JP2020530298A - Pd−1およびpd−l1結合物質 - Google Patents
Pd−1およびpd−l1結合物質 Download PDFInfo
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- VYXXMAGSIYIYGD-NWAYQTQBSA-N propan-2-yl 2-[[[(2R)-1-(6-aminopurin-9-yl)propan-2-yl]oxymethyl-(pyrimidine-4-carbonylamino)phosphoryl]amino]-2-methylpropanoate Chemical compound CC(C)OC(=O)C(C)(C)NP(=O)(CO[C@H](C)Cn1cnc2c(N)ncnc12)NC(=O)c1ccncn1 VYXXMAGSIYIYGD-NWAYQTQBSA-N 0.000 description 1
- 230000000722 protumoral effect Effects 0.000 description 1
- 208000005333 pulmonary edema Diseases 0.000 description 1
- JFINOWIINSTUNY-UHFFFAOYSA-N pyrrolidin-3-ylmethanesulfonamide Chemical compound NS(=O)(=O)CC1CCNC1 JFINOWIINSTUNY-UHFFFAOYSA-N 0.000 description 1
- 230000007115 recruitment Effects 0.000 description 1
- 230000008929 regeneration Effects 0.000 description 1
- 238000011069 regeneration method Methods 0.000 description 1
- 230000006941 response to substance Effects 0.000 description 1
- 102220219561 rs1060503777 Human genes 0.000 description 1
- 102200044937 rs121913396 Human genes 0.000 description 1
- 102200115907 rs121918081 Human genes 0.000 description 1
- 102200115315 rs121918084 Human genes 0.000 description 1
- 102200004185 rs199472688 Human genes 0.000 description 1
- 102220044576 rs200254470 Human genes 0.000 description 1
- 102220024619 rs267607627 Human genes 0.000 description 1
- 102220005261 rs33926796 Human genes 0.000 description 1
- 102220000379 rs397514441 Human genes 0.000 description 1
- 102220344309 rs397514441 Human genes 0.000 description 1
- 102200141681 rs6170 Human genes 0.000 description 1
- 102200085943 rs6190 Human genes 0.000 description 1
- 102200114571 rs74315431 Human genes 0.000 description 1
- 102220273516 rs768267292 Human genes 0.000 description 1
- 102220339220 rs771012029 Human genes 0.000 description 1
- 102220157938 rs886063483 Human genes 0.000 description 1
- 238000013207 serial dilution Methods 0.000 description 1
- 125000003607 serino group Chemical group [H]N([H])[C@]([H])(C(=O)[*])C(O[H])([H])[H] 0.000 description 1
- 230000035939 shock Effects 0.000 description 1
- 230000008054 signal transmission Effects 0.000 description 1
- 238000002741 site-directed mutagenesis Methods 0.000 description 1
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulphite Substances [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 1
- 210000004872 soft tissue Anatomy 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 230000009870 specific binding Effects 0.000 description 1
- 206010062261 spinal cord neoplasm Diseases 0.000 description 1
- 210000004085 squamous epithelial cell Anatomy 0.000 description 1
- 210000004500 stellate cell Anatomy 0.000 description 1
- 210000000130 stem cell Anatomy 0.000 description 1
- 208000003265 stomatitis Diseases 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 230000008093 supporting effect Effects 0.000 description 1
- 210000000225 synapse Anatomy 0.000 description 1
- 238000002626 targeted therapy Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 108091007466 transmembrane glycoproteins Proteins 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 230000003827 upregulation Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 230000008728 vascular permeability Effects 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 229940055760 yervoy Drugs 0.000 description 1
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- C07K16/2803—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 immunoglobulin superfamily
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Abstract
Description
本出願は、2017年8月9日出願の米国特許仮出願第62/542,921号の利益および優先権を主張する。この特許の内容は、参照によりその全体が本明細書に組み込まれる。
本発明は、一部は、PD−1またはPD−L1を結合する結合物質および治療薬および診断薬としてのそれらの使用に関する。
本明細書と共に電子申請された次記のテキストファイルの内容は、その全体が参照により本明細書に組み込まれる:配列リストのコンピュータ可読形式コピー(ファイル名:ORN−034PC_ST25、作成日付:2018年8月8日、ファイルサイズ:827KB)。
種々の実施形態では、本発明のPD−1またはPD−L1結合物質は、PD−1またはPD−L1に特異的に結合できるタンパク質ベースの物質である。種々の実施形態では、本発明のPD−1またはPD−L1結合物質は、PD−1またはPD−L1を機能的に調節することなくPD−1またはPD−L1に特異的に結合できるタンパク質ベースの物質である。
2PD23
QVQLQESGGGLVQPGGSLRLSCAASGFSMDYYAIAWFRQAPGKEREEISCITGSDFMVDTYYVASVKGRFTISRDNAENTAYLQMNNLKPEDTGVYFCAVRSTANTLCPSHYSVMDYWGKGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号70);
2PD26
QVQLQESGGGLVQAGGSLRLSCAASGFSMDYYAIAWFRQAPGKEREEISCITGSDFMVDTYYVASVKGRFTISRDNAENTAYLQMNNLKPEDTGVYFCAVRSTANTLCPSHYSVMDYWGKGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号71);
2PD90
QVQLQESGGGLVQPGGSLRLSCSASGFSVDYYAIAWFRQAPGKEREEISCITGSDFMVDTYYVASVKGRFTISRDNAKNTAYLQMNSLKPEDTGVYFCAVRSTANTLCPSHYSIMDYWGKGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号72);
2PD−106
QVQLQESGGGLVQPGGSLRLSCSASGFSMDYYAIAWFRQAPGKEREEISCITGSDFMVDTYYVASVKGRFTISRDNAKNTAHLQMNSLKPEDTGVYFCAVRSTANTLCPSHYSVMDYWGKGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号73);
2PD−16
QVQLQESGGGLVQAGGSLRLSCAASGGFNRVSYMGWYRQAPGTKRELVASVTSGGEITIADSVKGRFTVSRDNSKNTLYLQMNGLKPEDGATYWCNADIWVSDARMYNYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号74);
2PD71
QVQLQESGGGLVQTGESLRLSCAASGGFNRVSYMGWYRQAPGSKRELVASVTSGGEITVADSVKGRFTVSRDNNKNTLYLQMNGLKPEDGATYWCNADIWVSDARMYNYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号75);
2PD−152
QVQLQESGGGLVQTGESLRLSCAASGIIKSINFMGWYRQPPGTKRELVASTTSDGRTTVADSVKGRFTISRDNAKNTIYLEMSSLKPEDTATYWCNADIWLPSDRMYNYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号76);
2PD−12
QVQLQESGGGLVQAGGSLRLSCAVSGFILDYYGIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNALNTLYLQMNSLKPEDTAVYHCATATLCDGGIWGYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号77);
3PD55
QVQLQESGGGLAQAGGSLRLSCEGSGLSLDYDGVGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRGNALNTLYLQMNSLKPEDTAVYYCATATLCDGGIWGYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号78);
3PD82
QVQLQESGGGSVQPGGSLRLSCAVSGFILDYYGIGWFRQAPGKEREAVSCISSSDGSTYYADSVKGRFTISRDNALNTLYLQMNSLKPEDTAVYYCATATLCDGGIWGYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号:79);
2PD8
QVQLQESGGGSVQAGDSLRLSCTASGRTFSSLGMGWFRQAPGKEREFVSAIAWNGASTYYTESVKGRFTISRDDAKNTVYLQMNSLKPTDTAVYFCAASGLGSVVVTANEYDYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号80);
2PD27
QVQLQESGGGSVQPGKSLRLSCAASGRTFSSLGMGWFRQAPGKEREFVSAIAWNGASTYYTESVKGRFTISRDDAKNTVYLQMNSLKPTDTAVYFCAASGLGSVVVTANEYDYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号81);
2PD82
QVQLQESGGGLVQPGGSLRLSCTTSGFAFGSYDMGWVRQAPGKGPEWVSGINSGGRITDYADSVTGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCAQGDRSSWHYYGMDYWGKGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号82);または
3PD36
QVQLQESGGGLVQPGGSLRLSCAASGFSFGNNDMSWVRQAPGKGPEWVSAINSGGGSTYYADSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCATKSDPMTNEYDLWGXGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号83)。
102C3:
QVQLQESGGGLVQAGKSLRLSCAASGSIFSIHAMGWFRQAPGKEREFVAAITWSGGITYYEDSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAADRAESSWYDYWGQGTQVTVSS(配列番号1246);または
102C12:
QVQLQESGGGLVQAGKSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAGDKHQSSWYDYWGQGTQVTVSS(配列番号1247)。
EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAGDKHQSSWYDYWGQGTLVTVSS(配列番号87);
EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTATYYCAGDKHQSSWYDYWGQGTLVTVSS(配列番号88);
EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTATYYCAGDKHQSSWYDYWGQGTLVKVSS(配列番号89);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAEMSGISGWDYWGQGTQVQVSS(配列番号90);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAEMSGISGWDYWGQGTLVTVKS(配列番号91);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAEMSGISGWDYWGQGTLVTVQS(配列番号92);
EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVKVSS(配列番号93);
EVQLVESGGGLVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVQVSS(配列番号94);
EVQLVESGGGLVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVTVKS(配列番号95);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVTVQS(配列番号96);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVTVSS(配列番号97);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVKVSS(配列番号98);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVQVSS(配列番号99);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVTVKS(配列番号100);
EVQLVESGGGVVQPGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAAEMSGISGWDYWGQGTLVTVQS(配列番号101);
EVQLVESGGGVVQPGGSLRLSCAASGGTFSFYGMGWFRQAPGKEREFVADIRTSAGRTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAAEMSGISGWDYWGQGTLVTVSS(配列番号102);
DVQLVESGGGVVQPGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAAEMSGISGWDYWGQGTLVTVSS(配列番号103);
DVQLVESGGGVVQPGGSLRLSCAASGGTFSFYGMGWFRQAPGKEREFVADIRTSAGRTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAAEMSGISGWDYWGQGTLVTSSA(配列番号104);
EVQLVESGGGLVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTATYYCAAEMSGISGWDYWGQGTLVKVSSA(配列番号105);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAEMSGISGWDYWGQGTLVQVSSA(配列番号106);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAEMSGISGWDYWGQGTLVTVKSA(配列番号107);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAEMSGISGWDYWGQGTLVTVQSA(配列番号108);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAEMSGISGWDYWGQGTLVKVSSA(配列番号109);
EVQLVESGGGLVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVQVSSA(配列番号110);
EVQLVESGGGLVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVTVKSA(配列番号111);
EVQLVESGGGLVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVTVQSA(配列番号112);
EVQLVESGGGLVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVTVSSA(配列番号113);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVKVSSA(配列番号114);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVQVSSA(配列番号115);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVTVKSA(配列番号116);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVTVQSA(配列番号117);
EVQLVESGGGVVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAAEMSGISGWDYWGQGTLVTVSSA(配列番号118);
EVQLVESGGGVVQPGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAAEMSGISGWDYWGQGTLVTVSSA(配列番号119);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSS(配列番号120);
EVQLVESGGGLVQPGGSLRLSCAASGSIASIHAMGWERQAPGKEREEVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAIYYCAGDKHQSSWYDYWGQGTLVTVSS(配列番号121);
EVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWERQAPGKEREEVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSS(配列番号122);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWERQAPGKEREEVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGVVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVSSA(配列番号123);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWERQAPGKEREEVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGVVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVSSA(配列番号124);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWERQAPGKEREEVAVITVSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSFYDYWGQGTLVTVSS(配列番号125);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITVSGGITYYADSVKGRFTISRDQSKNTVYLQMNSLRPEDTALYYCAGDKHQSSFYDYWGQGTLVTVSS(配列番号126);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITVSGGITYYADSVKGRFTISRDPSKNTVYLQMNSLRPEDTALYYCAGDKHQSSFYDYWGQGTLVTVSS(配列番号127);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITVSGGITYYADSVKGRFTISRDPSKNTVYLQMNSLRPEDTALYYCAGDKHQSSFYDYWGQGTLVTVSS(配列番号128);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITVSGGITYYADSVKGRFTISRDQSKNTVYLQMNSLRPEDTALYYCAGDKHQSSFYDYWGQGTLVTVSS(配列番号129);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITVSGGITYYADSVKGRFTISRDSSKNTVYLQMNSLRPEDTALYYCAGDKHQSSFYDYWGQGTLVTVSS(配列番号130);
EVQLVESGGGLVQPGGSLRLSCAASGSIASIHAMGWERQAPGKEREEVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAIYYCAGDKHQSSWYDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGGSLRLSCAASGSIASIHAMGWERQAPGKEREEVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAIYYCAGDKHQSSWYDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGLVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTAVYYCTIGGSLSRSSQGTLVTVSS(配列番号131);および
MQIPQAPWPVVWAVLQLGWRPGWFLDSPDRPWNPPTFSPALLVVTEGDNATFTCSFSNTSESFVLNWYRMSPSNQTDKLAAFPEDRSQPGQDCRFRVTQLPNGRDFHMSVVRARRNDSGTYLCGAISLAPKAQIKESLRAELRVTERRAEVPTAHPSPSPRPAGQFQTLVVGVVGGLLGSLVLLVWVLAVICSRAARGTIGARRTGQPLKEDPSAVPVFVDYGELDFQWREKTPEPPVPCVPEQTEYATIVFPSGMGTSSPARRGSADGPRSAQPLRPEDGHCSWPL(配列番号132)。
EVQLVESGGGLVQAGGSLRLSCAASGGTFSFYGMGWFRQAPGKEQEFVADIRTSAGRTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCAAEMSGISGWDYWGQGTQVTVSS(配列番号133);
EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTATYYCAGDKHQSSWYDYWGQGTLVTVSS(配列番号134);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAGDKHQSSWYDYWGQGTLVKVSS(配列番号135);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAGDKHQSSWYDYWGQGTLVQVSS(配列番号136);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAGDKHQSSWYDYWGQGTLVTVKS(配列番号137);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAGDKHQSSWYDYWGQGTLVTVQS(配列番号138);
EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVKVSS(配列番号139);
EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVQVSS(配列番号140);
EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVTVKS(配列番号141);
EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVTVQS(配列番号142);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSS(配列番号143);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVKVSS(配列番号144);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVQVSS(配列番号145);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVTVKS(配列番号146);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVTVQS(配列番号147);
EVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSS(配列番号148);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSS(配列番号149);
EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTATYYCAGDKHQSSWYDYWGQGTLVTVSSA(配列番号150);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAGDKHQSSWYDYWGQGTLVKVSSA(配列番号151);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAGDKHQSSWYDYWGQGTLVQVSSA(配列番号152);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAGDKHQSSWYDYWGQGTLVTVKSA(配列番号153);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMCWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAGDKHQSSWYDYWGQGTLVTVQSA(配列番号154);
EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMCWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVKVSSA(配列番号155);
EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVQVSSA(配列番号156);
EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVTVKSA(配列番号157);
EVQLVESGGGLVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVTVQSA(配列番号158);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSSA(配列番号159);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVKVSSA(配列番号160);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVQVSSA(配列番号161);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVTVKSA(配列番号162);
EVQLVESGGGVVQAGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTALYYCAGDKHQSSWYDYWGQGTLVTVQSA(配列番号163);
EVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSSA(配列番号164);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSSA(配列番号165);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAIITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSS(配列番号166);
EVQLVESGGGLVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTAIYYCAGDKHQSSWYDYWGQGTLVTVSS(配列番号167);
EVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSS(配列番号168);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGVVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVSSA(配列番号169);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSWYDYWGQGTLVTVSSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSGGGGSEVQLVESGGGVVQPGNSLRLSCAASGFTFSSFGMSWVRQAPGKGLEWVSSISGSGSDTLYADSVKGRFTISRDNAKTTLYLQMNSLRPEDTALYYCTIGGSLSRSSQGTLVTVSSA(配列番号170);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITVSGGITYYADSVKGRFTISRDNSKNTVYLQMNSLRPEDTALYYCAGDKHQSSFYDYWGQGTLVTVSS(配列番号171);
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITVSGGITYYADSVKGRFTISRDQSKNTVYLQMNSLRPEDTALYYCAGDKHQSSFYDYWGQGTLVTVSS(配列番号172);および
DVQLVESGGGVVQPGGSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITVSGGITYYADSVKGRFTISRDPSKNTVYLQMNSLRPEDTALYYCAGDKHQSSFYDYWGQGTLVTVSS(配列番号173)。
2LIG2
QVQLQESGGGLVQAGGSLRLSCAASGFTLDYYAIGWFRQAPGKEREEVSCISSSDGSTYYADSVKGRFTISRDNAKNTVNLQMNSLKPEDTAVYYCATDGWSSCRHGIN−EYLYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号286);
または
2LIG3
QVQLQESGGGLVQAGGSLRLSCTASGTIFSINHMDWFRQAPGKQRELVALITSDGFPTYADSAKGRFTISRDNTKKTVSLQMNSLKPEDTAVYYCHVSSGVYNYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号287);
または
2LIG16
QVQLQESGGGLVQPGGSLRLSCAASGFTFDDYGMSWVRQAPGKGLEWVSAIRWNGGSTNYADSVKGRFTISRDNAKNTLYLQMNSLKSEDTAVYYCA−QGYY−CSGYGCPRGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号288);
または
2LIG22
QVQLQESGGGLVQPGGSLRLSCAASGFTLDYYAINWFRQAPGKEREEVSCISSSDGSTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCATSGWRLCRPTDEYDYSYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号289);
または
2LIG27
QVQLQESGGGVVQAGGSLRLSCTASGTIFSINRMDWFRQAPGKQRELVALITSDGTPTYADSAKGRFTISRDNTKKTVSLQMNSLKPEDTAVYYCHVSSGVYNYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号290);
または
2LIG29
QVQLQESGGGLVQTGGSLRLSCAASGFTFSSYGMSWVRQTPGKGPEWVSAIDSGGGSTSYADSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCA−QGYY−CSGYGCSDYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号291);
または
2LIG30
QVQLQESGGGLVQPGGSLRLSCAASGKIFSGNDMGWYRQAPGKQRELVGIITSGGITDYADAVKGRFTISRDNAKNMMYLQMNSLKPEDTAVYYCNMRDRTIWWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号292);
または
2LIG34
QVQLQESGGGSVQAGGSLRLSCTASGTIFSINRMDWFRQAPGKQRELVALITSDGTPTYADSAKGRFTISRDNTKKTVSLQMNSLKPEDTAVYYCHVSSGVYNYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号293);
または
2LIG35
QVQLQESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQTPGKGPEWVSAIDSGGGSTSYADSVKGRFTTSRDNAKNTLYLQMNSLKPEDTAVYYCA−QGYY−CSGYGCSDYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号294);
または
2LIG48
QVQLQESGGGLVQPGGSLRLSCAASGFTFNDYAMSWVRQAPGKGLEWVSGIRSNGGYTNYADSVKGRFTISRDNAKNTLYLQMNSLKSEDTAVYYCA−QGYY−CSGYGCYPGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号295);
または
2LIG65
QVQLQESGGGLVQAGGSLRLSCAASGFNLDPYAIAWFRQAPGKEREEVSCISSSDVGTYYADSVKGRFTISRDNAKKTVYLQMNSLKPEDTAVYYCATDGYYYCSDYPHPLYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号296);
または
2LIG85
QVQLQESGGGLVQPGGSLRLSCAASGFTFTAYAMSWFRQAPGKEREEVSCINSSDGSTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYHCATDGWRDCTWSNEYAYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号297);
または
2LIG86
QVQLQESGGGLVQPGGSLRLSCAASGFTFDYYAIGWFRQAPGKEREEVSCISGSDSSTYYADSVKGRFTIVRDNAQNTVYLQMNSLKPEDTAIYYCAVTGWRTCRGLNEYDYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号298);
または
2LIG89
QVQLQESGGGLVQPGGSLRLSCAASGFNLDPYAIAWFRQAPGKEREEVSCISSSDVGTYYADSVKGRFTISRDNTKKTVYLQMNSLKPEDTAVYYCATDGYYYCSDYPHPLYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号299);
または
2LIG97
QVQLQESGGGLVQAGESLRLSCTASGTIFSINRMDWFRQAPGKQRELVALITSDGTPTYADSAKGRFTISRDNTKKTVSLQMNSLKPEDTAVYYCHVSSGVYNYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号300);
または
2LIG99
QVQLQESGGGLVQAGGSLRLSCTASGTIFSINRMDWFRQAPGKQRELVALITSDGTPAYADSAKGRFTISRDNTKKTVSLQMNSLKPEDTAVYYCHVSSGVYNYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号301);
または
2LIG109
QVQLQESGGGLVQSGGSLRLSCKTSGFTFSSYGMSWVRQTPGKGPEWVSAIDSGGGSTSYADSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCAQGYY−CSGYGCSDYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号302);
または
2LIG127
QVQLQESGGGLVQPGGSLRLSCAASGFNLDPYAIGWFRQAPGKEREEVSCISSGDGSKYYADSVKGRFTMSRDNAKKTVYLQMNSLKPEDTAVYYCATDGYYYCSDYPHPLYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号303);
または
2LIG139
QVQLQESGGGLVQPGGSLRLSCAVSGFNLDPYAIAWFRQAPGKEREEVSCISSSDVGTYYADSVKGRFTISRDNAKKTVYLQMNSLKPEDTAVYYCATDGYYYCSDYPHPLYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号304);
または
2LIG176
QVQLQESGGGLVQAGGSLRLSCAASESIFSIEAMGWYRQAPGKQRELVAAIFGGGFTNYADSVKGRFTISRDNANRTVYLQMNSLKPEDTAVYYCNADLVSGSSRLYDYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号305);
または
2LIG189
QVQLQESGGGLVQAGGSLRLSCAASGKIFSGNDMGWYRQAPGKQRELVGIITSGGITDYADAVKGRFTISRDNAKNMMYLQMNSLKPEDTAVYYCNMRDRTIWWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号306);
または
3LIG3
QVQLQESGGGLVQPGGSLRLSCAASGFTLDYYAIGWFRQAPGKEREEVSCISSSDGSTYYADSVKGRFTISRDNAKNTVNLQMNSLKPEDTAVYYCATDGWSSCRHGINEYLYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号307);
または
3LIG7
QVQLQESGGGLVQAGGSLRLSCAASGFTFSSYGMSWVRQTPGKGPEWVSAIDSGGGSTSYADSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCAQGYY−CSGYGCSDYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号308);
または
3LIG8
QVQLQESGGGLVQPGGSLRLSCTASGTIFSINRMDWFRQAPGKQRELVALITSDGTPTYADSAKGRFTISRDNTKKTVSLQMNSLKPEDTAVYYCHVSSGVYNYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号309);
または
3LIG9
QVQLQESGGGLVQPGGSLRLSCAASGFTFSSYGMSWVRQTPGKGPEWVSAIDSGGGSTSYADSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCAQGYYCSGYGCSDYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号310);
または
3LIG18
QVQLQESGGGLVQPGGSLRLSCAASGFNLDPYAIAWFRQAPGKEREEVSCISSSDVGTYYADSVKGRFTISRDNAKKTVYLQMNSLKPEDTAVYYCATDGYYYCSDYPHPLYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号311);
または
3LIG20
QVQLQESGGGLVXAGGSLRLSCAASGRTFSISAMGWFRQAPGKEREFVAAITWSGGSTSYTDSVKGRFTISRDNAKNTLYLQMNSLKPEDTAIYYCAAMGRTNYGVIYDPNMYNYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号312);
または
3LIG28
QVQLQESGGGLVQPGGSLRLSCAASGFTLDYYAINWFRQAPGKEREEVSCISSSDGSTYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAVYYCATSGWRLCRPTDEYDYLYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号313);
または
3LIG29
QVQLQESGGGLVQAGGSMRLSCAASGFTFSSYGMSWVRQTPGKGPEWVSAIDSGGGSTSYADSVKGRFTISRDNAKNTLYLQMNSLKPEDTAVYYCAQGYYCSGYGCSDYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号314);
または
3LIG30
QVQLQESGGGTVQAGGSLRLSCAASGFTFNDYAMSWVRQAPGKGLEWVSGIRSNGGYTNYADSVKGRFTISRDNAKNTLYLQMNSLKSEDTAVYYCAQGYYCSGYGCYPGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号315);
または
3LIG33
QVQLQESGGGLVQPGTSLRLSCAASGFTLDYYAIGWFRQAPGKEREEVSCISSSDGSTYYADSVKGRFTISRDNAKNTVNLQMNSLKPEDTAVYYCATDGWSSCRHGINEYLYWGQGTQVTVSSAAAYPYDVPDYGSHHHHHH(配列番号316)。
シグナル伝達物質とのキメラおよび融合体
種々の実施形態では、本発明のPD−1またはPD−L1結合物質は、1種類または複数種類のシグナル伝達物質とのキメラまたは融合体の一部である。したがって、本発明は、例えば、PD−1またはPD−L1に対する標的化部分および1種類または複数種類のシグナル伝達物質を含むキメラまたは融合タンパク質を提供する。
種々の実施形態では、本発明のPD−1またはPD−L1結合物質は、本明細書に記載の1種類または複数種類のシグナル伝達物質および/または1つまたは複数の追加の標的化部分のキメラまたは融合体の一部である。したがって、本発明は、例えば、1種類または複数種類のシグナル伝達物質およびPD−1またはPD−L1に対する標的化部分および/または1つまたは複数の追加の標的化部分を含むキメラまたは融合タンパク質を提供する。
SNTSESFK(SNTSESF)FRVTQLAPKAQIKE−NH2
種々の実施形態では、PD−1またはPD−L1結合物質は、1つまたは複数の官能基、残基、または部分を含み得る。種々の実施形態では、1つまたは複数の官能基、残基、または部分は、本明細書に記載のうちのいずれかのシグナル伝達物質または標的化部分に結合されるか、または遺伝的に融合される。いくつかの実施形態では、このような官能基、残基または部分は、1つまたは複数の望ましい特性または官能基を本発明のPD−1またはPD−L1結合物質に付与する。このような官能基およびそれらをPD−1またはPD−L1結合物質に導入する技術の例は、当技術分野において既知であり、例えば、Remington’s Pharmaceutical Sciences,16th ed.,Mack Publishing Co.,Easton,Pa.(1980)を参照されたい。
種々の実施形態では、PD−1またはPD−L1結合物質は、VHHである標的化部分を含む。種々の実施形態では、VHHは、特定の生物源または特定の調製法に限定されない。例えば、VHHは通常、次記により得ることができる:(1)天然の重鎖抗体のVHHドメインを単離することにより;(2)天然のVHHドメインをコードするヌクレオチド配列の発現により;(3)天然のVHHドメインの「ヒト化」により、またはこのようなヒト化VHHドメインをコードする核酸の発現により;(4)ヒト由来などの哺乳動物種由来などの任意の動物種由来の天然のVHドメインの「ラクダ化」、またはこのようなラクダ化VHドメインをコードする核酸の発現により;(5)当該技術分野で記載の「ドメイン抗体」または「Dab」の「ラクダ化」により、またはこのようなラクダ化VHドメインをコードする核酸の発現により;(6)当該技術分野において既知のタンパク質、ポリペプチドまたはその他のアミノ酸配列のための合成または半合成技術を用いることにより;(7)当該技術分野において既知の核酸合成技術を用いてVHHをコードする核酸を調製し、続けて、こうして得られた拡散を発現させることにより;および/または(8)前述の1つまたは複数の任意の組み合わせにより。
本明細書で記載のPD−1またはPD−L1結合物質(および/またはいずれか他の治療薬)は、無機酸もしくは有機酸と反応できる、充分に塩基性の官能基を有し、または無機酸もしくは有機酸と反応できる、カルボキシル基を有して、薬学的に許容可能な塩を形成できる。薬学的に許容可能な酸付加塩は、当該技術分野でよく知られているように、薬学的に許容可能な酸から形成される。このような塩は、例えば、Journal of Pharmaceutical Science,66,2−19(1977およびThe Handbook of Pharmaceutical Salts;Properties,Selection,and Use.P.H.Stahl and C.G.Wermuth(eds.),Verlag,Zurich(Switzerland)2002、に挙げられた薬学的に許容可能な塩を含む。これらの文献は参照によりその全体が本明細書に組み込まれる。
種々の実施形態では、本発明は、本明細書で記載のPD−1またはPD−L1結合物質(および/またはいずれか他の治療薬)および薬学的に許容可能な担体または賦形剤を含む医薬組成物に関する。いくつかの実施形態では、本発明は、本発明のPD−1またはPD−L1結合物質を含む医薬組成物に関する。別の実施形態では、本発明は、本明細書に記載のうちのいずれか他の治療薬を含む医薬組成物に関する。さらなる実施形態では、本発明は、本発明のPD−1またはPD−L1結合物質と本明細書に記載のうちのいずれか他の治療薬との組み合わせを含む医薬組成物に関する。本明細書で記載のいずれの医薬組成物も、薬学的に許容可能な担体またはビークルを含む組成物の成分として、対象に投与することができる。このような組成物は必要に応じ、適切な投与用の形態を与えるように、適切な量の薬学的に許容可能な賦形剤を含み得る。
本発明により投与されるPD−1またはPD−L1結合物質および/または本明細書に記載のうちのいずれかの治療薬の実際の用量は、特定の剤形および投与方法に応じて変わることは理解されよう。当業者なら、PD−1またはPD−L1結合物質の作用を変え得る多くの要因(例えば、体重、性別、食事、投与時期、投与経路、排出速度、対象の状態、薬剤の組み合わせ、遺伝的素因および反応感度)を考慮に入れることができる。投与は、最大耐量の範囲内で連続的にまたは1種類または複数種類の別々の投与量で実施できる。与えられた一連の条件に対する最適投与速度は、従来の用量投与試験を使って、当業者により確認できる。
種々の実施形態では、本発明の医薬組成物は、追加の治療薬と共に同時投与される。同時投与は、同時または順次であってよい。
本明細書に記載の方法および組成物は、限定されないが、癌、感染症、免疫異常、および炎症性疾患または状態を含む、種々の疾患および障害を治療する用途がある。
本発明はまた、本明細書に記載のうちのいずれかのPD−1またはPD−L1結合物質の投与(例えば、追加の治療薬を含み、または含まず)のためのキットを提供する。キットは、本明細書に記載の少なくとも1種類の本発明の医薬組成物を含む、材料または成分の集合体である。したがって、いくつかの実施形態では、キットは、本明細書に記載の少なくとも1種類の医薬組成物を含む。
本明細書で使用される場合、「a」、「an」、または「the」は、1つ(1種類)または2つ以上(2種類以上)を意味し得る。
PD−1またはPD−L1抗体を含むヒトAcTaferonアルファによる標的化の効率を、STAT1リン酸化のFACSベース定量化により調べた。具体的には、標的化を、一次末梢血単核球(PBMC)、遺伝子導入Hek293T細胞(PD−1標的化について)、またはヒト乳癌細胞株MDA−MB−321(PD−L1標的化について)で分析した。以下の抗体を使用した:
抗PD−1抗体:
−Pem:ペムブロリズマブ/キイトルーダ(Merck)
−Niv:ニボルマブ/オプジーボ(BMS)
抗PD−L1抗体:
−Ate:アテゾリズマブ/テセントリク/MPDL3280(Roche/Genetech)
−Dur:デュルバルマブ/MEDI4736(Celgene/AstraZeneca)
−Ave:アベルマブ/MSB0010718C(Merck/Pfizer)
−Bms:BMS−936559/MDX−1105(BMS)
重鎖:配列番号1244
軽鎖:配列番号1245
Hek293T細胞に、リン酸カルシウムを用いて膜結合型のPD−1またはPD−L1を遺伝子導入した。遺伝子導入の2日後に、細胞を再懸濁し、PD−L1 Ab−AFN(FACS緩衝液:2%FBS;0.5mM EDTAを補充したPBS中1μg/ml)と4℃で2時間インキュベートした。2回の洗浄後に、細胞をFITC標識THE HIS抗体(GenScript;4℃で1時間)とインキュベートした。結合を、CellQuest Pro Version 4.0.2ソフトウェア(BD Biosciences)を使用して、FACSCalibur測定器(BD Biosciences)で測定した。図2中のデータは、PD−L1 AFNがPD−L1遺伝子導入細胞に選択的に結合し、一方でPD−1 AFNがPD−1発現細胞のみに結合したことを示す。
健康なドナーのバフィーコート由来のPBMCを、Lymphoprep(StemCell Technologies)を用いる密度勾配遠心分離により単離した。細胞をFACS緩衝液(2%FBS、PBS中0.5mMのEDTA)で2回洗浄し、FITC結合抗ヒトPD−1(クローンPD−1.3.1.3;Miltenyi Biotec)を用いて4℃で20分間染色した。2回の洗浄剤後に、細胞を段階希釈PD−1 Ab−AFNを用いて37℃で15分間刺激した。固定(10分間、37℃、Fix Buffer I;BD Biosciences)および透過処理(30分、氷上、Perm III Buffer I;BD Biosciences)および洗浄後に、細胞を抗STAT1 pY701 Ab(BD Biosciences)で染色した。試料を、CellQuest Pro Version 4.0.2ソフトウェア(BD Biosciences)を使用して、FACSCalibur(BD Biosciences)で取得した。図3のデータは、ペムブロリズマブおよびニボルマブ結合AcTaferonはPD−1陽性PBMC中でSTAT1をリン酸化できたが、PD−1陰性PBMC中ではリン酸化できなかったことを示す。
Hek293T細胞に、リン酸カルシウムを用いてヒトPD−1または空のベクターを遺伝子導入した。2日後に、細胞を再懸濁し、段階希釈PD−1 AFNで刺激した(15分、37℃)。pSTAT1を上述のように定量化した。図4のデータは、PD−1 Ab AFNが、PD−1発現Hek293T細胞ではSTAT1リン酸化を効率的に誘導するが、モック遺伝子導入細胞ではリン酸化を誘導しないことを示す。
MDA−MB−321細胞を、10%FBSを補充したDMEM培地中で、PD−(L)1 AFNを用いて37℃で15分間刺激した。刺激後、pSTAT1を上述のように定量化した。PD−L1結合AFNは、STAT1を効率的にリン酸化でき、それによりPD−L1標的化作用を示すが、PD−1結合AFNはそうではなかった(図5)。
ELISAアッセイを、PD−1抗原に対して本明細書の別の場所で記載のように行って種々のPD−1 VHHの結合親和性を評価した。PD−1 VHHの親和性を、以下の表1に表す(列A/対照を参照):
抗ヒトPD−L1 VHHの、PD−1との相互作用を阻害するそれらの能力についての最初のスクリーニング後に、次のPD−L1 VHHをさらなる特性評価用に選択した:2LIG3(配列番号287)、2LIG27(配列番号290)、2LIG97(配列番号300)、2LIG99(配列番号301)、3LIG8(配列番号309)、2LIG189(配列番号306)、および2LIG176(配列番号305)。
PD−L1標的化モノクローナル抗体であるモノクローナル抗体アテゾリズマブ(Ate)を、標的細胞に対するインターフェロン活性の特異性を評価するための試料として選択した。
PD−L1 VHH 2LIG99を、ヒトPD−L1 VHH標的化AcTaferon(AFN)のインビボ抗腫瘍効力を評価するために選択した。
AcTaferon(AFN)のヒトPD−1(プログラム死1)標的化の効率を、FACSにおけるPD−1または空のベクター遺伝子導入Hek293T細胞中のSTAT1リン酸化の定量化により調べた。
102C3:
QVQLQESGGGLVQAGKSLRLSCAASGSIFSIHAMGWFRQAPGKEREFVAAITWSGGITYYEDSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAADRAESSWYDYWGQGTQVTVSS(配列番号1246);および
102C12:
QVQLQESGGGLVQAGKSLRLSCAASGSIASIHAMGWFRQAPGKEREFVAVITWSGGITYYADSVKGRFTISRDNAKNTVYLQMNSLKPEDTAIYYCAGDKHQSSWYDYWGQGTQVTVSS(配列番号1247)。
本発明をその特定の実施形態と関連付けて説明してきたが、その実施形態はさらに修正が可能であり、本出願は、一般的に、本発明の原理に従った本発明の任意の変形、使用、または改変を包含することが意図され、本発明が属する技術内の既知のまたは日常的な実施の範囲に入る、および上に示されるおよび以下の添付の請求項の範囲に入る本質的な特徴に該当し得る本開示からの乖離を含むものと理解されよう。
本明細書で引用されている全ての特許および刊行物は、参照によりその全体が本明細書に組み込まれる。
Claims (46)
- 配列番号301、287、290、300、305、306、および309のうちの1つと少なくとも90%の同一性を有するアミノ酸配列を含むPD−L1結合物質。
- 3つの相補性決定領域(CDR1、CDR2、およびCDR3)を含む少なくとも1つの標的化部分を含むPD−L1結合物質であって、
(a)CDR1が、配列番号199、181、178、183、189、196、201、および206のうちのいずれか1つから選択されるアミノ酸配列を含み;
(b)CDR2が、配列番号259、260、241、242、245、246、263、および264のうちのいずれか1つから選択されるアミノ酸配列を含み;ならびに
(c)CDR3が、配列番号268、272、および277のうちのいずれか1つから選択されるアミノ酸配列を含む、
PD−L1結合物質。 - 前記標的化部分が、単一ドメイン抗体である、請求項1または2に記載のPD−L1結合物質。
- 前記標的化部分が、VHH、ヒト化VHH、またはラクダ化VHHを含む、請求項3に記載のPD−L1結合物質。
- 1種類または複数種類のシグナル伝達物質を含む、請求項1〜4のいずれか1項に記載のPD−L1結合物質。
- 前記シグナル伝達物質が、インターフェロン、インターロイキン、および腫瘍壊死因子のうちの1つまたは複数から選択され、これらはいずれも任意に改変されていてもよい、請求項5に記載のPD−L1結合物質。
- 1種類または複数種類の追加のシグナル伝達物質を含む、請求項1〜6のいずれか1項に記載のPD−L1結合物質。
- 前記1つまたは複数の追加の標的化部分が腫瘍抗原を認識し、任意に腫瘍抗原を機能的に調節してもよい、請求項7に記載のPD−L1結合物質。
- 前記1つまたは複数の追加の標的化部分が免疫細胞上の抗原を認識し、任意に免疫細胞上の抗原を機能的に調節してもよい、請求項8に記載のPD−L1結合物質。
- 前記免疫細胞が、T細胞、B細胞、樹状細胞、マクロファージ、好中球、およびNK細胞から選択される、請求項9に記載のPD−L1結合物質。
- 細胞傷害性T細胞を腫瘍細胞にまたは腫瘍環境に動員する、請求項1〜10のいずれか1項に記載のPD−L1結合物質。
- PD−L1を認識してPD−L1に結合し、その活性を実質的に機能的に調節するかあるいはその活性を実質的に機能的に調節しない、請求項1〜11のいずれか1項に記載のPD−L1結合物質。
- 請求項1〜12のいずれか1項に記載のPD−L1結合物質をコードする組換え核酸組成物。
- 請求項13に記載の核酸を含む宿主細胞。
- 3つの相補性決定領域(CDR1、CDR2、およびCDR3)を含む少なくとも1つの標的化部分を含むPD−1結合物質であって、
(a)CDR1が、配列番号2〜23のうちのいずれか1つから選択されるアミノ酸配列を含み;
(b)CDR2が、配列番号24〜54のうちのいずれか1つから選択されるアミノ酸配列を含み;および
(c)CDR3が、配列番号55〜69のうちのいずれか1つから選択されるアミノ酸配列を含む、
PD−1結合物質。 - 3つの相補性決定領域(CDR1、CDR2、およびCDR3)を含む少なくとも1つの標的化部分を含むPD−L1結合物質であって、
(a)CDR1が、配列番号177〜207のうちのいずれか1つから選択されるアミノ酸配列を含み;
(b)CDR2が、配列番号208〜266のうちのいずれか1つから選択されるアミノ酸配列を含み;および
(c)CDR3が、配列番号267〜285のうちのいずれか1つから選択されるアミノ酸配列を含む、
PD−L1結合物質。 - 前記標的化部分が、単一ドメイン抗体である、請求項15または16に記載のPD−1またはPD−L1結合物質。
- 前記標的化部分が、VHH、ヒト化VHH、またはラクダ化VHHを含む、請求項17に記載のPD−1またはPD−L1結合物質。
- 配列番号70〜83、1246、または1247のうちの1つと少なくとも90%の同一性を有するアミノ酸配列を含む、請求項18に記載のPD−1結合物質。
- 配列番号286〜316のうちの1つと少なくとも90%の同一性を有するアミノ酸配列を含む、請求項18に記載のPD−L1結合物質。
- 1種類または複数種類のシグナル伝達物質を含む、請求項15〜20のいずれか1項に記載のPD−1またはPD−L1結合物質。
- 前記シグナル伝達物質が、インターフェロン、インターロイキン、および腫瘍壊死因子のうちの1つまたは複数から選択され、これらはいずれも任意に改変されていてもよい、請求項21に記載のPD−1またはPD−L1結合物質。
- 1つまたは複数の追加の標的化部分を含む、請求項15〜22のいずれか1項に記載のPD−1またはPD−L1結合物質。
- 前記1つまたは複数の追加の標的化部分が腫瘍抗原を認識し、任意に腫瘍抗原を機能的に調節してもよい、請求項23に記載のPD−1またはPD−L1結合物質。
- 前記1つまたは複数の追加の標的化部分が免疫細胞上の抗原を認識し、任意に免疫細胞上の抗原を機能的に調節してもよい、請求項24に記載のPD−1またはPD−L1結合物質。
- 前記免疫細胞が、T細胞、B細胞、樹状細胞、マクロファージ、好中球、およびNK細胞から選択される、請求項25に記載のPD−1またはPD−L1結合物質。
- 細胞傷害性T細胞を腫瘍細胞にまたは腫瘍環境に動員する、請求項15〜26のいずれか1項に記載のPD−1またはPD−L1結合物質。
- PD−1またはPD−L1を認識して結合し、その活性を実質的に機能的に調節するかあるいはその活性を実質的に機能的に調節しない、請求項15〜27のいずれか1項に記載のPD−1またはPD−L1結合物質。
- 請求項15〜28のいずれか1項に記載のPD−1またはPD−L1結合物質をコードする組換え核酸組成物。
- 請求項29に記載の核酸を含む宿主細胞。
- 癌、感染症、免疫異常、および/または自己免疫疾患のうちの1つまたは複数を有する患者における使用に適している、請求項15〜28のいずれか1項に記載のPD−1またはPD−L1結合物質。
- PD−1またはPD−L1を標的とする抗原または受容体認識ドメインを含む標的化部分ならびにインターフェロン、インターロイキン、および腫瘍壊死因子のうちの1つまたは複数から選択されるシグナル伝達物質を含むキメラの有効量を、投与を必要とする患者に投与することを含む、癌を治療または予防するための方法。
- 前記シグナル伝達物質が、改変されている、請求項32に記載の方法。
- 前記PD−1またはPD−L1結合物質が、請求項1〜12または請求項15〜28のいずれか1項に記載のPD−1またはPD−L1結合物質である、請求項32または請求項33に記載の方法。
- 前記PD−1結合物質が、3つの相補性決定領域(CDR1、CDR2、およびCDR3)を含む少なくとも1つの標的化部分を含み、
(a)CDR1が、配列番号2〜23のうちのいずれか1つから選択されるアミノ酸配列を含み;
(b)CDR2が、配列番号24〜54のうちのいずれか1つから選択されるアミノ酸配列を含み;および
(c)CDR3が、配列番号55〜69のうちのいずれか1つから選択されるアミノ酸配列を含む、
請求項32〜34のいずれか1項に記載の方法。 - 前記PD−L1結合物質が、3つの相補性決定領域(CDR1、CDR2、およびCDR3)を含む少なくとも1つの標的化部分を含み、
(a)CDR1が、配列番号177〜207のうちのいずれか1つから選択されるアミノ酸配列を含み;
(b)CDR2が、配列番号208〜266のうちのいずれか1つから選択されるアミノ酸配列を含み;および
(c)CDR3が、配列番号267〜285のうちのいずれか1つから選択されるアミノ酸配列を含む、
請求項32〜34のいずれか1項に記載の方法。 - 前記癌が、基底細胞癌、胆道癌、膀胱癌、骨癌、脳および中枢神経系癌、乳癌、腹膜の癌、子宮頸癌、絨毛癌、結腸および直腸癌、結合組織癌、消化器系の癌、子宮内膜癌、食道癌、眼癌、頭頸部の癌、胃癌(胃腸癌を含む)、神経膠芽腫、肝癌、ヘパトーマ、上皮内腫瘍、腎臓癌または腎性癌(kidney or renal cancer)、喉頭癌、白血病、肝臓癌、肺癌(例えば、小細胞肺癌、非小細胞肺癌、肺腺癌、および肺扁平上皮癌)、黒色腫、骨髄腫、神経芽腫、口腔癌(唇、舌状、舌、口内、および咽頭)、卵巣癌、膵臓癌、前立腺癌、網膜芽細胞腫、横紋筋肉腫、直腸癌、呼吸器系癌、唾液腺癌腫、肉腫、皮膚癌、扁平上皮細胞癌、胃癌、精巣癌、甲状腺癌、子宮または子宮内膜癌、泌尿器系の癌、外陰癌、ホジキンリンパ腫および非ホジキンリンパ腫、ならびにB細胞リンパ腫を含むリンパ腫(低悪性度/濾胞性非ホジキンリンパ腫(NHL)を含む)、小リンパ球性(SL)NHL、中悪性度/濾胞性NHL、中悪性度びまん性NHL、高悪性度免疫芽細胞NHL、高悪性度リンパ芽球性NHL、高悪性度小型非切れ込み核細胞性NHL、巨大腫瘤病変NHL、マントル細胞リンパ腫、エイズ関連リンパ腫、およびワルデンシュトレームマクログロブリン血症、慢性リンパ性白血病(CLL)、急性リンパ性白血病(ALL)、毛様細胞性白血病、慢性骨髄芽球性白血病、ならびに他の癌腫および肉腫、および移植後リンパ増殖性疾患(PTLD)、ならびに母斑症、浮腫(例えば脳腫瘍に関連するもの)、およびメグズ症候群に関連する異常血管増殖のうちの1つまたは複数から選択される、請求項32〜36のいずれか1項に記載の方法。
- 癌、感染症、免疫異常、および/または自己免疫疾患のうちの1つまたは複数の治療における使用のための請求項1〜37のいずれか1項に記載のPD−1またはPD−L1結合物質。
- 癌、感染症、免疫異常、および/または自己免疫疾患のうちの1つまたは複数を治療するための薬物の製造のための請求項1〜38のいずれか1項に記載のPD−1またはPD−L1結合物質の使用。
- (a)請求項1〜12または16〜28のいずれか1項に記載のPD−L1結合物質;および
(b)野生型IFNα2に比べて改善された安全性を付与する1つまたは複数の変異を有する改変ヒトIFNα2
を含むキメラタンパク質であって、
前記標的化部分および前記改変シグナル伝達物質が、任意に1つまたは複数のリンカーにより連結されていてもよい、キメラタンパク質。 - 前記改変ヒトIFNα2が、位置R120、M148、R149、およびL153に1つまたは複数の変異を含む、請求項40に記載のキメラタンパク質。
- 前記改変ヒトIFNα2が、R120E、R149A、およびL153Aから選択される1つまたは複数の変異を含む、請求項40に記載のキメラタンパク質。
- 前記改変ヒトIFNα2が、R120E変異と、R149AまたはL153A変異のいずれかとを含む、請求項40に記載のキメラタンパク質。
- (a)請求項1〜12または請求項16〜28のいずれか1項に記載のPD−L1結合物質;および
(b)野生型IFNβに比べて改善された安全性を付与する1つまたは複数の変異を有する改変ヒトIFNβ
を含むキメラタンパク質であって、
前記標的化部分および前記改変シグナル伝達物質が、任意に1つまたは複数のリンカーにより連結されていてもよい、キメラタンパク質。 - 前記改変ヒトIFNβが、位置W22、R27、L32、R35、V148、L151、R152、およびY155に1つまたは複数の変異を含む、請求項44に記載のキメラタンパク質。
- 前記改変ヒトIFNβが、W22G、R27G、L32A、L32G、R35A、R35G、V148G、L151G、R152A、R152Gから選択される1つまたは複数の変異を含む、請求項45に記載のキメラタンパク質。
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JP7423511B2 (ja) | 2024-01-29 |
CA3069994A1 (en) | 2019-02-14 |
EP3664829A1 (en) | 2020-06-17 |
WO2019032663A1 (en) | 2019-02-14 |
US11498966B2 (en) | 2022-11-15 |
US20200407448A1 (en) | 2020-12-31 |
CN111328286A (zh) | 2020-06-23 |
EP3664829A4 (en) | 2021-05-05 |
US20230295304A1 (en) | 2023-09-21 |
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