JP7001652B2 - 生体系におけるプロテアーゼ活性を検出するための組成物及び方法 - Google Patents
生体系におけるプロテアーゼ活性を検出するための組成物及び方法 Download PDFInfo
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Description
C225v5AB重鎖アミノ酸配列:
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSQDTAIYYCARALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK*(配列番号2)
C225v5抗体軽鎖アミノ酸配列:
QILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*(配列番号16)
C225v4抗体重鎖アミノ酸配列:
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK*(配列番号244)
C225v6抗体重鎖アミノ酸配列:
QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSQDTAIYYCARALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYASTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK*(配列番号253)
Av1抗体重鎖アミノ酸配列:
QVQLQESGPGLVRPSQTLSLTCTVSGYSITSDHAWSWVRQPPGRGLEWIGYISYSGITTYNPSLKSRVTISRDNSKNTLYLQMNSLRAEDTAVYYCARSLARTTAMDYWGQGSLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号254)
Av1抗体軽鎖アミノ酸配列:
DIQMTQSPSSLSASVGDRVTITCRASQDISSYLNWYQQKPGKAPKLLIYYTSRLHSGVPSRFSGSGSGTDFTFTISSLQPEDIATYYCQQGNTLPYTFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号255)
4D11軽鎖配列
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号26)
4D11重鎖配列
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIDPEGRQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDIGGRSAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号28)
4D11v2重鎖配列
EVHLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIDPEGRQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDIGGRSAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号256)
4D11v2軽鎖配列
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLXKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号257)
可変軽鎖アミノ配列Lc4
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号258)
可変重鎖アミノ配列Hc4
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDIGGRSAFDYWGQGTLVTVSS(配列番号259)
可変軽鎖アミノ配列Lc5
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号260)
可変重鎖アミノ配列Hc5
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSPPYHGQFDYWGQGTLVTVSS(配列番号261)
可変軽鎖アミノ配列Lc7
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号262)
可変重鎖アミノ配列Hc7
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSPPFFGQFDYWGQGTLVTVSS(配列番号263)
可変軽鎖アミノ配列Lc8
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号264)
可変重鎖アミノ配列Hc8
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKHIGRTNPFDYWGQGTLVTVSS(配列番号265)
可変軽鎖アミノ配列Lc13
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号266)
可変重鎖アミノ配列Hc13
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTEYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSAAAFDYWGQGTLVTVSS(配列番号267)
可変軽鎖アミノ配列Lc16
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号268)
可変重鎖アミノ配列Hc16
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSPPYYGQFDYWGQGTLVTVSS(配列番号269)
可変軽鎖アミノ配列Lc19
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号270)
可変重鎖アミノ配列Hc19
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSPPFFGQFDYWGQGTLVTVSS(配列番号271)
可変軽鎖アミノ配列Lc21
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号272)
可変重鎖アミノ配列Hc21
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDIGGRSAFDYWGQGTLVTVSS(配列番号273)
可変軽鎖アミノ配列Lc24
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号274)
可変重鎖アミノ配列Hc24
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEEMGWQTLYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSAAAFDYWGQGTLVTVSS(配列番号275)
可変軽鎖アミノ配列Lc26
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号276)
可変重鎖アミノ配列Hc26
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDIGGRSAFDYWGQGTLVTVSS(配列番号277)
可変軽鎖アミノ配列Lc27
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号278)
可変重鎖アミノ配列Hc27
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSPPFYGQFDYWGQGTLVTVSS(配列番号279)
可変軽鎖アミノ配列Lc28
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号280)
可変重鎖アミノ配列Hc28
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSPPFFGQFDYWGQGTLVTVSS(配列番号281)
可変軽鎖アミノ配列Lc30
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号282)
可変重鎖アミノ配列Hc30
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEEMGWQTLYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYAKSAAAFDYWGQGTLVTVSS(配列番号283)
可変軽鎖アミノ配列Lc31
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号284)
可変重鎖アミノ配列Hc31
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDIGGRSAFDYWGQGTLVTVSS(配列番号285)
可変軽鎖アミノ配列Lc32
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号286)
可変重鎖アミノ配列Hc32
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIDPEGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSAAAFDYWGQGTLVTVSS(配列番号287)
可変軽鎖アミノ配列Lc37
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号288)
可変重鎖アミノ配列Hc37
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSPPHNGQFDYWGQGTLVTVSS(配列番号289)
可変軽鎖アミノ配列Lc39
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号290)
可変重鎖アミノ配列Hc39
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTEYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSAAAFDYWGQGTLVTVSS(配列番号291)
可変軽鎖アミノ配列Lc40
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号292)
重鎖アミノ配列Hc40
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSPPFFGQFDYWGQGTLVTVSS(配列番号293)
可変軽鎖アミノ配列Lc47
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSVVAPLTFGQGTKVEIKR(配列番号294)
可変重鎖アミノ配列Hc47
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIDEMGWQTEYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSAAAFDYWGQGTLVTVSS(配列番号295)
可変4B2軽鎖
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTLDAPPQFGQGTKVEIKR(配列番号296)
可変4B2重鎖
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEQMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDIGGRSAFDYWGQGTLVTVSS(配列番号297)
可変4D11軽鎖
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKR(配列番号22)
可変4D11重鎖
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIDPEGRQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDIGGRSAFDYWGQGTLVTVSS(配列番号24)
可変4E7軽鎖
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQSLVAPLTFGQGTKVEIKR(配列番号298)
可変4E7重鎖
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEEMGWQTKYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSAAAFDYWGQGTLVTVSS(配列番号299)
可変4E11軽鎖
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQALDAPLMFGQGTKVEIKR(配列番号300)
可変4E11重鎖
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIEPMGQLTEYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDIGGRSAFDYWGQGTLVTVSS(配列番号301)
可変6B7軽鎖
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQALVAPLTFGQGTKVEIKR(配列番号302)
可変6B7重鎖
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIDEMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSAAAFDYWGQGTLVTVSS(配列番号303)
可変6F8軽鎖
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQALVAPLTFGQGTKVEIKR(配列番号304)
可変6F8重鎖
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIDEMGWQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSAAAFDYWGQGTLVTVSS(配列番号305)
W-(CH2)n-でQ
ここで、
Wは、--NH--CH2--又は--CH2--である;
Qは、アミノ酸、ペプチドである;及び
nは、0~20の整数である。
W-(CH2)n-Q
ここで、
Wは、--NH--CH2--又は--CH2--であり;
Qは、アミノ酸、ペプチドであり;及び
nは、0~20の整数である。
他に定義しない限り、本発明に関連して使用される科学技術用語は、当業者によって一般的に理解される意味を有するものとする。さらに、文脈によって必要とされない限り、単数形の用語は複数を含むものとし、複数形の用語は単数を含むものとする。一般に、本明細書に記載の細胞及び組織培養、分子生物学、ならびにタンパク質及びオリゴ又はポリヌクレオチド化学、及びハイブリダイゼーションに関連して利用される命名法、及び技術は、当技術分野で公知であり一般的に使用されている。組換えDNA、オリゴヌクレオチド合成、ならびに組織培養及び形質転換(例えば、エレクトロポレーション、リポフェクション)のために、標準的な技術が使用される。酵素反応及び精製技術は、製造業者の仕様に従って行われるか、又は当技術分野で一般的なように又は本明細書に記載のように達成される。前述の技術及び手順は、一般的に当技術分野で公知の従来法により行われるか、又は本明細書を通して引用され考察されている様々な一般的文献やより具体的な文献に記載されているように行われる。例えば、Sambrook et al. Molecular Cloning: A Laboratory Manual (2d ed., Cold Spring Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989))を参照されたい。本明細書に記載の分析化学、合成有機化学、ならびに医薬及び製薬化学、に関連して使用される命名法、及びこれらの実験手順や技術は、当該分野で周知で一般的に使用されているものである。化学合成、化学分析、薬学的調製、製剤化、及び送達、ならびに患者の治療のために、標準的な技術が使用される。
キット、及び/又は本開示の方法で用いられる活性化可能抗体及び/又はコンジュゲート化活性化可能抗体は、生体試料中の少なくとも1つの標的に特異的である。生体試料は、例えば、新鮮な細胞試料、凍結細胞試料、新鮮な組織試料、及び/又は凍結組織試料である。いくつかの実施態様において、試料は、癌又は他の腫瘍性状態に罹患しているか、罹患しているリスクがあるか、又は罹患していると疑われる患者からのものである。いくつかの実施態様において、試料は、炎症性疾患に罹患しているか、罹患しているリスクがあるか、又は罹患していると疑われる患者からのものである。いくつかの実施態様において、試料は、自己免疫疾患に罹患しているか、罹患しているリスクがあるか、又は罹患していると疑われる患者からのものである。いくつかの実施態様において、試料は、線維性疾患に罹患しているか、罹患しているリスクがあるか、又は罹患していると疑われる患者からのものである。いくつかの実施態様において、試料は、難聴に罹患しているか、罹患しているリスクがあるか、又は罹患していると疑われる患者からのものである。
活性化可能抗体及び/又はコンジュゲート化活性化可能抗体は、患者試料中の標的の検出に有用であり、従って診断薬として有用である。例えば、活性化可能抗体及び/又はコンジュゲート化活性化可能抗体は、患者試料中の標的のレベルを検出するためのインビトロアッセイ、例えばELISAで使用される。いくつかの実施態様において、活性化可能抗体及び/又はコンジュゲート化活性化可能抗体は、患者試料、例えば組織中の標的レベルを検出するために、インサイチュアッセイ、例えば本明細書に開示されるインサイチュイメージングで使用される。いくつかの実施態様において、活性化可能抗体及び/又はコンジュゲート化活性化可能抗体は、患者又は患者の試料、例えば器官又は組織中の標的レベルを検出するために、本明細書に開示されるものなどのエクスビボアッセイで使用される。本明細書に開示されるいくつかの実施態様において、活性化可能抗体及び/又はコンジュゲート化活性化可能抗体は、患者中の標的レベルを検出するために、インビボアッセイ、例えばインビボイメージングで使用される。これらの実施態様のいずれにおいても、対象は、例えば表1に列記したもの、又はそれらの任意の組み合わせからの標的である。
3954-1204-C225v5活性化可能抗体の重鎖ヌクレオチド配列:
[C225v5(配列番号1)]
[caggtgcagctgaaacagagcggcccgggcctggtgcagccgagccagagcctgagcattacctgcaccgtgagcggctttagcctgaccaactatggcgtgcattgggtgcgccagagcccgggcaaaggcctggaatggctgggcgtgatttggagcggcggcaacaccgattataacaccccgtttaccagccgcctgagcattaacaaagataacagcaaaagccaggtgttttttaaaatgaacagcctgcaaagccaggataccgcgatttattattgcgcgcgcgcgctgacctattatgattatgaatttgcgtattggggccagggcaccctggtgaccgtgagcgcggctagcaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgaactgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaatga](配列番号1)
3954-1204-C225v5活性化可能抗体重鎖アミノ酸配列:
[C225v5(配列番号2)]
[QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSQDTAIYYCARALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK*](配列番号2)
3954-1204-C225v5活性化可能抗体軽鎖ヌクレオチド配列:
[スペーサー(配列番号5)][マスク(配列番号6)][リンカー1(配列番号7)][1204 基質(配列番号8)][リンカー2(配列番号9)][C225(配列番号10)]
[caaggccagtctggccag][tgcatctcacctcgtggttgtccggacggcccatacgtcatgtac][ggctcgagcggtggcagcggtggctctggtggatccggt][ctgagcggccgttccgataatcat][ggcagtagcggtacc][cagatcttgctgacccagagcccggtgattctgagcgtgagcccgggcgaacgtgtgagctttagctgccgcgcgagccagagcattggcaccaacattcattggtatcagcagcgcaccaacggcagcccgcgcctgctgattaaatatgcgagcgaaagcattagcggcattccgagccgctttagcggcagcggcagcggcaccgattttaccctgagcattaacagcgtggaaagcgaagatattgcggattattattgccagcagaacaacaactggccgaccacctttggcgcgggcaccaaactggaactgaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgttag](配列番号3)
3954-1204-C225v5活性化可能抗体軽鎖アミノ酸配列:
[スペーサー(配列番号11)][マスク(配列番号12)][リンカー1(配列番号13)][1204 基質(配列番号14)][リンカー2(配列番号15)][C225(配列番号16)]
[QGQSGQ][CISPRGCPDGPYVMY][GSSGGSGGSGGSG][LSGRSDNH][GSSGT][QILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*](配列番号4)
3954-NSUB-C225v5マスク化抗体軽鎖ヌクレオチド配列:
[スペーサー(配列番号5)][マスク(配列番号6)][リンカー1-非切断可能基質リンカー2(配列番号19)][C225(配列番号10)]
[caaggccagtctggccag][tgcatctcacctcgtggttgtccggacggcccatacgtcatgtac][ggctcgagcggtggcagcggtggctctggtggctcaggtggaggctcgggcggtgggagcggcggttct][cagatcttgctgacccagagcccggtgattctgagcgtgagcccgggcgaacgtgtgagctttagctgccgcgcgagccagagcattggcaccaacattcattggtatcagcagcgcaccaacggcagcccgcgcctgctgattaaatatgcgagcgaaagcattagcggcattccgagccgctttagcggcagcggcagcggcaccgattttaccctgagcattaacagcgtggaaagcgaagatattgcggattattattgccagcagaacaacaactggccgaccacctttggcgcgggcaccaaactggaactgaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgttag](配列番号17)
3954-NSUB-C225v5仮面抗体軽鎖アミノ酸配列:
[スペーサー(配列番号11)][マスク(配列番号12)][リンカー1-非切断可能基質リンカー2(配列番号20)][C225(配列番号16)]
[QGQSGQ][CISPRGCPDGPYVMY][GSSGGSGGSGGSGGGSGGGSGGS][QILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*](配列番号18)
PBA=親抗体(例えば、セツキシマブ)と比較した抗EGFR活性化可能抗体の活性化と結合の%、
Ab EGFR=セツキシマブ結合を用いた切片上のEGFR IHCの染色強度、
Pb EGFR=抗EGFR活性化可能抗体インサイチュイメージングを用いた切片上のEGFR IHCの染色強度、
Abインサイチュイメージング=セツキシマブ結合の強度、
Pbインサイチュイメージング=抗EGFR活性化可能抗体の結合強度。
抗Jagged抗体構築物及び抗Jagged活性化可能抗体構築物:
4D11軽鎖可変領域ヌクレオチド配列
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCGGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGACGGTTGTGGCGCCTCCGTTATTCGGCCAAGGGACCAAGGTGGAAATCAAACGT(配列番号21)
4D11軽鎖可変領域アミノ酸配列
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKR(配列番号22)
4D11重鎖可変領域ヌクレオチド配列
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGTCAAGTATTGACCCGGAAGGTCGGCAGACATATTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAAGACATCGGCGGCAGGTCGGCCTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCA(配列番号23)
4D11重鎖可変領域アミノ酸配列
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIDPEGRQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDIGGRSAFDYWGQGTLVTVSS(配列番号24)
4D11軽鎖ヌクレオチド配列
GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCGGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGACGGTTGTGGCGCCTCCGTTATTCGGCCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT(配列番号25)
4D11軽鎖アミノ酸配列
DIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号26)
4D11重鎖ヌクレオチド配列
GAGGTGCAGCTGTTGGAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCCTGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCCGCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGTCAAGTATTGAAGAGATGGGTTGGCAGACAAAGTACGCAGACTCCGTGAAGGGCCGGTTCACCATCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCCTGAGAGCCGAGGACACGGCCGTATATTACTGTGCGAAATCGGCTGCTGCTTTTGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTAGCACCAAGGGCCCATCGGTCTTCCCCCTGGCACCCTCCTCCAAGAGCACCTCTGGGGGCACAGCGGCCCTGGGCTGCCTGGTCAAGGACTACTTCCCCGAACCGGTGACGGTGTCGTGGAACTCAGGCGCCCTGACCAGCGGCGTGCACACCTTCCCGGCTGTCCTACAGTCCTCAGGACTCTACTCCCTCAGCAGCGTGGTGACCGTGCCCTCCAGCAGCTTGGGCACCCAGACCTACATCTGCAACGTGAATCACAAGCCCAGCAACACCAAGGTGGACAAGAAAGTTGAGCCCAAATCTTGTGACAAAACTCACACATGCCCACCGTGCCCAGCACCTGAACTCCTGGGGGGACCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACACCCTCATGATCTCCCGGACCCCTGAGGTCACATGCGTGGTGGTGGACGTGAGCCACGAAGACCCTGAGGTCAAGTTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATGCCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCACGTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAGGACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCTCCAACAAAGCCCTCCCAGCCCCCATCGAGAAAACCATCTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTGTACACCCTGCCCCCATCCCGGGAGGAGATGACCAAGAACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTATCCCAGCGACATCGCCGTGGAGTGGGAGAGCAATGGGCAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGCTGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCTCACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTCTTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACCACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAAA(配列番号27)
4D11重鎖アミノ酸配列
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSSIDPEGRQTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKDIGGRSAFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(配列番号28)
5342-1204-4D11軽鎖ヌクレオチド配列
CAAGGCCAGTCTGGCCAGTGCAATATTTGGCTCGTAGGTGGTGATTGCAGGGGCTGGCAGGGGGGCTCGAGCGGTGGCAGCGGTGGCTCTGGTGGTCTGAGCGGCCGTTCCGATAATCATGGCGGCGGTTCTGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCGGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGACGGTTGTGGCGCCTCCGTTATTCGGCCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT(配列番号29)
5342-1204-4D11軽鎖アミノ酸配列
QGQSGQCNIWLVGGDCRGWQGGSSGGSGGSGGLSGRSDNHGGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEXFATYYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号30)
5342-PLGL-4D11軽鎖ヌクレオチド配列
CAAGGCCAGTCTGGCCAGTGCAATATTTGGCTCGTAGGTGGTGATTGCAGGGGCTGGCAGGGGGGCTCGAGCGGTGGCAGCGGTGGCTCTGGTGGCTCAGGTGGAGGCTCGCCACTGGGCCTGGGCGGTTCTGACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACCATCACTTGCCGGGCAAGTCAGAGCATTAGCAGCTATTTAAATTGGTATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCGGCATCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAACTTACTACTGTCAACAGACGGTTGTGGCGCCTCCGTTATTCGGCCAAGGGACCAAGGTGGAAATCAAACGTACGGTGGCTGCACCATCTGTCTTCATCTTCCCGCCATCTGATGAGCAGTTGAAATCTGGAACTGCCTCTGTTGTGTGCCTGCTGAATAACTTCTATCCCAGAGAGGCCAAAGTACAGTGGAAGGTGGATAACGCCCTCCAATCGGGTAACTCCCAGGAGAGTGTCACAGAGCAGGACAGCAAGGACAGCACCTACAGCCTCAGCAGCACCCTGACGCTGAGCAAAGCAGACTACGAGAAACACAAAGTCTACGCCTGCGAAGTCACCCATCAGGGCCTGAGCTCGCCCGTCACAAAGAGCTTCAACAGGGGAGAGTGT(配列番号31)
5342-PLGL-4D11軽鎖アミノ酸配列
QGQSGQCNIWLVGGDCRGWQGGSSGGSGGSGGSGGGSPLGLGGSDIQMTQSPSSLSASVGDRVTITCRASQSISSYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQTVVAPPLFGQGTKVEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(配列番号32)
3954-1204-C225v4活性化可能抗体重鎖ヌクレオチド配列:
[C225v4(配列番号243)]
[caggtgcagctgaaacagagcggcccgggcctggtgcagccgagccagagcctgagcattacctgcaccgtgagcggctttagcctgaccaactatggcgtgcattgggtgcgccagagcccgggcaaaggcctggaatggctgggcgtgatttggagcggcggcaacaccgattataacaccccgtttaccagccgcctgagcattaacaaagataacagcaaaagccaggtgttttttaaaatgaacagcctgcaaagcaacgataccgcgatttattattgcgcgcgcgcgctgacctattatgattatgaatttgcgtattggggccagggcaccctggtgaccgtgagcgcggctagcaccaagggcccatcggtcttccccctggcaccctcctccaagagcacctctgggggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgtcagtcttcctcttccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctgcccccatcccgggatgaactgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaatga](配列番号243)
3954-1204-C225v4活性化可能抗体重鎖アミノ酸配列:
[C225v4(配列番号244)]
[QVQLKQSGPGLVQPSQSLSITCTVSGFSLTNYGVHWVRQSPGKGLEWLGVIWSGGNTDYNTPFTSRLSINKDNSKSQVFFKMNSLQSNDTAIYYCARALTYYDYEFAYWGQGTLVTVSAASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK*](配列番号244)
3954-1204-C225v4活性化可能抗体軽鎖ヌクレオチド配列:
[スペーサー(配列番号5)][マスク(配列番号6)][リンカー1(配列番号7)][1204基質(配列番号8)][リンカー2(配列番号9)][C225v4(配列番号247)]
[caaggccagtctggccag][tgcatctcacctcgtggttgtccggacggcccatacgtcatgtac][ggctcgagcggtggcagcggtggctctggtggatccggt][ctgagcggccgttccgataatcat][ggcagtagcggtacc][cagatcttgctgacccagagcccggtgattctgagcgtgagcccgggcgaacgtgtgagctttagctgccgcgcgagccagagcattggcaccaacattcattggtatcagcagcgcaccaacggcagcccgcgcctgctgattaaatatgcgagcgaaagcattagcggcattccgagccgctttagcggcagcggcagcggcaccgattttaccctgagcattaacagcgtggaaagcgaagatattgcggattattattgccagcagaacaacaactggccgaccacctttggcgcgggcaccaaactggaactgaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgttag](配列番号245)
3954-1204-C225v4活性化可能抗体軽鎖アミノ酸配列:
[スペーサー(配列番号11)][マスク(配列番号12)][リンカー1(配列番号13)][1204基質(配列番号14)][リンカー2(配列番号15)][C225v4(配列番号248)]
[QGQSGQ][CISPRGCPDGPYVMY][GSSGGSGGSGGSG][LSGRSDNH][GSSGT][QILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*](配列番号246)
3954-NSUB-C225v4マスク化抗体軽鎖ヌクレオチド配列:
[スペーサー(配列番号5)][マスク(配列番号6)][リンカー1-非切断可能基質-リンカー2(配列番号19)][C225(配列番号247)]
[caaggccagtctggccag][tgcatctcacctcgtggttgtccggacggcccatacgtcatgtac][ggctcgagcggtggcagcggtggctctggtggctcaggtggaggctcgggcggtgggagcggcggttct][cagatcttgctgacccagagcccggtgattctgagcgtgagcccgggcgaacgtgtgagctttagctgccgcgcgagccagagcattggcaccaacattcattggtatcagcagcgcaccaacggcagcccgcgcctgctgattaaatatgcgagcgaaagcattagcggcattccgagccgctttagcggcagcggcagcggcaccgattttaccctgagcattaacagcgtggaaagcgaagatattgcggattattattgccagcagaacaacaactggccgaccacctttggcgcgggcaccaaactggaactgaaacgtacggtggctgcaccatctgtcttcatcttcccgccatctgatgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtggaaggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgttag](配列番号249)
3954-NSUB-C225v4マスク化抗体軽鎖アミノ酸配列:
[スペーサー(配列番号11)][マスク(配列番号12)][リンカー1-非切断可能基質-リンカー2(配列番号20)][C225v4(配列番号248)]
[QGQSGQ][CISPRGCPDGPYVMY][GSSGGSGGSGGSGGGSGGGSGGS][QILLTQSPVILSVSPGERVSFSCRASQSIGTNIHWYQQRTNGSPRLLIKYASESISGIPSRFSGSGSGTDFTLSINSVESEDIADYYCQQNNNWPTTFGAGTKLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC*](配列番号250)
HT29異種移植腫瘍担持マウスに、12.5mg/kgのAlexa Fluor 750コンジュゲート化活性化可能抗EGFR抗体を腹腔内注射した。イメージングの1時間前に、マウスに、クエンチしたPEG化Cy5.5基質プローブ(2nmol)を静脈内注射した。活性化可能抗EGFR抗体の注射の24時間後、IVIS Spectrum/CT imaging system (Caliper LifeSciences)を使用して、マウスをイメージングした。この処置中、マウスを37℃で気体麻酔(5%イソフルラン)下で維持した。750nmでの標識活性化可能抗EGFR抗体構築物の分布は、抗体活性化とEGFR受容体結合の指標であるため、この波長でのイメージングを使用して、活性化可能抗EGFR抗体3954-1204-c225v4と非切断可能マスク化抗EGFR抗体3954-NSUB-c225v4との蓄積レベルを評価した。腫瘍組織内のプローブの活性化動態を追跡することにより、基質切断のレベルを評価するために、680nmでのイメージングを使用した.最後に、剖検を使用して、エクスビボで生体内分布を評価した。結果は、図13A及び13Bに示される。
本発明をその詳細な説明に則して記載したが、以上の記載は本発明の範囲を例示することを意図するものであり、これを限定することを意図するものではない。本発明の範囲は、添付の特許請求の範囲により定められる。他の側面、利点、及び変形例も、添付の特許請求の範囲内に含まれる。
Claims (34)
- 第1の活性化可能抗体を用いて、第2の活性化可能抗体による治療対象の患者を選択するインビトロの方法であって、
前記第1の活性化可能抗体は、非切断状態において、
(i)標的に特異的に結合する抗体又はその抗原結合断片(AB)と、
(ii)前記ABに連結された、切断剤であるプロテアーゼの基質として機能するポリペプチドである切断可能部分(CM)と、
(iii)前記CMを介して前記ABに連結されたマスキング部分(MM)と
を含み、
ここで、前記第1の活性化可能抗体が前記CMにおいて切断されると、前記第1の活性化可能抗体が活性化されると共に、前記第1の活性化可能抗体が非切断状態にある場合には、前記MMが前記標的に対する前記ABの特異的結合と干渉することにより、前記標的に対する前記ABの結合が阻害されるように構成され、
前記第2の活性化可能抗体は、非切断状態において、
(i)前記第1の活性化可能抗体と同一の標的に特異的に結合するABと、
(ii)前記第1の活性化可能抗体と同一のプロテアーゼの基質として機能するポリペプチドであるCMと、
(iii)前記CMを介して前記ABに連結されたMMと
を含み、
ここで、前記第2の活性化可能抗体が非切断状態にある場合には、前記MMが前記標的に対する前記ABの特異的結合と干渉するように構成され、
前記方法は、
I.前記患者から採取され、支持マトリックスに結合された組織試料内における、共局在化する切断剤及び標的の存在又は不在を検出する工程
を含み、前記工程Iにおける検出は、
(a)前記第1の活性化可能抗体を非切断状態で前記組織試料と接触させ、
(b)前記組織試料を前記支持マトリックスに結合されたまま洗浄し、
(c)前記組織試料内に活性化状態の前記第1の活性化可能抗体が検出可能なレベルで存在するか否かを原位置(in situ)で測定する
ことを含み、
ここで、前記組織試料内に活性化状態の前記第1の活性化可能抗体が検出可能なレベルで存在する場合には、前記患者は前記共局在化する切断剤及び標的の存在について陽性であると共に、前記組織試料内に活性化状態の前記第1の活性化可能抗体が検出可能なレベルで存在しない場合、惹いては、前記切断剤若しくは前記標的、又は前記切断剤及び前記標的の両方が、組織試料中に検出可能なレベルで存在しない又は共局在しない場合には、前記患者は前記共局在化する切断剤及び標的の存在について陰性であり、
前記方法は更に、
II.前記工程Iにおいて前記共局在化する切断剤及び標的の存在について陽性であると判断された前記患者を、非切断状態にある前記第2の活性化可能抗体の治療有効量による治療対象として選択する工程を含む、方法。 - 前記組織試料内に活性化状態の前記第1の活性化可能抗体が検出可能なレベルで存在するか否かの原位置での測定が、検出可能な標識に連結された前記第1の活性化可能抗体を用いて、或いは、活性化状態の前記第1の活性化可能抗体に特異的に結合する、検出可能な標識を含む二次試薬を用いて実施される、請求項1に記載の方法。
- 前記第1の活性化可能抗体と前記第2の活性化可能抗体とが同一である、請求項1又は2に記載の方法。
- 前記第1の活性化可能抗体と前記第2の活性化可能抗体とが異なる、請求項1又は2に記載の方法。
- 前記組織試料が凍結組織試料である、請求項1~4の何れか一項に記載の方法。
- 前記組織試料が腫瘍組織試料である、請求項1~5の何れか一項に記載の方法。
- 前記患者が、癌に罹患している患者、癌に罹患する虞がある患者、又は癌に罹患していると疑われる患者である、請求項1~6の何れか一項に記載の方法。
- 前記患者が、炎症性疾患に罹患している患者、炎症性疾患に罹患する虞がある患者、又は炎症性疾患に罹患していると疑われる患者である、請求項1~6の何れか一項に記載の方法。
- 前記ABが、ベバシズマブ、ラニビズマブ、セツキシマブ、パニツムマブ、インフリキシマブ、アダリムマブ、ナタリズマブ、バシリキシマブ、エクリズマブ、エファリズマブ、トシツモマブ、イブリツモマブ、チウキセタン、リツキシマブ、オセルリズマブ、オファツムマブ、オビヌツズマブ、ダクリズマブ、ブレンツキシマブベドチン、ゲムツズマブ、ゲムツズマブオゾガマイシン、アレムツズマブ、アブシキシマブ、オマリズマブ、トラスツズマブ、トラスツズマブエムタンシン、パリビズマブ、イピリムマブ、トレメリムマブ、Hu5c8、ペルツズマブ、エルツマキソマブ、アバタセプト、タネズマブ、バビツキシマブ、ザルツムマブ、マプタムマブ、マツズマブ、ニモツズマブ、ICR62、mAb528、CH806、MDX-447、エドレコロマブ、RAV12、huJ591、エタネルセプト、アレファセプト、アナキンラ、GC1008、アデカツムマブ、フィギツムマブ、トシリズマブ、ウステキヌマブ、及びデノスマブからなる群から選択される抗体、又は、前記群から選択される抗体の抗原結合断片である、請求項1~8の何れか一項に記載の方法。
- 前記ABが、1-92-LFA-3、抗ルイス-Y、アペリンJ受容体、APRIL、BAFF、CS補体、C-242、CD2、CD3、CD9、CD11a、CD19、CD20、CD22、CD25、CD28、CD30、CD33、CD40、CD40L、CD41、CD44、CD47、CD52、CD56、CD64、CD70、CD80、CD86、CD95、CDI17、CD132(IL-2RG)、CD133、CD137、CD138、CDI72A、CEACAM5(CEA)、CEACAM6(NCA-90)、CLAUDIN-3、CLAUDIN-4、cMet、コラーゲン、Cripto、CSFR、CSFR-1、CTLA-4、CTGF、CXCLI0、CXCL13、CXCRI、CXCR2、CXCR4、CYR61、DL44、DLL4、DPP-4、EGFR、エンドセリンB受容体(ETBR)、EpCAM、EPHA2、ERBB3、RSVのFタンパク質、FAP、FGF-2、FGF8、FGFRI、FGFR2、FGFR3、FGFR4、葉酸受容体、G-CSF、G-CSFR、GLUTI、GLUT4、GM-CSF、GM-CSFR、GP IIb/IIIa受容体s、Gpl30、GPIIB/IIIA、GPNMB、HER2/neu、HGF、hGH、ヒアルロニダーゼ、IFNα、IFNβ、IFNγ、IgE、IgE受容体(FceRI)、IGF、IGFIR、ILIB、ILIR、IL2、ILI1、IL12、IL12p40、IL-12R、IL-12Rbetal、IL13、IL13R、IL15、ILI7、IL18、IL21、IL23、IL23R、IL27/IL27R(wsxl)、IL29、IL-3IR、IL3l/IL31R、IL2R、IL4、IL4R、IL6、IL6R、インシュリン受容体、Jaggedリガンド、Jagged1、Jagged2、LIF-R、MRP4、MUCI、ムチン-16、Na/K ATPase、好中球エラスターゼ、NGF、ニカストリン、Notch受容体、Notch1、Notch2、Notch3、Notch4、NOV、OSM-R、PAR2、PDGF-AA、PDGF-BB、PDGFRα、PDGFRβ、PD-I、PD-LI、PD-L2、ホスファチジル-セリン、PIGF、PSCA、PSMA、RAAG12、RAGE、SLC44A4、スフィンゴシンIリン酸、TGFβ、TLR2、TLR4、TLR6、TLR7、TLR8、TLR9、TNFα、TNFR、TRAIL-RI、TRAIL-R2、トランスフェリン、トランスフェリン受容体、TRK-A、TRK-B、uPAR、VCAM-1、VEGF、VEGF-A、VEGF-B、VEGF-C、VEGF-D、VEGFRI、VEGFR2、VEGFR3、WISP-I、WISP-2、WISP-3、α-4インテグリン、α-Vインテグリン、α4βlインテグリン、及びα4β7インテグリンからなる群より選択される標的に結合する抗体、又は、前記群から選択される標的に結合する抗体の抗原結合断片である、請求項1~9の何れか一項に記載の方法。
- 前記第1の活性化可能抗体が検出可能な標識を更に含む、請求項1~10の何れか一項に記載の方法。
- 前記工程Iが、活性化状態の前記第1の活性化可能抗体に特異的に結合する、検出可能な標識を含む二次試薬を用いて実施される、請求項1~11の何れか一項に記載の方法。
- 前記検出可能な標識が、造影剤、コントラスト剤、酵素、蛍光標識、発色団、色素、放射性同位体、1若しくは2以上の金属イオン、又はリガンドに基づく標識である、請求項1~12の何れか一項に記載の方法。
- 前記検出可能な標識が蛍光色素である、請求項13に記載の方法。
- 非切断状態の前記の第1及び/又は第2の活性化可能抗体が、N末端からC末端に向かって、MM-CM-AB又はAB-CM-MMの構造を有する、請求項1~14の何れか一項に記載の方法。
- 前記抗体の抗原結合断片が、Fab断片、F(ab’)2断片、scFv、及びscAbからなる群より選択される、請求項1~15の何れか一項に記載の方法。
- 前記MMの前記ABに対する結合の平衡解離定数が、前記ABの前記標的に対する平衡解離定数よりも大きい、請求項1~16の何れか一項に記載の方法。
- 前記MMが、前記標的への結合について、切断状態の前記ABと干渉又は競合しない、請求項1~17の何れか一項に記載の方法。
- 前記MMが、40アミノ酸長以下のポリペプチドである、請求項1~18の何れか一項に記載の方法。
- 前記MMのポリペプチドのアミノ酸配列が、前記標的のアミノ酸配列と異なると共に、前記ABの天然結合パートナーの何れに対しても、50%以上のアミノ酸配列同一性を有さない、請求項1~19の何れか一項に記載の方法。
- 前記MMが、前記標的に対して25%を超えるアミノ酸配列同一性を有さない、請求項1~20の何れか一項に記載の方法。
- 前記MMが、前記標的に対して10%を超えるアミノ酸配列同一性を有さない、請求項21に記載の方法。
- 前記CMが、ADAMS、ADAMTS、アスパラギン酸プロテアーゼ、アスパラギン酸カテプシン、カスパーゼ、システインカテプシン、システインプロテイナーゼ、KLK、メタロプロテイナーゼ、MMP、セリンプロテアーゼ、凝固因子プロテアーゼ、及びII型膜貫通セリンプロテアーゼからなる群より選択されるプロテアーゼの基質である、請求項1~22の何れか一項に記載の方法。
- 前記CMが、ADAMS、ADAM9、ADAMI0、ADAM12、ADAMIS、ADAM17/TACE、ADAMDECI、ADAMTSI、ADAMTS4、ADAMTS5、BACE、Renin、カテプシンD、カテプシンE、カスパーゼ1、カスパーゼ2、カスパーゼ3、カスパーゼ4、カスパーゼ5、カスパーゼ6、カスパーゼ7、カスパーゼ8、カスパーゼ9、カスパーゼ10、カスパーゼ14、カテプシンB、カテプシンC、カテプシンK、カテプシンL、カテプシンS、カテプシンV/L2、カテプシンX/Z/P、クルジパイン、レグメイン、オトゥバイン-2、KLK4、KLK5、KLK6、KLK7、KLK8、KLKI0、KLKI1、KLK13、KLK14、メプリン、ネプリライシン、PSMA、BMP-1、MMPI、MMP2、MMP3、MMP7、MMP8、MMP9、MMP10、MMP11、MMP12、MMP13、MMP14、MMP15、MMP16、MMP17、MMP19、MMP20、MMP23、MMP24、MMP26、MMP27、活性化タンパク質C、カテプシンA、カテプシンG、キマーゼ、FVIla、FIXa、FXa、FXI、FXIIa、エラスターゼ、グランザイムB、グアニジノベンゾアターゼ、HtrAl、ヒト好中球エラスターゼ、ラクトフェリン、マラプシン、NS3/4A、PACE4、プラスミン、PSA、tPA、トロンビン、トリプターゼ、uPA、DESCI、DPP-4、FAP、ヘプシン、マトリプターゼ-2、MT-SPI/マトリプターゼ、TMPRSS2、TMPRSS3、及びTMPRSS4からなる群より選択されるプロテアーゼの基質である、請求項1~23の何れか一項に記載の方法。
- 前記CMが、15アミノ酸長以内のポリペプチドである、請求項1~24の何れか一項に記載の方法。
- 前記の第1及び/又は第2の活性化可能抗体が、前記MMと前記CMとの間に連結ペプチドを含む、請求項1~25の何れか一項に記載の方法。
- 前記の第1及び/又は第2の活性化可能抗体が、前記CMと前記ABとの間に連結ペプチドを含む、請求項1~26の何れか一項に記載の方法。
- 前記の第1及び/又は第2の活性化可能抗体が、第1の連結ペプチド(LP1)及び第2の連結ペプチド(LP2)を含むと共に、非切断状態における前記の第1及び/又は第2の活性化可能抗体が、N末端からC末端に向かってMM-LP1-CM-LP2-AB又はAB-LP2-CM-LP1-MMの配置を有する、請求項1~27の何れか一項に記載の方法。
- 前記2つの連結ペプチドが必ずしも互いに同一ではない、請求項28に記載の方法。
- LP1及びLP2のうち少なくとも一方が、(GS)n、(GGS)n、(GSGGS)n(配列番号33)、及び(GGGS)n(配列番号34)からなる群(ここでnは1以上の整数を表す。)より選択されるアミノ酸配列を含む、請求項1~29の何れか一項に記載の方法。
- LP1及びLP2のうち少なくとも一方が、GGSG(配列番号35)、GGSGG(配列番号36)、GSGSG(配列番号37)、GSGGG(配列番号38)、GGGSG(配列番号39)、及びGSSSG(配列番号40)からなる群より選択されるアミノ酸配列を含む、、請求項30に記載の方法。
- 非切断状態における前記の第1及び/又は第2の活性化可能抗体がスペーサーを含むと共に、前記スペーサーが前記MMに直接連結され、N末端からC末端に向かってスペーサー-MM-CM-ABの配置を有する、請求項1~31の何れか一項に記載の方法。
- 非切断状態における前記の第1及び/又は第2の活性化可能抗体がスペーサーを含むと共に、前記スペーサーが前記MMに直接連結され、N末端からC末端に向かってAB-CM-MM-スペーサーの配置を有する、請求項1~31の何れか一項に記載の方法。
- 前記支持マトリックスがスライドである、請求項1~33の何れか一項に記載の方法。
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