JP7281824B2 - Cd99-発現癌を標的にするための組成物および方法 - Google Patents
Cd99-発現癌を標的にするための組成物および方法 Download PDFInfo
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Description
本出願は、2018年1月8日に出願された米国特許仮出願第62/614,779号、2018年4月9日に出願された同第62/654,617号、2018年4月9日に出願された同第62/654,625号、2018年9月12日に出願された同第62/730,374号、2018年9月12日に出願された同第62/730,397号、2018年11月15日に出願された同第62/767,864号、および2018年11月15日に出願された同第62/767,867号の利益を主張し、これらは全て参照によりそれらの全体が本明細書に援用される。
本出願は、2019年1月6日に作成された「320103-2030 Sequence Listing_ST25」と題するASCII.txtファイルとして電子形式で出願された配列表を含む。配列表の内容は、その全体が本明細書に援用される。
VLI-VHI-VLT-VHT、
VLT-VHT-VLI-VHI、
VHT-VLT-VHI-VLI、
VHI-VLI-VHT-VLT、
VLI-VHI-VHT-VLT、
VLT-VHT-VHI-VLI、
式中、「VLI」は、免疫細胞抗原に特異的な軽鎖可変ドメインであり、
「VHT」は、CD99に特異的な重鎖可変ドメインであり、
「VLT」は、CD99に特異的な軽鎖可変ドメインであり、
「VHI」は、免疫細胞抗原に特異的な重鎖可変ドメインであり、
「-」は、ペプチドリンカーまたはペプチド結合からなる。
免疫細胞抗原は、ヒトNK細胞、T細胞、単球、マクロファージまたは顆粒球上で発現される細胞表面分子であってもよい。例えば、細胞表面分子は、抗原CD2、CD3、CD16、CD64、CD89、NKp30、NKp44、NKp46、NKp80(KLR-F1)、NKG2C、またはNKG2Dであり得る。
GAGGTTCAACTGCAACAGTCTGGGGCAGAGCTTGTGAAGCCAGGGGCCTCAGTCAAGTTGTCCTGCACAGCTTCTGGCTTCGACATTAAAGACACCTATATCCACTGGGTGAAACAGAGGCCTGAACAGGGCCTGGAGTGGATTGGAAGGATTGATCCTGCGAATGGTGATACTAGATATGACCCGGAATTCCAGGGCAAGGCCTCTCTAACAGCTGACACATCCTCCAATACAGCCTACCTACAATTCAGCAACCTGACATCTGAAGACACTGCCGTCTATTACTGTGCTAGAAGAGGCGGCCTCTCCTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA(配列番号23、1H3H7)。
EVQLEESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSS(配列番号24、4C5E2)。
GAGGTGCAGCTGGAGGAGTCTGGTGGAGGATTGGTGCAGCCTAAAGGATCATTGAAACTCTCATGTGCCGCCTCCGGTTTCACCTTCAATACCTATGCCATGTACTGGGTCTGCCAGGCTCCAGGAAAGGGTTTGAAATGGGTTGCTCGCATAAGAAGTAAAGTTAATAATTATGCAACATATTATGCCGATTCAGTGAAAGACAGATTCACCATCTCCAGAGATGATTCACAAAACATGCTCTTTCTGCACATGAACAACCTGAAAACTGAGGACACTGCCATATATTTCTGTGTGAGAGATCCTATGGACTACTGGGGTCAAGGAATCTCAGTCACCGTCTCCTCA(配列番号25、4C5E2)。
EVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSS(配列番号26、4C5H10)。
GAGGTGCAGCTTGTTGAGTCTGGTGGAGGATTGGTGCAGCCTAAAGGATCATTGAAACTCTCATGTGCCGCCTCCGGTTTCACCTTCAATACCTATGCCATGTACTGGGTCTGCCAGGCTCCAGGAAAGGGTTTGAAATGGGTTGCTCGCATAAGAAGTAAAGTTAATAATTATGCAACATATTATGCCGATTCAGTGAAAGACAGATTCACCATCTCCAGAGATGATTCACAAAACATGCTCTTTCTGCACATGAACAACCTGAAAACTGAGGACACTGCCATATATTTCTGTGTGAGAGATCCTATGGACTACTGGGGTCAAGGAATCTCAGTCACCGTCTCCTCA(配列番号27、4C5H10)。
QVQLQQSGAELARPGASVKLSCKASGYTFTTFWMQWVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSS(配列番号28、9G12C9)。
CAGGTTCAGCTCCAGCAGTCTGGGGCTGAGCTGGCAAGACCTGGGGCTTCAGTGAAGTTGTCCTGCAAGGCTTCTGGCTACACGTTTACTACTTTCTGGATGCAGTGGGTAAAACAGAGGCCTGGACAGGGTCTGGAATGGATTGGGACTATTTATCCTGGAGATGATGATACTAGGTACACTCAGAAATTCAAGGGCAGGGCCACATTGACTGCAGATAAATCGTCCACCACAGCCTACATGCAACTCAGCAACTTGTCATCTGAGGACTCTGCGGTCTATTACTGTGCAAGATCGGGGTATGAGAGGGGCCCATACTACTTTGACTCCTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA(配列番号29、9G12C9)。
DVKLQESGAELARPGASVKLSCKASGYTFTTFWMQRVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSS(配列番号:30、9G12G6 HB1)。
GATGTGAAGCTTCAGGAGTCTGGGGCTGAGCTGGCAAGACCTGGGGCTTCAGTGAAGTTGTCCTGCAAGGCTTCTGGCTACACGTTTACTACTTTCTGGATGCAGCGGGTAAAACAGAGGCCTGGACAGGGTCTGGAATGGATTGGGACTATTTATCCTGGAGATGATGATACTAGGTACACTCAGAAATTCAAGGGCAGGGCCACATTGACTGCAGATAAATCGTCCACCACAGCCTACATGCAACTCAGCAACTTGTCATCTGAGGACTCTGCGGTCTATTACTGTGCAAGATCGGGGTATGAGAGGGGCCCATACTACTTTGACTCCTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA(配列番号31、9G12G6 HB1)。
CAGGTGCAGCTGAAGGAGTCTGGGGCTGAGCTGGCAAGACCTGGGGCTTCAGTGAAGTTGTCCTGCAAGGCTTCTGGCTACACGTTTACTACTTTCTGGATGCAGTGGGCAAAACAGAGGCCTGGACAGGGTCTGGAATGGATTGGGACTATTTATCCTGGAGATGATGATACTAGGTACACTCAGAAATTCAAGGGCAGGGCCACATTGACTGCAGATAAATCGTCCACCACAGCCTACATGCAACTCAGCAACTTGTCATCTGAGGACTCTGCGGTCTATTACTGTGCAAGATCGGGGTATGAGAGGGGCCCATACTACTTTGACTCCTGGGGCCAAGGCACCACTCTCACAGTCTCCTCA(配列番号33、9G12G6 HB3)。
GACATCCAGATGACTCAGTCTCCAGCCTCCCTATCTGCATCTGTGGGAGAAACTGTCACCATCACATGTCGAGCAAGTGGGAATATTCACAATTATTTAGCATGGTATCAGCAGAAACAGGGAAAATCTCCTCAGCTCCTGGTCTATAATGCAAAAACCTTAGCAGATGGTGTGCCATCAAGGTTCAGTGGCAGTGGATCAGGAACACAATATTCTCTCAAGATCAACAGCCTGCAGCCTGAAGATTTTGGGAGTTATTACTGTCAACATTTTTGGAGTACTCCGTGGACGTTCGGTGGAGGCACCAAGCTGGAAATCAAA(配列番号:35、1H3H9)。
GNSWSHSLRSLSVTIGQPASISCKSSQSLLDGNGKTYLNWLLQRPGQSPKRLLYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPRTFGGGTKLEIK(配列番号:36、1H3H7 LC1)。
GNSWRHSPRSLSVTIGQPASISCKSSQSLLDGNGKTYLNWLLQRPGQSPKRLLYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPRTFGGGTKLEIK(配列番号37、1H3H7 LC2)。
DIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIK(配列番号38、4C5E2)。
GATATTGTGATGACTCAGGCTGCACCCTCTGTACCTGTCACTCCTGGGGAGTCAGTATCCATCTCCTGCGGGTCTAGTAAGAGTCTCCTGCATAGTAATGGCAACACTTACTTGTATTGGTTCCTGCAGAGGCCAGGCCAGTCTCCTCAGCTCCTGATATATCGGGTGTCCAACCTTGCCTCAGGAGTCCCAGACAGGTTCAGTGGCAGTGGGTCAGGAACTGCTTTCACACTGAGAATCAGTAGAGTGGAGGCTGAGGATGTGGGTGTTTATTACTGTATGCAACATCTAGAATATCCGTACACGTTCGGAGGGGGGACCAGGCTGGAAATAAAA(配列番号39、4C5E2)。
DIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIK(配列番号40、4C5H10)。
GATATTGTGATGACTCAGGCTGCACCCTCTGTACCTGTCACTCCTGGGGAGTCAGTATCCATCTCCTGCGGGTCTAGTAAGAGTCTCCTGCATAGTAATGGCAACACTTACTTGTATTGGTTCCTGCAGAGGCCAGGCCAGTCTCCTCAGCTCCTGATATATCGGGTGTCCAACCTTGCCTCAGGAGTCCCAGACAGGTTCAGTGGCAGTGGGTCAGGAACTGCTTTCACACTGAGAATCAGTAGAGTGGAGGCTGAGGATGTGGGTGTTTATTACTGTATGCAACATCTAGAATATCCGTACACGTTCGGAGGGGGGACCAGGCTGGAAATAAAA(配列番号41、4C5H10)。
DTVMSQSPSSLAVSVGEKITMSCKSSQSLLCRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK(配列番号42、9G12C9)。
GACACTGTGATGTCACAGTCCCCATCCTCCCTAGCTGTTTCAGTTGGAGAGAAGATAACTATGAGCTGCAAGTCCAGTCAGAGTCTTTTATGTCGTAGCAATCAAAAGAACTACTTGGCCTGGTACCAGCAGAAACCAGGGCAGTCTCCTAAACAGCTGATTTACTGGGCATCTACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTGTGAAGGCTGAAGACCTGGCAGTTTATTACTGTCAGCAATATTATAGTTATCCGCTCACGTTCGGTGCTGGCACCAAGCTGGAGCTGAAA(配列番号43、9G12C9)。
GACACTGTGATGTCACAGTCCCCATCCTCCCTAGCTGTTTCAGTTGGAGAGAAGATAACTATGAGCTGCAAGTCCAGTCAGAGTCTTTTATATCGTAGCAATCAAAAGAACTACTTGGCCTGGTACCAGCAGAAACCAGGGCAGTCTCCTAAACAGCTGATTTACTGGGCATCTACTAGGGAATCTGGGGTCCCTGATCGCTTCACAGGCAGTGGATCTGGGACAGATTTCACTCTCACCATCAGCAGTGTGAAGGCTGAAGACCTGGCAGTTTATTACTGTCAGCAATATTATAGTTATCCGCTCACGTTCGGTGCTGGCACCAAGCTGGAGCTGAAA(配列番号45、9G12G6)。
EVQLQQSGAELVKPGASVKLSCTASGFDIKDTYIHWVKQRPEQGLEWIGRIDPANGDTRYDPEFQGKASLTADTSSNTAYLQFSNLTSEDTAVYYCARRGGLSWGQGTTLTVSSGGGGSGGGGSGGGGSDIQMTQSPASLSASVGETVTITCRASGNIHNYLAWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSGSGTQYSLKINSLQPEDFGSYYCQHFWSTPWTFGGGTKLEIK(配列番号47)。
EVQLQQSGAELVKPGASVKLSCTASGFDIKDTYIHWVKQRPEQGLEWIGRIDPANGDTRYDPEFQGKASLTADTSSNTAYLQFSNLTSEDTAVYYCARRGGLSWGQGTTLTVSSGGGGSGGGGSGGGGSGNSWSHSLRSLSVTIGQPASISCKSSQSLLDGNGKTYLNWLLQRPGQSPKRLLYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPRTFGGGTKLEIK(配列番号48)。
EVQLQQSGAELVKPGASVKLSCTASGFDIKDTYIHWVKQRPEQGLEWIGRIDPANGDTRYDPEFQGKASLTADTSSNTAYLQFSNLTSEDTAVYYCARRGGLSWGQGTTLTVSSGGGGSGGGGSGGGGSGNSWRHSPRSLSVTIGQPASISCKSSQSLLDGNGKTYLNWLLQRPGQSPKRLLYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPRTFGGGTKLEIK(配列番号49)。
EVQLQQSGAELVKPGASVKLSCTASGFDIKDTYIHWVKQRPEQGLEWIGRIDPANGDTRYDPEFQGKASLTADTSSNTAYLQFSNLTSEDTAVYYCARRGGLSWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIK(配列番号50)。
EVQLQQSGAELVKPGASVKLSCTASGFDIKDTYIHWVKQRPEQGLEWIGRIDPANGDTRYDPEFQGKASLTADTSSNTAYLQFSNLTSEDTAVYYCARRGGLSWGQGTTLTVSSGGGGSGGGGSGGGGSDTVMSQSPSSLAVSVGEKITMSCKSSQSLLCRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK(配列番号51)。
EVQLQQSGAELVKPGASVKLSCTASGFDIKDTYIHWVKQRPEQGLEWIGRIDPANGDTRYDPEFQGKASLTADTSSNTAYLQFSNLTSEDTAVYYCARRGGLSWGQGTTLTVSSGGGGSGGGGSGGGGSDTVMSQSPSSLAVSVGEKITMSCKSSQSLLYRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK(配列番号52)。
EVQLEESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSSGGGGSGGGGSGGGGSDIQMTQSPASLSASVGETVTITCRASGNIHNYLAWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSGSGTQYSLKINSLQPEDFGSYYCQHFWSTPWTFGGGTKLEIK(配列番号53)。
EVQLEESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSSGGGGSGGGGSGGGGSGNSWSHSLRSLSVTIGQPASISCKSSQSLLDGNGKTYLNWLLQRPGQSPKRLLYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPRTFGGGTKLEIK(配列番号54)。
EVQLEESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSSGGGGSGGGGSGGGGSGNSWRHSPRSLSVTIGQPASISCKSSQSLLDGNGKTYLNWLLQRPGQSPKRLLYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPRTFGGGTKLEIK(配列番号55)。
EVQLEESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSSGGGGSGGGGSGGGGSDIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIK(配列番号56)。
EVQLEESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSSGGGGSGGGGSGGGGSDTVMSQSPSSLAVSVGEKITMSCKSSQSLLCRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK(配列番号57)。
EVQLEESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSSGGGGSGGGGSGGGGSDTVMSQSPSSLAVSVGEKITMSCKSSQSLLYRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK(配列番号58)。
EVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSSGGGGSGGGGSGGGGSDIQMTQSPASLSASVGETVTITCRASGNIHNYLAWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSGSGTQYSLKINSLQPEDFGSYYCQHFWSTPWTFGGGTKLEIK(配列番号59)。
EVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSSGGGGSGGGGSGGGGSGNSWSHSLRSLSVTIGQPASISCKSSQSLLDGNGKTYLNWLLQRPGQSPKRLLYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPRTFGGGTKLEIK(配列番号60)。
EVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSSGGGGSGGGGSGGGGSGNSWRHSPRSLSVTIGQPASISCKSSQSLLDGNGKTYLNWLLQRPGQSPKRLLYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPRTFGGGTKLEIK(配列番号61)。
EVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSSGGGGSGGGGSGGGGSDIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIK(配列番号62)。
EVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSSGGGGSGGGGSGGGGSDTVMSQSPSSLAVSVGEKITMSCKSSQSLLCRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK(配列番号63)。
EVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSSGGGGSGGGGSGGGGSDTVMSQSPSSLAVSVGEKITMSCKSSQSLLYRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK(配列番号64)。
QVQLQQSGAELARPGASVKLSCKASGYTFTTFWMQWVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSDIQMTQSPASLSASVGETVTITCRASGNIHNYLAWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSGSGTQYSLKINSLQPEDFGSYYCQHFWSTPWTFGGGTKLEIK(配列番号65)。
QVQLQQSGAELARPGASVKLSCKASGYTFTTFWMQWVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSGNSWSHSLRSLSVTIGQPASISCKSSQSLLDGNGKTYLNWLLQRPGQSPKRLLYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPRTFGGGTKLEIK(配列番号66)。
QVQLQQSGAELARPGASVKLSCKASGYTFTTFWMQWVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSGNSWRHSPRSLSVTIGQPASISCKSSQSLLDGNGKTYLNWLLQRPGQSPKRLLYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPRTFGGGTKLEIK(配列番号67)。
QVQLQQSGAELARPGASVKLSCKASGYTFTTFWMQWVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIK(配列番号68)。
QVQLQQSGAELARPGASVKLSCKASGYTFTTFWMQWVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSDTVMSQSPSSLAVSVGEKITMSCKSSQSLLCRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK(配列番号69)。
QVQLQQSGAELARPGASVKLSCKASGYTFTTFWMQWVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSDTVMSQSPSSLAVSVGEKITMSCKSSQSLLYRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK(配列番号70)。
DVKLQESGAELARPGASVKLSCKASGYTFTTFWMQRVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSDIQMTQSPASLSASVGETVTITCRASGNIHNYLAWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSGSGTQYSLKINSLQPEDFGSYYCQHFWSTPWTFGGGTKLEIK(配列番号71)。
DVKLQESGAELARPGASVKLSCKASGYTFTTFWMQRVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSGNSWSHSLRSLSVTIGQPASISCKSSQSLLDGNGKTYLNWLLQRPGQSPKRLLYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPRTFGGGTKLEIK(配列番号72)。
DVKLQESGAELARPGASVKLSCKASGYTFTTFWMQRVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSGNSWRHSPRSLSVTIGQPASISCKSSQSLLDGNGKTYLNWLLQRPGQSPKRLLYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPRTFGGGTKLEIK(配列番号73)。
DVKLQESGAELARPGASVKLSCKASGYTFTTFWMQRVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIK(配列番号74)。
DVKLQESGAELARPGASVKLSCKASGYTFTTFWMQRVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIK(配列番号75)。
DVKLQESGAELARPGASVKLSCKASGYTFTTFWMQRVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSDTVMSQSPSSLAVSVGEKITMSCKSSQSLLCRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK(配列番号76)。
DVKLQESGAELARPGASVKLSCKASGYTFTTFWMQRVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSDTVMSQSPSSLAVSVGEKITMSCKSSQSLLYRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK(配列番号77)。
QVQLKESGAELARPGASVKLSCKASGYTFTTFWMQWAKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSDIQMTQSPASLSASVGETVTITCRASGNIHNYLAWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSGSGTQYSLKINSLQPEDFGSYYCQHFWSTPWTFGGGTKLEIK(配列番号78)。
QVQLKESGAELARPGASVKLSCKASGYTFTTFWMQWAKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSGNSWSHSLRSLSVTIGQPASISCKSSQSLLDGNGKTYLNWLLQRPGQSPKRLLYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPRTFGGGTKLEIK(配列番号79)。
QVQLKESGAELARPGASVKLSCKASGYTFTTFWMQWAKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSGNSWRHSPRSLSVTIGQPASISCKSSQSLLDGNGKTYLNWLLQRPGQSPKRLLYLVSKLDSGVPDRFTGSGSGTDFTLKISRVEAEDLGIYYCWQGTHFPRTFGGGTKLEIK(配列番号80)。
QVQLKESGAELARPGASVKLSCKASGYTFTTFWMQWAKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIK(配列番号81)。
QVQLKESGAELARPGASVKLSCKASGYTFTTFWMQWAKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSDIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIK(配列番号82)。
QVQLKESGAELARPGASVKLSCKASGYTFTTFWMQWAKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSDTVMSQSPSSLAVSVGEKITMSCKSSQSLLCRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK(配列番号83)。
QVQLKESGAELARPGASVKLSCKASGYTFTTFWMQWAKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSSGGGGSGGGGSGGGGSDTVMSQSPSSLAVSVGEKITMSCKSSQSLLYRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELK(配列番号84)。
DIQMTQSPASLSASVGETVTITCRASGNIHNYLAWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSGSGTQYSLKINSLQPEDFGSYYCQHFWSTPWTFGGGTKLEIKGGGGSGGGGSGGGGSEVQLQQSGAELVKPGASVKLSCTASGFDIKDTYIHWVKQRPEQGLEWIGRIDPANGDTRYDPEFQGKASLTADTSSNTAYLQFSNLTSEDTAVYYCARRGGLSWGQGTTLTVSS(配列番号85)。
DIQMTQSPASLSASVGETVTITCRASGNIHNYLAWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSGSGTQYSLKINSLQPEDFGSYYCQHFWSTPWTFGGGTKLEIKGGGGSGGGGSGGGGSEVQLEESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSS(配列番号86)。
DIQMTQSPASLSASVGETVTITCRASGNIHNYLAWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSGSGTQYSLKINSLQPEDFGSYYCQHFWSTPWTFGGGTKLEIKGGGGSGGGGSGGGGSEVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSS(配列番号87)。
DIQMTQSPASLSASVGETVTITCRASGNIHNYLAWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSGSGTQYSLKINSLQPEDFGSYYCQHFWSTPWTFGGGTKLEIKGGGGSGGGGSGGGGSQVQLQQSGAELARPGASVKLSCKASGYTFTTFWMQWVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSS(配列番号88)。
DIQMTQSPASLSASVGETVTITCRASGNIHNYLAWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSGSGTQYSLKINSLQPEDFGSYYCQHFWSTPWTFGGGTKLEIKGGGGSGGGGSGGGGSDVKLQESGAELARPGASVKLSCKASGYTFTTFWMQRVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSS(配列番号89)。
DIQMTQSPASLSASVGETVTITCRASGNIHNYLAWYQQKQGKSPQLLVYNAKTLADGVPSRFSGSGSGTQYSLKINSLQPEDFGSYYCQHFWSTPWTFGGGTKLEIKGGGGSGGGGSGGGGSQVQLKESGAELARPGASVKLSCKASGYTFTTFWMQWAKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSS(配列番号90)。
DIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIKGGGGSGGGGSGGGGSEVQLQQSGAELVKPGASVKLSCTASGFDIKDTYIHWVKQRPEQGLEWIGRIDPANGDTRYDPEFQGKASLTADTSSNTAYLQFSNLTSEDTAVYYCARRGGLSWGQGTTLTVSS(配列番号91)。
DIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIKGGGGSGGGGSGGGGSEVQLEESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSS(配列番号92)。
DIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIKGGGGSGGGGSGGGGSEVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSS(配列番号93)。
DIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIKGGGGSGGGGSGGGGSQVQLQQSGAELARPGASVKLSCKASGYTFTTFWMQWVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSS(配列番号94)。
DIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIKGGGGSGGGGSGGGGSDVKLQESGAELARPGASVKLSCKASGYTFTTFWMQRVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSS(配列番号95)。
DIVMTQAAPSVPVTPGESVSISCGSSKSLLHSNGNTYLYWFLQRPGQSPQLLIYRVSNLASGVPDRFSGSGSGTAFTLRISRVEAEDVGVYYCMQHLEYPYTFGGGTRLEIKGGGGSGGGGSGGGGSQVQLKESGAELARPGASVKLSCKASGYTFTTFWMQWAKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSS(配列番号96)。
DTVMSQSPSSLAVSVGEKITMSCKSSQSLLCRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELKGGGGSGGGGSGGGGSEVQLQQSGAELVKPGASVKLSCTASGFDIKDTYIHWVKQRPEQGLEWIGRIDPANGDTRYDPEFQGKASLTADTSSNTAYLQFSNLTSEDTAVYYCARRGGLSWGQGTTLTVSS(配列番号97)。
DTVMSQSPSSLAVSVGEKITMSCKSSQSLLCRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELKGGGGSGGGGSGGGGSEVQLEESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSS(配列番号98)。
DTVMSQSPSSLAVSVGEKITMSCKSSQSLLCRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELKGGGGSGGGGSGGGGSEVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSS(配列番号99)。
DTVMSQSPSSLAVSVGEKITMSCKSSQSLLCRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELKGGGGSGGGGSGGGGSQVQLQQSGAELARPGASVKLSCKASGYTFTTFWMQWVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSS(配列番号100)。
DTVMSQSPSSLAVSVGEKITMSCKSSQSLLCRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELKGGGGSGGGGSGGGGSDVKLQESGAELARPGASVKLSCKASGYTFTTFWMQRVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSS(配列番号101)。
DTVMSQSPSSLAVSVGEKITMSCKSSQSLLCRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELKGGGGSGGGGSGGGGSQVQLKESGAELARPGASVKLSCKASGYTFTTFWMQWAKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSS(配列番号102)。
DTVMSQSPSSLAVSVGEKITMSCKSSQSLLYRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELKGGGGSGGGGSGGGGSEVQLQQSGAELVKPGASVKLSCTASGFDIKDTYIHWVKQRPEQGLEWIGRIDPANGDTRYDPEFQGKASLTADTSSNTAYLQFSNLTSEDTAVYYCARRGGLSWGQGTTLTVSS(配列番号103)。
DTVMSQSPSSLAVSVGEKITMSCKSSQSLLYRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELKGGGGSGGGGSGGGGSEVQLEESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSS(配列番号104)。
DTVMSQSPSSLAVSVGEKITMSCKSSQSLLYRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELKGGGGSGGGGSGGGGSEVQLVESGGGLVQPKGSLKLSCAASGFTFNTYAMYWVCQAPGKGLKWVARIRSKVNNYATYYADSVKDRFTISRDDSQNMLFLHMNNLKTEDTAIYFCVRDPMDYWGQGISVTVSS(配列番号105)。
DTVMSQSPSSLAVSVGEKITMSCKSSQSLLYRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELKGGGGSGGGGSGGGGSQVQLQQSGAELARPGASVKLSCKASGYTFTTFWMQWVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSS(配列番号106)。
DTVMSQSPSSLAVSVGEKITMSCKSSQSLLYRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELKGGGGSGGGGSGGGGSDVKLQESGAELARPGASVKLSCKASGYTFTTFWMQRVKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSS(配列番号107)。
DTVMSQSPSSLAVSVGEKITMSCKSSQSLLYRSNQKNYLAWYQQKPGQSPKQLIYWASTRESGVPDRFTGSGSGTDFTLTISSVKAEDLAVYYCQQYYSYPLTFGAGTKLELKGGGGSGGGGSGGGGSQVQLKESGAELARPGASVKLSCKASGYTFTTFWMQWAKQRPGQGLEWIGTIYPGDDDTRYTQKFKGRATLTADKSSTTAYMQLSNLSSEDSAVYYCARSGYERGPYYFDSWGQGTTLTVSS(配列番号108)。
本開示の組成物および方法に使用することができる抗体としては、任意のクラスの全免疫グロブリン(すなわち、無傷の抗体)、その断片、および少なくとも抗体の抗原結合可変ドメインを含有する合成タンパク質が挙げられる。可変ドメインは、抗体間で配列が異なり、その特定の抗原に対する各特定の抗体の結合および特異性に使用される。しかしながら、可変性は、通常、抗体の可変ドメインを通じて均等に分布していない。典型的には、軽鎖および重鎖可変ドメインの両方において相補性決定領域(CDR)または超可変領域と呼ばれる3つのセグメントに濃縮される。可変ドメインのより高度に保存された部分は、フレームワーク(FR)と呼ばれる。天然の重鎖および軽鎖の可変ドメインは、それぞれ4つのFR領域を含み、主にβシートの立体配置をとり、3つのCDRによって連結され、CDRは、ループを形成してβシート構造を連結し、場合によって、はその一部を形成する。各鎖中のCDRは、FR領域によって近接して一緒に保持され、他方の鎖からのCDRとともに、抗体の抗原結合部位の形成に寄与する。
薬学的に許容される担体中に開示される分子を含む医薬組成物もまた開示される。医薬担体は、当業者に既知である。これらは、最も典型的には、生理的pHにおける滅菌水、食塩水、および緩衝溶液などの溶液を含む、ヒトへの薬物投与のための標準的な担体であろう。例えば、好適な担体およびそれらの製剤は、Remington: The Science and Practice of Pharmacy (21 ed.) ed.PP.Gerbino,Lippincott Williams & Wilkins,Philadelphia,PA.2005に記載されている。典型的には、製剤中に適量の薬学的に許容される塩を使用して、製剤を等張性にする。薬学的に許容される担体の例としては、限定されないが、食塩水、リンゲル液、およびデキストロース溶液が挙げられる。溶液のpHは、好ましくは約5~約8、より好ましくは約7~約7.5である。溶液には、RNA分解酵素が含まれないようにすべきである。さらなる担体としては、抗体を含有する固体疎水性ポリマーの半透性マトリックス等の徐放性調製物が挙げられ、マトリックスは、成形品、例えば、フィルム、リポソームまたは微小粒子の形態である。当業者には明白であろうが、例えば、投与される組成物の投与経路および濃度に応じて、ある特定の担体がより好ましいことがある。
治療上有効量の開示される医薬組成物を対象に投与することによって、対象においてCD99発現癌を治療するための方法も開示される。本方法は、対象に、フルダラビン、シタラビン、シクロホスファミド、イダルビシン、ダウノルビシン等の化学療法、またはイムブルビカ、ミドスタウリン、イデラリシブ等の標的阻害剤、またはPD1もしくはPDL1阻害剤等の免疫剤を投与することをさらに含むことができる。
CARは、一般に、リンパ球活性化に関与する膜貫通シグナル伝達モチーフを有するモノクローナル抗体(mAb)の単鎖可変断片(scFv)由来の抗原認識ドメインを組み込む(Sadelain M,et al.Nat Rev Cancer 2003 3:35-45)。CD99特異的キメラ抗原受容体(CAR)に対する抗腫瘍活性を増強するために、免疫エフェクター細胞内で発現することができるCD99特異的CARが、本明細書に開示される。
SP-CD99-HG-TM-CSR-SD、または
SP-CD99-HG-TM-SD-CSR、によって定義され、
式中、「SP」は、任意選択的なシグナルペプチドを表し、
式中、「CD99」は、CD99結合領域を表し、
式中、「HG」は、任意選択的なヒンジドメインを表し、
式中、「TM」は膜貫通ドメインを表し、
式中、「CSR」は、1つまたは複数の共刺激シグナル伝達領域を表し、
式中、「SD」は、シグナル伝達ドメインを表し、
式中、「-」は、ペプチド結合またはリンカーを表す。
また、開示される免疫エフェクター細胞においてCD99特異的CARの発現を可能にする、開示されるCD99特異的CARをコードするポリヌクレオチドおよびポリヌクレオチドベクターも開示される。
また、開示されるCAR(本明細書では「CAR-T細胞」とも称される)を発現するように改変される免疫エフェクター細胞も開示される。これらの細胞は、好ましくは、治療される対象から得られる(すなわち、自己細胞である)。しかしながら、一部の実施形態では、免疫エフェクター細胞株またはドナーエフェクター細胞(同種)が使用される。免疫エフェクター細胞は、いくつかの供給源から得ることができ、末梢血単核細胞、骨髄、リンパ節組織、臍帯血、胸腺組織、感染部位からの組織、腹水、胸水、脾臓組織、および腫瘍が含まれる。免疫エフェクター細胞は、Ficoll(商標)分離等の当業者に既知の任意の数の技術を使用して、対象から採取された血液から得ることができる。例えば、個体の循環血液からの細胞は、アフェレーシスによって得ることができる。一部の実施形態では、免疫エフェクター細胞は、例えば、PERCOLL(商標)勾配を介した遠心分離によって、または対向流遠心溶出によって、赤血球を溶解させ、単球を枯渇させることによって末梢血リンパ球から単離される。免疫エフェクター細胞の特定のサブ集団は、陽性または陰性選択技術によってさらに単離され得る。例えば、免疫エフェクター細胞は、例えば、所望の免疫エフェクター細胞の陽性選択に十分な期間、抗体結合ビーズとインキュベートすることによって、陽性選択細胞に固有の表面マーカーに対する抗体の組み合わせを使用して単離され得る。あるいは、免疫エフェクター細胞集団の濃縮は、陰性選択細胞に固有の表面マーカーに対する抗体の組み合わせを使用して、陰性選択によって達成することができる。
開示されるCARを発現する免疫エフェクター細胞は、CD99発現癌細胞に対する抗腫瘍免疫応答を誘発することができる。開示されるCAR修飾免疫エフェクター細胞によって誘発される抗腫瘍免疫応答は、能動または受動免疫応答であってもよい。加えて、CAR媒介性免疫応答は、CD99に特異的な免疫応答をCAR修飾免疫エフェクター細胞が誘導する養子免疫療法の手法の一部であり得る。
用語「アミノ酸配列」は、アミノ酸残基を表す略称、文字、記号または単語のリストを指す。本明細書で使用されるアミノ酸の略称は、アミノ酸の従来の1文字コードであり、以下のように表される。A.アラニン、B.アスパラギンまたはアスパラギン酸、C.システイン、D.アスパラギン酸、E.グルタミン酸、グルタミン酸、F.フェニルアラニン、G.グリシン、H.ヒスチジン、I.イソロイシン、K.リジン、L.ロイシン、M.メチオニン、N.アスパラギン、P.プロリン、Q.グルタミン、R.アルギニン、S.セリン、T.スレオニン、V.バリン、W.トリプトファン、Y.チロシン、Z.グルタミンまたはグルタミン酸。
EL4-hCD99細胞を、ハイブリドーマ由来の抗体/上清とインキュベートした。次いで、細胞をLive dead Zombie Green色素で染色し、F(ab2)抗mIgG-PEで染色した。INTELLICYTハイスループットスクリーナー(iQue)を使用して、CD99 PEに対して陽性の細胞を評価した。図1は、CD99-PE分析において生細胞に使用されるゲートを示すフローサイトメトリープロットを含む。図2は、CD99-PE分析に使用される陽性(右)および陰性(左)対照を示すフローサイトメトリープロットを含む。左のヒストグラムは、上清、すなわち抗体(Abs)、を使用しなかった対照試料のものである。右ヒストグラムは、PE標識CD99抗体を使用した陽性対照である。ゲートは、CD99-PE陽性集団を表す。図3は、CD99に対して陽性であるハイブリドーマを示すフローサイトメトリープロットを含む。ヒストグラムの下部の数字は、ウェル/ハイブリドーマを表す。
Claims (23)
- CD99抗原結合ドメイン、膜貫通ドメイン、細胞内シグナル伝達ドメイン、および共刺激シグナル伝達領域を含み、
前記CD99抗原結合ドメインが、CD99に特異的に結合する抗体の単鎖可変断片(scFv)であり、前記scFvが、CDR1、CDR2およびCDR3配列を有する可変重(V H )ドメイン、ならびにCDR1、CDR2およびCDR3配列を有する可変軽(V L )ドメインを含み、
(a)前記V H ドメインの前記CDR1配列が、配列番号1のアミノ酸配列を含み、前記V H ドメインの前記CDR2配列が、配列番号5のアミノ酸配列を含み、前記V H ドメインの前記CDR3配列が、配列番号8のアミノ酸配列を含み、前記V L ドメインの前記CDR1配列が、配列番号12のアミノ酸配列を含み、前記V L ドメインの前記CDR2配列が、配列番号16のアミノ酸配列を含み、および前記V L ドメインの前記CDR3配列が、配列番号19のアミノ酸配列を含む;または、
(b)前記V H ドメインの前記CDR1配列が、配列番号2のアミノ酸配列を含み、前記V H ドメインの前記CDR2配列が、配列番号6のアミノ酸配列を含み、前記V H ドメインの前記CDR3配列が、配列番号9のアミノ酸配列を含み、前記V L ドメインの前記CDR1配列が、配列番号13のアミノ酸配列を含み、前記V L ドメインの前記CDR2配列が、配列番号17のアミノ酸配列を含み、および前記V L ドメインの前記CDR3配列が、配列番号20のアミノ酸配列を含む;または、
(c)前記V H ドメインの前記CDR1配列が、配列番号4のアミノ酸配列を含み、前記V H ドメインの前記CDR2配列が、配列番号7のアミノ酸配列を含み、前記V H ドメインの前記CDR3配列が、配列番号10のアミノ酸配列を含み、前記V L ドメインの前記CDR1配列が、配列番号14のアミノ酸配列を含み、前記V L ドメインの前記CDR2配列が、配列番号18のアミノ酸配列を含み、および前記V L ドメインの前記CDR3配列が、配列番号21のアミノ酸配列を含む、キメラ抗原受容体(CAR)ポリペプチド。 - 前記V H ドメインが、配列番号22のアミノ酸配列を含み、前記V L ドメインが、配列番号34、36又は37のアミノ酸配列を含む、請求項1に記載のポリペプチド。
- 前記scFvが、配列番号47~49からなる群から選択されるアミノ酸配列を含む、請求項2に記載のポリペプチド。
- 前記V H ドメインが、配列番号24又は26のアミノ酸配列を含み、前記V L ドメインが、配列番号38のアミノ酸配列を含む、請求項1に記載のポリペプチド。
- 前記scFvが、配列番号56及び62からなる群から選択されるアミノ酸配列を含む、請求項4に記載のポリペプチド。
- 前記V H ドメインが、配列番号28のアミノ酸配列を含み、前記V L ドメインが、配列番号42のアミノ酸配列を含む、請求項1に記載のポリペプチド。
- 前記scFvが、配列番号69からなる群から選択されるアミノ酸配列を含む、請求項6に記載のポリペプチド。
- 前記共刺激シグナル伝達領域が、CD27、CD28、4-1BB、OX40、CD30、CD40、PD-1、ICOS、リンパ球機能関連抗原-1(LFA-1)、CD2、CD7、LIGHT、NKG2C、B7-H3、CD83と特異的に結合するリガンド、およびこれらの任意の組み合わせからなる群から選択される共刺激分子の細胞質ドメインを含む、請求項1~7のいずれか一項に記載のポリペプチド。
- 前記CARポリペプチドが、式
SP-CD99-HG-TM-CSR-ISD、または
SP-CD99-HG-TM-ISD-CSR
によって定義され、式中、「SP」は、シグナルペプチドを表し、
「CD99」は、CD99結合領域を表し、
「HG」は、任意選択的なヒンジドメインを表し、
「TM」は、膜貫通ドメインを表し、
「CSR」は、共刺激シグナル伝達領域を表し、
「ISD」は、細胞内シグナル伝達ドメインを表し、および
「-」は二価リンカーを表す、請求項1~8のいずれか一項に記載のポリペプチド。 - 前記細胞内シグナル伝達ドメインが、CD3ゼータ(CD3ζ)シグナル伝達ドメインを含む、請求項1~9のいずれか一項に記載のポリペプチド。
- 請求項1~10のいずれか一項に記載の組換えポリペプチドをコードする単離された核酸。
- 請求項11に記載の単離された核酸を含むベクター。
- 請求項12に記載のベクターを含む細胞。
- 前記細胞が、αβT細胞、γδT細胞、ナチュラルキラー(NK)細胞、ナチュラルキラーT(NKT)細胞、B細胞、自然リンパ球細胞(ILC)、サイトカイン誘導キラー(CIK)細胞、細胞傷害性Tリンパ球(CTL)、リンホカイン活性化キラー(LAK)細胞、制御性T細胞、またはこれらの任意の組み合わせからなる群から選択される、請求項13に記載の細胞。
- 前記細胞が、前記CARの前記抗原結合ドメインがCD99に結合するときに、抗腫瘍免疫を示す、請求項14に記載の細胞。
- 請求項1に記載のキメラ抗原受容体(CAR)ポリペプチドを含む、細胞。
- 前記細胞が、自己または同種のエプスタインバーウイルス(EBV)特異的細胞傷害性リンパ球である、請求項16に記載の細胞。
- CD99発現癌を有する対象において抗癌免疫を提供するための医薬であって、前記対象に有効量の、請求項1~10のいずれか一項に記載のCARポリペプチドを発現するように遺伝子改変された免疫エフェクター細胞を含む、医薬。
- 前記免疫エフェクター細胞が、T細胞、ナチュラルキラー(NK)細胞、細胞傷害性Tリンパ球(CTL)、および制御性T細胞からなる群から選択される、請求項18に記載の医薬。
- 前記免疫エフェクター細胞が、自己または同種のエプスタインバーウイルス(EBV)特異的細胞傷害性リンパ球である、請求項18または19に記載の医薬。
- 前記対象にチェックポイント阻害剤の投与と組み合わせて投与される、請求項18~20のいずれか一項に記載の医薬。
- 前記チェックポイント阻害剤が、抗PD-1抗体、抗PD-L1抗体、抗CTLA-4抗体、またはこれらの組み合わせを含む、請求項21に記載の医薬。
- 前記癌が、骨髄異形成症候群、急性骨髄性白血病、または混合表現型(bi-phenotypic)白血病を含む、請求項18~22のいずれか一項に記載の医薬。
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