JP6605957B2 - 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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- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2863—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against receptors for growth factors, growth regulators
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- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2896—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
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- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
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- G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
- G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
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Landscapes
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- Peptides Or Proteins (AREA)
- Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)
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。
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本明細書に提供される実施例は、本明細書で活性化可能抗体3954−1204−C225v5と呼ばれる抗EGFR活性化可能抗体(本明細書において、3954−1204−C225v5活性化可能抗体、又は3954−1204−C225v5とも呼ばれる)を使用し、これは、EGFR結合配列、マスキング部分(MM)、及びプロテアーゼの基質である切断可能部分(CM)を含む。これらの例はまた、本明細書において、MMとEGFR結合配列との間に位置する非切断部分を含む、マスクされた抗体3954−NSUB−C225v5と呼ばれるマスクされた抗EGFR抗体構築物(また3954−NSUB−C225v5マスク化抗体、又は3954−NSUB−C225v5とも呼ばれる)を使用する。本明細書において提供される例は、これらの抗EGFR活性化可能抗体構築物を使用するが、これらの方法は、任意の活性化可能抗体に適用可能であることを理解すべきである。
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)
EGFRは、H292ヒト非小細胞肺癌細胞で高度に発現され、そしてこの異種移植腫瘍モデルにおけるセツキシマブの有効性は、複数の研究によって決定されている(例えば、Doody et al., Mol Cancer Ther October 2007 6; 2642; Chen et al., BMC Medicine 2012, 10:28を参照)。すなわち、活性化可能抗体のインサイチュイメージング手法で活性化可能抗体を検証するために、H292腫瘍組織試料が選択された。この研究(その結果は図2A及び図2Bに示されている)は、3954−1204−c225v5活性化可能抗EGFR抗体を、陽性対照及び陰性対照としてのそれぞれ親抗体(セツキシマブ)及び3954−NSUB−c225v5(すなわち、非切断可能マスク化抗体)とともに使用した。H292異種移植凍結腫瘍組織切片をスライドグラス上に置き、PBS−T、続いてPBSで2回洗浄し、次に、広域スペクトルプロテアーゼ阻害剤カクテル又は緩衝液のみを用いて組織の30分間の前処理を行なった。Alexa Fluor-680(登録商標)標識された3954−1204−c225v5及びAlexa Fluor-680(登録商標)標識された3954−NSUB−c225v5を組織に適用し、暗所で1時間インキュベートした(蛍光の退色を防止するために)。インキュベーション後、1μg/mlのインキュベートした腫瘍切片をPBS−T、次にPBSで3回洗浄し、核マーカーDAPIを用いて1分間対比染色した。蛍光顕微鏡分析は、プロテアーゼ阻害剤による組織切片の前処理によって消失した3954−1204−c225v5の陽性染色を示し、これは、組織試料への3954−1204−c225v5の結合がタンパク質分解事象の結果であることを示した。3954−1204−c225v5の陽性染色はまた、組織を過剰の非標識(「コールド」)セツキシマブで前処理した時にも消失した。さらに、H292組織のインキュベーションは、プロテアーゼ阻害剤を用いた組織の前処理によって影響を受けなかったセツキシマブ抗体についての陽性染色を明らかにしたが、組織を非標識セツキシマブで前処理した時に、これは消失した。予想されたように、プロテアーゼ阻害剤又は非標識セツキシマブで前処理したか又はしなかった組織では、非切断可能3954−NSUB−c225v5について何の信号も検出されなかった。
実施例2で上記した方法で、凍結した結腸直腸癌患者の腫瘍試料を使用して、ヒト組織に対するプロテアーゼ活性を検証するための活性化可能抗体インサイチュイメージングの適用性を評価した。まず、3954−1204−c225v5インサイチュイメージングとEGFR免疫組織染色(IHC)の二重染色を行って、蛍光シグナルの共局在を確認した(図3)。さらに、腫瘍組織を広域スペクトルプロテアーゼ阻害剤(PI)で前処理すると、3954−1204−c225v5の結合が完全に消失し(図3)、3954−1204−c225v5の活性化に必要であるプロテアーゼ活性の阻害の成功を示した。
本実施例は、本開示の抗EGFR活性化可能抗体の活性化と結合のインサイチュイメージングの使用を記載する。結果は、本開示の抗EGFR活性化可能抗体が、組織によって発現されるプロテアーゼによって活性化され、その組織上のEGFR標的に結合することができることを示している。
本実施例は、抗EGFR活性化可能抗体の活性化と結合のための、患者の組織試料をスクリーニングするためのインサイチュイメージング手法の使用を記載する。結果は、本開示の抗EGFR活性化可能抗体が、癌患者の組織によって発現されるプロテアーゼによって活性化され、その組織上のEGFR受容体に結合することができることを示している。
本実施例は、抗EGFR抗体IHC及びA11抗体IHCと組合せた、抗EGFR活性化可能抗体の活性化と、エクスビボでのその生体組織への結合のインサイチュイメージングの使用を記載する。市販の抗EGFR抗体IHCの使用は、組織中のEGFR発現の量に、親抗体(例えばセツキシマブ)及び抗EGFR活性化可能抗体の染色を標準化することを可能にする。EGFR抗体との共染色はまた、EGFR発現に標準化されセツキシマブ染色に対して、抗EGFR活性化可能抗体のインサイチュイメージングの定性的定量化を可能にする。蛍光シグナルの定量は、例えばMetaMorphなどの研究イメージングのためのバイオ分析ソフトウェアを用いて行うことができる。MT−SP1(抗体A11)の活性部位を特異的に認識する抗体による組織の染色はまた、MT−SP1(活性化可能抗体3954−1204−c225v4、3954−1204−c225v5、及び3954−1204−c225v6の基質をタンパク質分解的に切断する酵素)の活性を追跡するために行うことができる。
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。
本実施例は、本開示の抗Jagged活性化可能抗体の活性化と結合のインサイチュイメージングの使用を記載する。
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)
本実施例は、抗Jagged活性化可能抗体の活性化と結合のために、膵臓癌の異種移植腫瘍組織及びヒト膵臓癌組織をスクリーニングするための、インサイチュイメージングの使用を記載する。結果は、本開示の抗Jagged活性化可能抗体が、そのような組織により発現されるプロテアーゼにより活性化されることができ、そのような組織上のJagged標的に結合することを示す。
本明細書に提供される実施例は、本明細書において活性化可能抗体3954−1204−C225v4と呼ばれる抗EGFR活性化可能抗体(本明細書において、3954−1204−C225v4活性化可能抗体、又は3954−1204−C225v4とも呼ばれる)を使用し、これは、EGFR結合配列、マスキング部分(MM)、及びプロテアーゼの基質である切断可能部分(CM)を含む。これらの例はまた、本明細書において、MMとEGFR結合配列との間に位置する非切断可能部分を含む、マスクされた抗体3954−NSUB−C225v4と呼ばれるマスク化抗EGFR抗体構築物(また3954−NSUB−C225v4マスク化抗体、又は3954−NSUB−C225v4とも呼ばれる)を使用する。本明細書において提供される例は、これらの抗EGFR活性化可能抗体構築物を使用するが、これらの方法は、任意の活性化可能抗体に適用可能であることを理解すべきである。
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。
本実施例は、単一のプロテアーゼによって切断される基質を含む非標識抗EGFR活性化可能抗体のインサイチュイメージングの使用を記載する。切断は、活性化可能抗体のAB部分に特異的に結合する二次抗体を用いて検出された。結果は、非標識活性化可能抗体の活性化と結合を評価する能力を示す。
本例は、組織マイクロアレイ(TMA)中での発現及び/又は活性化を検出するための、活性化可能抗体の使用を説明する。抗Jagged抗体4D11を、非小細胞肺癌(NSCLC)TMA及び乳癌(BC)TMAとともに使用した。NSCLC及びBC患者の腫瘍試料のほとんどは、Jagged発現が陽性であった。同じNSCLC及びBCのTMAを、本明細書において5342−1204−4D11と呼ぶ活性化可能抗Jagged抗体と接触させた。NSCLCの97%とBC患者の腫瘍試料の100%は、5342−1204−4D11活性化可能抗Jagged抗体の結合と活性化が陽性であった。さらに図21に示されるように、BC患者腫瘍試料の80%超は、高活性化率(++又は+++)と解析された。同じNSCLCとBCのTMAを、プロテアーゼMT−SP1に結合するA11抗体と接触させた。NSCLCの77%とBC患者の腫瘍試料の98%がMT−SP1活性が陽性であった。8個のNSCLC腫瘍は、MT−SP1活性が欠如していたが、5342−1204−4D11活性化可能な抗Jagged抗体の結合と活性化を示し、これは、5342−1204−4D11活性化可能な抗Jagged抗体の活性化におけるプロテアーゼの関与を示唆している。
本実施例は、H292異種移植研究からの細針吸引試料にインサイチュイメージングを使用する方法について記載する。簡単に説明すると、以下の吸引方法が使用された:結節をピンセットで採取後に固定化した。クリニックで使用されるゲージ(例えば22〜25)に最も近い23ゲージ針を、前後運動で約20秒間僅かに吸引して使用した。針は小さなバイアル中に空にして、直ちにドライアイスで凍結した。異種移植片は、吸引処置後に採取し、吸引試料と一致するように標識し、抽出後すぐに凍結した。
本明細書に提供される研究は、抗Jagged抗体4D11と活性化可能な抗Jagged抗体5342−1204−4D11を使用する。抗Jagged抗体及び活性化可能な抗Jagged抗体は、ヒト原発性膵臓腺癌細胞株であるBxPC3細胞を用いて試験した。
本明細書に提供される試験は、活性化可能抗EGFR抗体3954−1204−c225v5を使用する。活性化可能抗EGFR抗体は、ヒト非小細胞肺癌細胞株であるH292細胞を用いて試験した。
取り扱いが困難な骨髄や他の組織を薄片化し染色する方法を開発するために、適切なプロトコルを確立する前に、いくつかの手順を試験した。最初に、使い捨て刃 を使用するルーチン薄片化手順を試みた。次に、硬い試料で使用される時、より大きな安定性と少ない振動を有するため、16cmの炭化タングステンナイフを評価した。次に、以下のように粘着テープの使用を試みた:組織を粘着テープの上に置き、次に薄片化した;組織が直接スライドに接触するように、粘着テープに接着した組織をスライド上に置いた;テープの除去と組織切片への移動のための様々な方法を試みたが、成功しなかった;そのような方法は、スライドへの組織切片の接着のために許可される温度と時間の効果を評価することを含んだ。これらの失敗が、染色操作中に試料をスライドに移動させることを試みず、組織切片を粘着テープ上に残すことの評価につながり、その結果、後述の成功したプロトコルが得られた。以下のプロトコルは、骨髄組織の薄片化と染色を記載するが、この方法はまた、他の困難な組織の薄片化と染色にも使用することができることを理解されたい。
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 (23)
- 支持マトリックスに結合された生体試料中の共局在する切断剤及び標的の存在又は不在を検出するインビトロの方法であって、
(a)支持マトリックスに結合された生体試料を、活性化可能抗体と接触させ、ここで活性化可能抗体は、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、非切断状態にある活性化可能抗体のABの標的への結合を阻害するマスキング部分(MM)と、ABに連結された切断可能部分(CM)とを含み、ここでCMはプロテアーゼの基質として機能するポリペプチドであり、ここで前記切断剤はプロテアーゼであり、前記切断剤によって前記活性化可能抗体のCMが切断されると、前記活性化可能抗体が活性化され、
(b)生体試料中の活性化された活性化可能抗体のレベルをインサイチュ(in situ)で測定する
ことを含み、
ここで、生体試料中に活性化された活性化可能抗体が検出可能なレベルで存在すれば、生体試料中に切断剤及び標的が存在し、且つ共局在していることを示し、生体試料中に活性化された活性化可能抗体が検出可能なレベルで存在しなければ、生体試料中に切断剤、標的、又は切断剤及び標的の双方が不在であるか、又は検出可能なレベルで存在せず、若しくは共局在していないことを示す、方法。 - 活性化可能抗体が、検出可能な標識を含む、請求項1に記載の方法。
- 試料中の活性化可能抗体のレベルの測定が、活性化された抗体に特異的に結合する二次試薬を用いて達成され、前記二次試薬が、検出可能な標識を含む、請求項1に記載の方法。
- 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、染料、放射性同位体、一又は二以上の金属イオン、又はリガンド系標識を含む、請求項2又は3に記載の方法。
- 非切断状態の活性化可能抗体がN末端からC末端に向かって以下の構造的配置:MM−CM−AB又はAB−CM−MMを有する、請求項1に記載の方法。
- 標的が表1に列記された標的の群から選択される、請求項1に記載の方法。
- ABが表2に列記された抗体の群から選択される抗体であり、或いは当該抗体から誘導される、請求項1に記載の方法。
- 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に記載の方法。
- MMのABに対する結合の平衡解離定数が、ABの標的に対する結合の平衡解離定数よりも大きい、請求項1に記載の方法。
- MMが、切断状態の活性化可能抗体のABの標的に対する結合と干渉又は競合しない、請求項1に記載の方法。
- MMがアミノ酸長40以下のポリペプチドである、請求項1に記載の方法。
- MMのポリペプチド配列が、標的のポリペプチド配列とは異なると共に、ABの天然結合パートナーの何れとも50%超の同一性を有さない、請求項1に記載の方法。
- MMが標的に対して25%超のアミノ酸配列同一性を有しない、請求項1に記載の方法。
- MMが標的に対して10%超のアミノ酸配列同一性を有しない、請求項1に記載の方法。
- CMが、表3に列記のプロテアーゼの群から選択されるプロテアーゼの基質である、請求項1に記載の方法。
- CMが、アミノ酸長15以下のポリペプチドである、請求項1に記載の方法。
- 活性化可能抗体が、MMとCMとの連結ペプチドを含む、請求項1に記載の方法。
- 活性化可能抗体が、CMとABとの連結ペプチドを含む、請求項1に記載の方法。
- 活性化可能抗体が第一の連結ペプチド(LP1)及び第二の連結ペプチド(LP2)を含むと共に、非切断状態の活性化可能抗体が、N末端からC末端に向かって下記:MM−LP1−CM−LP2−AB又はAB−LP2−CM−LP1−MMという構造的配置を有する、請求項1に記載の方法。
- 前記二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19に記載の方法。
- LP1又はLP2の少なくとも一方が、(GS)n、(GGS)n、(GSGGS)n(配列番号33)、及び(GGGS)n(配列番号34)からなる群より選択されるアミノ酸配列(ここでnは1以上の整数である)を含む、請求項19に記載の方法。
- LP1又はLP2の少なくとも一方が、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19に記載の方法。
- 非切断状態の活性化可能抗体がスペーサーを含み、ここでスペーサーはMMに直接連結されると共に、スペーサーのN末端からC末端に向かって−MM−CM−ABという構造的配置を有する、請求項1に記載の方法。
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