEGQLQWLNRRANALLANGVELRDNQLVVPSEGLYLIYSQVLFKGQGCPSTHVLLTHTISRIAVSYQTKVNLLSAIKSPCQRETPEGAEAKPWYEPIYLGGVFQLEKGDRLSAEINRPDYLDFAESGQVYFGIIAL
のアミノ酸配列を有する。
TNF-β(配列番号182)
LPGVGLTPSAAQTARQHPKMHLAHSNLKPAAHLIGDPSKQNSLLWRANTDRAFLQDGFSLSNNSLLVPTSGIYFVYSQVVFSGKAYSPKATSSPLYLAHEVQLFSSQYPFHVPLLSSQKMVYPGLQEPWLHSMYHGAAFQLTQGDQLSTHTDGIPHLVLSPSTVFFGAFAL
のアミノ酸配列を有する。
TRAIL
MAMMEVQGGPSLGQTCVLIVIFTVLLQSLCVAVTYVYFTNELKQMQDKYSKSGIACFLKEDDSYWDPNDEESMNSPCWQVKWQLRQLVRKMILRTSEETISTVQEKQQNISPLVRERGPQRVAAHITGTRGRSNTLSSPNSKNEKALGRKINSWESSRSGHSFLSNLHLRNGELVIHEKGFYYIYSQTYFRFQEEIKENTKNDKQMVQYIYKYTSYPDPILLMKSARNSCWSKDAEYGLYSIYQGGIFELKENDRIFVSVTNEHLIDMDHEASFFGAFLVG
のアミノ酸配列を有する。
IL-1β(成熟型、野生型)
APVRSLNCTLRDSQQKSLVMSGPYELKALHLQGQDMEQQVVFSMSFVQGEESNDKIPVALGLKEKNLYLSCVLKDDKPTLQLESVDPKNYPKKKMEKRFVFNKIEINNKLEFESAQFPNWYISTSQAENMPVFLGGTKGGQDITDFTMQFVSS(配列番号183)
のアミノ酸配列を有する。
IL-2(成熟、野生型)
APTSSSTKKTQLQLEHLLLDLQMILNGINNYKNPKLTRMLTFKFYMPKKATELKHLQCLEEELKPLEEVLNLAQSKNFHLRPRDLISNINVIVLELKGSETTFMCEYADETATIVEFLNRWITFCQSIISTLT(配列番号184)
のアミノ酸配列を有する。
IL-4(成熟型、野生型)
HKCDITLQEIIKTLNSLTEQKTLCTELTVTDIFAASKNTTEKETFCRAATVLRQFYSHHEKDTRCLGATAQQFHRHKQLIRFLKRLDRNLWGLAGLNSCPVKEANQSTLENFLERLKTIMREKYSKCSS(配列番号185)
のアミノ酸配列を有する。
IL-6(成熟型、野生型)
APVPPGEDSKDVAAPHRQPLTSSERIDKQIRYILDGISALRKETCNKSNMCESSKEALAENNLNLPKMAEKDGCFQSGFNEETCLVKIITGLLEFEVYLEYLQNRFESSEEQARAVQMSTKVLIQFLQKKAKNLDAITTPDPTTNASLTTKLQAQNQWLQDMTTHLILRSFKEFLQSSLRALRQM(配列番号186)
のアミノ酸配列を有する。
IL-13(成熟型、野生型)
SPGPVPPSTALRELIEELVNITQNQKAPLCNGSMVWSINLTAGMYCAALESLINVSGCSAIEKTQRMLSGFCPHKVSAGQFSSLHVRDTKIEVAQFVKDLLLHLKKLFREGRFN(配列番号187)
のアミノ酸配列を有する。
IL-18(野生型)
MAAEPVEDNCINFVAMKFIDNTLYFIAEDDENLESDYFGKLESKLSVIRNLNDQVLFIDQGNRPLFEDMTDSDCRDNAPRTIFIISMYKDSQPRGMAVTISVKCEKISTLSCENKIISFKEMNPPDNIKDTKSDIIFFQRSVPGHDNKMQFESSSYEGYFLACEKERDLFKLILKKEDELGDRSIMFTVQNEDL(配列番号188)
のアミノ酸配列を有する。
IL-33(野生型)
MKPKMKYSTNKISTAKWKNTASKALCFKLGKSQQKAKEVCPMYFMKLRSGLMIKKEACYFRRETTKRPSLKTGRKHKRHLVLAACQQQSTVECFAFGISGVQKYTRALHDSSITGISPITEYLASLSTYNDQSITFALEDESYEIYVEDLKKDEKKDKVLLSYYESQHPSNESGDGVDGKMLMVTLSPTKDFWLHANNKEHSVELHKCEKPLPDQAFFVLHNMHSNCVSFECKTDPGVFIGVKDNHLALIKVDSSENLCTENILFKLSET(配列番号189)
のアミノ酸配列を有する。
いくつかの態様において、本発明のキメラタンパク質は、場合によって1またはそれより多いリンカーを含む。いくつかの態様において、本発明のキメラタンパク質は、標的化部分およびシグナル伝達剤を連結するリンカーを含む。いくつかの態様において、本発明のキメラタンパク質は、シグナル伝達剤内にリンカーを含む(例えば一本鎖TNFの場合、それは2つのリンカーを含み三量体を生じることができる)。
本発明のキメラタンパク質を産生するための方法を本明細書に記載する。例えば、当該技術分野で公知の方法を用いて、本発明のキメラタンパク質をコードするDNA配列(例えば修飾シグナル伝達剤および標的化部分およびリンカーをコードするDNA配列)を化学的に合成できる。合成DNA配列を、例えば発現調節配列を含む他の適切なヌクレオチド配列に連結して、所望のキメラタンパク質をコードする遺伝子発現構築物を産生できる。したがって、多様な態様において、本発明は、本発明のキメラタンパク質をコードするヌクレオチド配列を含む単離核酸を提供する。
本明細書記載のキメラタンパク質は、無機酸または有機酸と反応可能な十分に塩基性の官能基、あるいは無機塩基または有機塩基と反応可能なカルボキシル基を有して、薬学的に許容されうる塩を形成できる。薬学的に許容されうる酸付加塩は、当該技術分野で周知であるように、薬学的に許容されうる酸から形成される。こうした塩は、例えば、本明細書にその全体が援用されるJournal of Pharmaceutical Science, 66, 2-19(1977)およびThe Handbook of Pharmaceutical Salts; Properties, Selection, and Use. P. H. StahlおよびC. G. Wermuth(監修), Verlag, Zurich (Switzerland) 2002に列挙される薬学的に許容されうる塩を含む。
多様な態様において、本発明は、本明細書記載のキメラタンパク質および薬学的に許容されうるキャリアーまたは賦形剤を含む、薬学的組成物に関する。本明細書記載の任意の薬学的組成物を、薬学的に許容されうるキャリアーまたはビヒクルを含む組成物の構成要素として、被験体に投与できる。こうした組成物は場合によって、適切な投与のための形を提供するように、適切な量の薬学的に許容されうる賦形剤を含んでよい。
本発明によって投与しようとするキメラタンパク質の実際の用量は、特定の投薬型、および投与様式に応じて多様であろうことが認識されるであろう。キメラタンパク質の作用を修飾しうる多くの要因(例えば体重、性別、食餌、投与時間、投与経路、排出率、被験体の状態、薬剤組み合わせ、遺伝的素質および反応感度)が、当業者によって考慮されてよい。投与を連続して、あるいは最大許容用量内で1またはそれより多い別個の用量で実行することも可能である。所定の条件セットに対する最適投与率は、慣用的投薬型投与試験を用いて、当業者によって確認可能である。
多様な態様において本発明の薬学的組成物を、さらなる療法剤(単数または複数)と組み合わせて共投与する。共投与は、同時であるまたは連続的であってよい。
本明細書記載の方法および組成物は、限定されないが、癌、感染、免疫障害、自己免疫疾患、ならびに多くの他の疾患および障害を含む、多様な疾患および障害を治療するための適用を有する。
本発明はまた、本明細書記載の任意の剤(例えば多様なさらなる療法剤を伴うまたは伴わないキメラタンパク質)の投与のためのキットも提供する。キットは、本明細書記載の本発明の薬学的組成物の少なくとも1つを含む、物質または構成要素の集合である。したがって、いくつかの態様において、キットは、本明細書記載の薬学的組成物の少なくとも1つを含有する。
本明細書で使用する「a」、「an」、または「the」は、1または1より多くを意味してよい。
以下の実施例において、言及しない限り、IFNに対する突然変異は、ヒトIFN-α2、配列番号179に対するものである。
図1は、抗PD-L1 VHHおよびPBSに比較した際の、抗PD-L1ヒトIFN Q124Rキメラ構築物の抗腫瘍活性を示す。実験において、C57BL/6マウスに6x105 B16mCD20cl1黒色腫腫瘍細胞(マウス黒色腫細胞株)を皮下接種した(50μl)。腫瘍が、ノギスによって測定した際、±10mm2のサイズに到達した際、30μgの多様な構築物(100μl)での病変周囲治療を開始した。図1は、抗PD-L1がB16腫瘍モデルにおいて最小限の効果を有する一方、抗PD-L1-ヒトIFN Q124Rキメラは抗腫瘍活性および減少した腫瘍サイズを示したことを示す。
PD-1(プログラム細胞死タンパク質1)は、免疫チェックポイントとして機能し、T細胞のリガンドPD-L1(プログラム細胞死リガンド1)およびPD-L2に結合することによってT細胞の活性化を防止することにより、免疫系の下方制御において重要な役割を果たす。プレート結合アッセイをセットアップして、これらの2つのタンパク質間の相互作用に対するPD-1およびPD-L1 VHHの効果を評価した。
ヒトPD-L1(プログラム細胞死リガンド1)/減弱化IFNキメラ(「AcTaferon」)標的化の効率を、FACS分析によるヒトPD-L1陽性MDA-MB-321細胞株でのSTAT1リン酸化の定量により、調べた。
樹状細胞pSTATシグナル伝達アッセイを行った。研究したキメラは、抗ヒトPD-L1 VHH/ヒトIFN R149Aおよび抗ヒトPD-L1 VHH/ヒトIFN R33A/E120Rであった。2つの用量の剤を研究した:100ng/mlおよび500ng/ml。
本発明は、その特定の態様と関連して記載されてきているが、さらなる修飾が可能であり、本出願は、一般的に、本発明の原理にしたがい、かつ本発明が属する業内の公知のまたは慣用的な実施内で思い浮かぶような、かつ付随する請求項の範囲内に示すように、かつ従うように、本明細書の先の本質的な特徴に適用可能であるような本開示からの逸脱を含めて、本発明の任意の変形、使用または適応を含むと意図される。
本明細書に引用するすべての特許および刊行物は、その全体が本明細書に援用される。
Claims (7)
- (a)プログラム細胞死タンパク質1リガンド1(PD-L1)に特異的に結合する認識ドメインを含む、1つの標的化部分であって、組換えの重鎖のみの抗体(VHH)または一本鎖抗体(scFv)である、1つの標的化部分;および
(b)修飾シグナル伝達剤であって、前記修飾シグナル伝達剤は配列番号179の配列と少なくとも98%の同一性を有し、かつR149Aの突然変異を有するアミノ酸配列を含むヒトインターフェロンα2(IFNα2)であり、ここで前記突然変異型のヒトIFNα2は、野生型ヒトIFNα2と比較してIFN-α/β受容体(IFNAR)に対して減少したアフィニティまたは活性を有し、前記突然変異型のヒトIFNα2の減少したアフィニティまたは活性は、前記標的化部分により回復される、修飾シグナル伝達剤
を含むキメラタンパク質。 - 認識ドメインが、VHH またはヒト化VHH を含む、請求項1に記載のキメラタンパク質。
- 認識ドメインが、PD-L1を機能的に調節する、請求項1または2に記載のキメラタンパク質。
- 認識ドメインが、PD-L1に結合するがPD-L1を機能的に調節しない、請求項1または2に記載のキメラタンパク質。
- 癌を治療するための薬剤の製造のための請求項1~4のいずれか一項に記載のキメラタンパク質の使用。
- 前記キメラタンパク質は、1またはそれより多い追加の標的化部分を含む、請求項1~5のいずれか一項に記載のキメラタンパク質。
- 請求項1~6のいずれか一項に記載のキメラタンパク質および薬学的に許容されうる賦形剤またはキャリアーを含む、薬学的組成物。
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