JP2020514277A - プログラム死リガンド−1(pd−l1)に結合する抗体を使用する免疫 - Google Patents
プログラム死リガンド−1(pd−l1)に結合する抗体を使用する免疫 Download PDFInfo
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Abstract
Description
本出願は、2016年12月23日に出願された米国特許仮出願第62/438,622号の利益を主張し、参照によりその全体が本明細書に援用される。
本明細書に他に規定のない限り、本発明に関係して使用される科学及び技術用語は、当業者によって共通して理解される意味を有する。さらに、文脈によって他に要求されない限り、単数形の用語は、複数のものを含み、複数形の用語は、単数のものを含む。概して、本明細書に記載の細胞及び組織培養、分子生物学、免疫学、微生物学、遺伝学並びにタンパク質及び核酸化学並びにハイブリダイゼーションは、共通して使用されるものであり、当該技術分野で周知である。本発明の方法及び技術は、概して、当該技術分野で周知であり、他に指示されていない限り、本明細書全体で記載され、検討される様々な一般的、より詳細な参考文献に記載される通常の方法に従って実施される。例えば、Green and Sambrook,Molecular Cloning:A Laboratory Manual,第4版,Cold Spring Harbor Laboratory Press,Cold Spring Harbor,N.Y.(2012)を参照されたい、参照により本明細書に援用される。酵素反応及び精製技術は、当該技術分野で広く達成され、又は本明細書に記載されるように、製造者の仕様書に従って実施される。本明細書に記載の分析化学、合成有機化学及び医薬品化学及び製薬化学の実験的手順及び技術に関係して使用される命名法は、広く使用され、当該技術分野で周知されている。標準的な技術は、化学合成、化学分析、医薬品の調製、配合及び送達並びに対象の治療に使用される。
アラニン(A)、セリン(S)及びスレオニン(T)
アスパラギン酸(D)及びグルタミン酸(E)
アスパラギン(N)及びグルタミン(Q)
アルギニン(R)及びリジン(K)
イソロイシン(I)、ロイシン(L)、メチオニン(M)及びバリン(V)
フェニルアラニン(F)、チロシン(Y)及びトリプトファン(W)
「PD−L1」という用語は、本明細書で使用する場合、ヒトPD−L1(hPD−L1)、変異体、アイソフォーム及びhPD−L1の種の相同体並びにhPD−L1と少なくとも1つの共通エピトープを有する類似体を含む。様々な実施形態において、hPD−L1ポリペプチドは、本明細書で使用する場合、NCBI参照配列に記載のアミノ酸配列を含み得る。NP_054862.1(SEQ ID NO:1):
MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEME
DKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYG
GADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET
(SEQ ID NO:1)
ヒトPD−L1ポリペプチドに結合する新規抗体を生成する方法は、当業者に周知である。例えば、PD−L1ポリペプチドに特異的に結合するモノクローナル抗体を生成する方法は、検出可能な免疫反応を刺激するのに有効なPD−L1ポリペプチドを含む免疫原性組成物をマウスに投与することを含み得、マウスの抗体産生細胞(例えば、膵臓からの細胞)を得て、抗体産生細胞を骨髄腫細胞と融合して、抗体産生ハイブリドーマを得て、抗体産生ハイブリドーマに試験を行って、PD−L1ポリペプチドに特異的に結合するモノクローナル抗体を産生するハイブリドーマを識別することを含み得る。一度得られると、ハイブリドーマは細胞培地、任意に、ハイブリドーマ由来細胞がPD−L1ポリペプチドに特異的に結合するモノクローナル抗体を産生する培養条件で増殖することができる。モノクローナル抗体は、細胞培地から精製され得る。特定の望ましい抗体を識別するために、様々な異なる技術を抗体:抗原相互作用の試験に使用可能である。
PD−L1への結合について、例えば、標準ELISAによって本発明の抗体を試験することができる。例として、マイクロタイタープレートをPBSの精製されたPD−L1で被覆し、その後、PBSの5%ウシ血清アルブミンで遮断する。抗体の希釈液(例えば、PD−L1免疫化マウスの血漿の希釈液)を各ウェルに添加し、37℃で1〜2時間インキュベートする。プレートをPBS/Tweenで洗浄し、アルカリホスファターゼに結合した二次試薬(例えば、ヒト抗体については、ヤギ抗ヒトIgG Fc特異的ポリクローナル試薬)でインキュベートする。洗浄後、プレートをpNPP基質(1Mg/ml)で発達させ、405〜650のODで分析する。好ましくは、最も高い力価を発現するマウスを融合に使用する。ELISA分析を使用して、PD−L1免疫原に陽性の反応を示すハイブリドーマをスクリーニングすることもできる。高い結合活性でPD−L1に結合するハイブリドーマをサブクローン化し、さらに特徴付けを行う。各ハイブリドーマの1つのクローンは、親細胞の反応性を(ELISAにより)保持し、−140℃で保存した5〜10バイアルの細胞バンクを作製し、抗体の精製のために選択することができる。
本発明は、PD−L1抗原に特異的に結合するモノクローナル抗体及びその抗原結合断片を提供する。
EVQLQQSGAELVRPGSSVKMSCKTSGYSFTSYSINWVKQRPGQGLEWVAYIYIGNGYTEYNEKFKGKATLTSDTPSSTAYMQLSSLTSEDSAIYFCARWSLPNGMDYWGQGTSVTVSS(SEQ ID NO:12)
及びSEQ ID NO:16の軽鎖可変領域配列を含む。
DIVMTQSHKLMSTSIGDRVNITCKASQDVGISVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSTYRTFGGGTKLENK(SEQ ID NO:16)
gaggtccagcttcagcagtctggagctgaactggtgaggcctgggtcctcagtgaagatgtcctgcaagacttctggatattcattcacaagttacagtataaactgggtgaagcagaggcctggacagggcctggaatgggttgcatatatttatattggaaatggttatactgaatataatgagaagttcaagggcaaggccacactgacttcagacacaccctccagcacagcctacatgcagctcagcagcctgacatctgaggattctgcaatctatttctgtgcaagatggtcactacccaatggaatggactactgggggcaaggaacctcagtcaccgtctcctca(SEQ ID NO:13)
軽鎖は、SEQ ID NO:16に記載のアミノ酸配列と少なくとも約75%、少なくとも約80%、少なくとも約85%、少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、又は少なくとも約99%の同一性を有する配列、又はその対応するポリヌクレオチド配列SEQ ID NO:17を含む。
gacattgtgatgacccagtctcacaaactcatgtccacatcaataggagacagggtcaacatcacctgcaaggccagtcaggatgtgggtatttctgtagcctggtatcaacagaaaccaggacaatctcctaaactactgatttattgggcatccactcggcacactggagtccccgatcgcttcacaggcagtggatctgggacagatttcactctcaccattagtaatgtgcagtctgaggacttggcagattatttctgtcagcaatatagcacctatcggacgttcggtggaggcaccaagctggaaaacaaa(SEQ ID NO:17)
EVQLQQSGAELVRPGSSVKMSCKTSGYTFTSYSINWVKQRPGQGLEWIAYFYVGNGYTDYNEKFKGKATLTSDTSSSTAYMQLSSLTSEDSAIYFCARGGLPYYFDYWGQGTTLTVSS(SEQ ID NO:14)
及びSEQ ID NO:18の軽鎖可変領域配列を含む。
DIVMTQSHKFMSTSVGDRVSITCKTSQDVNTAVAWYQQKPGHSPKLLFYWASTRHTGVPDRFTGGGSGTDYTLTISSVQAEDLALYYCQQHYNTPLTFGAGTRLELK(SEQ ID NO:18)
gaggtccagcttcagcagtctggagctgaactggtgaggcctgggtcctcagtgaagatgtcctgcaagacttctggatatacattcacaagttacagtataaattgggtgaagcagaggcctggtcagggcctggaatggattgcatatttttatgttggaaatggttatactgactacaatgagaagttcaagggcaaggccacactgacttcagacacatcttccagcacagcctacatgcagctcagcagcctgacatctgaggactctgcaatctatttctgtgcacgagggggcctaccctactactttgactactggggccaaggcaccactctcacagtctcctca(SEQ ID NO:15)
軽鎖は、SEQ ID NO:18に記載のアミノ酸配列と少なくとも約75%、少なくとも約80%、少なくとも約85%、少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、又は少なくとも約99%の同一性を有する配列、又はその対応するポリヌクレオチド配列SEQ ID NO:19を含む。
gacattgtgatgacccagtctcacaaattcatgtccacatcagttggagacagggtcagcatcacctgcaagaccagtcaggatgtgaatactgctgtagcctggtatcaacaaaaaccagggcattctcctaaactactgttttactgggcatccacccggcacactggagtccctgatcgcttcacaggcggtggatctgggacagattatactctcaccatcagcagtgtgcaggctgaagacctggcactttattactgtcagcaacattataacactccgctcacgttcggtgctgggaccaggctggagctgaaa(SEQ ID NO:19)
軽鎖(カッパ)定常領域
RTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:48)
軽鎖(ラムダ)定常領域
GQPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS(SEQ ID NO:49)
重鎖定常領域
ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(SEQ ID NO:50)
MGWSWILLFLLSVTAGVHSEVQLQQSGAELVRPGSSVKMSCKTSGYTFTSYSINWVKQRPGQGLEWIAYFYVGNGYTDYNEKFKGKATLTSDTSSSTAYMQLSSLTSEDSAIYFCARGGLPYYFDYWGQGTTLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:51)
SEQ ID NO:53の軽鎖配列を含み、アミノ酸1〜19はリーダー配列である。
MGWSWILLFLLSVTAGVHSDIVMTQSHKFMSTSVGDRVSITCKTSQDVNTAVAWYQQKPGHSPKLLFYWASTRHTGVPDRFTGGGSGTDYTLTISSVQAEDLALYYCQQHYNTPLTFGAGTRLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:53)
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgaggtgcagctgcagcagagcggggcagaactggtgcggcctgggtcaagcgtgaagatgtcatgtaaaacaagcggctatactttcacatcctactctatcaactgggtgaagcagaggccaggacagggactggagtggatcgcctacttctatgtgggcaacggctacaccgactataatgagaagtttaagggcaaggccaccctgacaagcgatacaagctcctctaccgcctatatgcagctgagctccctgaccagcgaggactccgccatctacttctgcgcaaggggaggactgccatactattttgattattggggccagggcaccacactgacagtgtctagcgccagcaccaagggaccatccgtgttcccactggcaccatgcagcagatccacatctgagagcaccgccgccctgggatgtctggtgaaggactacttccctgagccagtgaccgtgtcttggaatagcggcgccctgacaagcggagtgcacacctttcctgccgtgctgcagtcctctggcctgtactccctgagctccgtggtgacagtgccctctagctccctgggcaccaagacatatacctgcaacgtggaccacaagccttctaataccaaggtggataagagggtggagagcaagtacggaccaccttgcccaccatgtccagcacctgagtttctgggaggaccaagcgtgttcctgtttcctccaaagcctaaggacacactgatgatcagccgcacacctgaggtgacctgcgtggtggtggacgtgtcccaggaggatccagaggtgcagttcaactggtacgtggatggcgtggaggtgcacaatgccaagaccaagcctagggaggagcagtttaactctacataccgcgtggtgagcgtgctgaccgtgctgcaccaggattggctgaacggcaaggagtataagtgcaaggtgtctaataagggcctgccatctagcatcgagaagacaatctccaaggcaaagggacagcctagggagccacaggtgtacaccctgcccccttcccaggaggagatgacaaagaaccaggtgtctctgacctgtctggtgaagggcttctatccaagcgacatcgccgtggagtgggagtccaatggccagcccgagaacaattacaagaccacaccacccgtgctggactccgatggctctttctttctgtattcccggctgaccgtggataagtctagatggcaggagggcaacgtgttcagctgttctgtgatgcacgaagcactgcacaaccattacactcagaagtccctgtccctgtccctgggcaaa(SEQ ID NO:52)
軽鎖は、SEQ ID NO:53に記載のアミノ酸配列と少なくとも約75%、少なくとも約80%、少なくとも約85%、少なくとも90%、91%、92%、93%、94%、95%、96%、97%、98%、又は少なくとも約99%の同一性を有する配列、又はその対応するポリヌクレオチド配列SEQ ID NO:54を有する。
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgatatcgtgatgacccagagccacaagtttatgagcaccagcgtcggagacagagtcagtattacctgcaaaaccagccaggatgtgaacaccgccgtggcctggtaccagcagaagccaggccactctcccaagctgctgttctattgggcaagcaccaggcacacaggagtgccagaccgctttaccggaggaggatccggaacagattacaccctgacaatcagctccgtgcaggcagaggacctggccctgtactattgccagcagcactataatacccctctgacattcggcgcaggaaccaggctggagctgaagagaacagtggccgccccaagcgtgttcatctttcccccttccgacgagcagctgaagtccggcaccgcctctgtggtgtgcctgctgaacaacttctaccccgggaggccaaggtgcagtggaaggtggataacgccctgcagtccggcaattctcaggagagcgtgaccgagcaggactccaaggattctacatatagcctgtctagcaccctgacactgtctaaggccgattacgagaagcacaaggtgtatgcctgcgaggtcactcaccaggggctgtcttcaccagtcaccaagtccttcaatcggggggaatgc(SEQ ID NO:54
MGWSWILLFLLSVTAGVHSEVQLVQSGAEVKKPGESLKISCKGSGYSFTSYSINWVRQMPGKGLEWMGYFYVGNGYTDYNEKFKGRVTMTRNTSISTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:55)
SEQ ID NO:56の軽鎖配列を含み、アミノ酸1〜19はリーダー配列である。
MGWSWILLFLLSVTAGVHSDIQMTQSPSTLSASVGDRVTITCKTSQDVNTAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQHYNTPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:56)。
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgaggtgcagctggtgcagagcggggcagaggtcaaaaagcctggcgaaagcctgaaaatctcctgtaagggaagcggatactcattcacctcttacagcatcaactgggtgcggcagatgccaggcaagggcctggagtggatgggctacttctatgtgggcaacggctacacagactataatgagaagtttaagggccgggtgaccatgacaagaaatacctccatctctacagcctatatggagctgagctccctgaggagcgaggataccgccgtgtactattgcgcccgcggggggctgccatactattttgactattggggacaggggactctggtgaccgtctcatccgcctctacaaagggcccctccgtgtttccactggctccctgcagcaggtctacatccgagagcaccgctgctctgggatgtctggtgaaggattacttccctgagccagtgaccgtgagctggaactccggagctctgacatccggagtgcacacctttcctgctgtgctgcagagctctggcctgtacagcctgtccagcgtggtgacagtgccatcttccagcctgggcaccaagacatatacctgcaacgtggaccataagcccagcaataccaaggtggataagagagtggagtctaagtacggaccaccttgcccaccatgtccagctcctgagtttctgggaggaccatccgtgttcctgtttcctccaaagcctaaggacaccctgatgatctctcgcacacccgaggtgacctgtgtggtggtggacgtgtcccaggaggatcctgaggtgcagttcaactggtacgtggatggcgtggaggtgcacaatgctaagaccaagcctagggaggagcagtttaacagcacataccgggtggtgtctgtgctgaccgtgctgcatcaggactggctgaacggcaaggagtataagtgcaaggtgagcaataagggcctgccatcttccatcgagaagacaatctctaaggctaagggacagcctagggagccacaggtgtacaccctgcccccttcccaggaggagatgacaaagaaccaggtgagcctgacctgtctggtgaagggcttctatccttctgacatcgctgtggagtgggagtccaatggccagccagagaacaattacaagaccacaccacccgtgctggactccgatggcagcttctttctgtattccaggctgaccgtggataagagccggtggcaggagggcaatgtgttttcttgttccgtgatgcacgaagcactgcacaaccactacactcagaagtccctgtcactgtccctgggcaag(SEQ ID NO:65)
軽鎖は、SEQ ID NO:56に記載のアミノ酸配列と少なくとも75%、少なくとも約80%、少なくとも約85%、少なくとも約90%、91%、92%、93%、94%、95%、96%、97%、98%、又は少なくとも約99%の同一性を有する配列、又はその対応するポリヌクレオチド配列SEQ ID NO:66を含む。
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgacattcagatgacacagagcccttcaacactgagcgcctccgtgggggatcgggtgactattacttgtaagaccagccaggacgtgaacaccgcagtggcatggtaccagcagaagccaggcaaggcccctaagctgctgatctattgggcctctacccggcacacaggcgtgccaagcagattctctggcagcggctccggcaccgagtttaccctgacaatcagctccctgcagcccgaggacttcgccacatactattgccagcagcattacaacacacccctgacattcggcggcgggacaaaactggaaatcaagaggaccgtggccgctcccagtgtcttcatttttccccctagcgacgaacagctgaaatccgggactgcttctgtggtctgtctgctgaacaatttctaccctcgcgaagccaaagtgcagtggaaggtcgataacgctctccagagtggcaattcacaggagagcgtgacagaacaggactccaaagattctacttatagtctgtctagtacactgactctgtccaaggcagactacgagaagcacaaagtgtatgcctgtgaagtcacccatcagggcctgtcaagccccgtgacaaagtcttttaacagaggggagtgt(SEQ ID NO:66)
MGWSWILLFLLSVTAGVHSEVQLVQSGAEVKKPGESLKISCKGSGYSFTSYSINWVRQAPGKGLEWMGYFYVGNGYTDYNEKFKGRVTMTRNTSISTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:57)
及びSEQ ID NO:58の軽鎖配列を含み、アミノ酸1〜19はリーダー配列である。
MGWSWILLFLLSVTAGVHSDIQLTQSPSSLSASVGDRVTITCKTSQDVNTAVAWYQQKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHYNTPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC(SEQ ID NO:58)
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgaggtgcagctggtgcagagcggggcagaagtcaagaagcctggggaaagcctgaaaatctcctgtaagggaagcggatactcattcacctcttacagcatcaactgggtgcggcaggcaccaggcaagggcctggagtggatgggctacttctatgtgggcaacggctacacagactataatgagaagtttaagggccgggtgaccatgacaagaaatacctccatctctacagcctatatggagctgagctccctgaggagcgaggataccgccgtgtactattgcgcccgcgggggactgccttactattttgactactggggacagggaacactggtgaccgtctcctctgcctctacaaagggcccctccgtgtttccactggctccctgcagcaggtctacatccgagagcaccgctgctctgggatgtctggtgaaggattacttccctgagccagtgaccgtgagctggaactccggagctctgacatccggagtgcacacctttcctgctgtgctgcagagctctggcctgtacagcctgtccagcgtggtgacagtgccatcttccagcctgggcaccaagacatatacctgcaacgtggaccataagcccagcaataccaaggtggataagagagtggagtctaagtacggaccaccttgcccaccatgtccagctcctgagtttctgggaggaccatccgtgttcctgtttcctccaaagcctaaggacaccctgatgatctctcgcacacccgaggtgacctgtgtggtggtggacgtgtcccaggaggatcctgaggtgcagttcaactggtacgtggatggcgtggaggtgcacaatgctaagaccaagcctagggaggagcagtttaacagcacataccgggtggtgtctgtgctgaccgtgctgcatcaggactggctgaacggcaaggagtataagtgcaaggtgagcaataagggcctgccatcttccatcgagaagacaatctctaaggctaagggacagcctagggagccacaggtgtacaccctgcccccttcccaggaggagatgacaaagaaccaggtgagcctgacctgtctggtgaagggcttctatccttctgacatcgctgtggagtgggagtccaatggccagccagagaacaattacaagaccacaccacccgtgctggactccgatggcagcttctttctgtattccaggctgaccgtggataagagccggtggcaggagggcaatgtgttttcttgttccgtgatgcacgaagcactgcacaaccactacactcagaagtccctgtcactgtccctgggcaag(SEQ ID NO:67)
軽鎖は、SEQ ID NO:58の記載のアミノ酸配列と少なくとも約75%、少なくとも約 80%、少なくとも約85%、少なくとも約90%、91%、92%、93%、94%、95%、96%、97%、98%又は少なくとも約99%の同一性を有する配列、又はその対応するポリヌクレオチド配列SEQ ID NO:68を含む。
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgacatccagctgacccagagcccaagtagcctgagcgcaagcgtcggggacagagtgactattacctgcaagacaagccaggacgtgaacaccgcagtggcatggtaccagcagaagccaggacaggcacctaggctgctgatctattgggcctctacccggcacacaggcgtgccaagcagattctctggcagcggctccggcaccgactttaccctgacaatcagctccctgcagcccgaggatttcgccacatactattgccagcagcattacaacactcctctgacattcgggggggggacaaaactggaaatcaaaaggaccgtggccgctcccagtgtcttcatttttccccctagcgacgaacagctgaaatccgggactgcttctgtggtctgtctgctgaacaatttctaccctcgcgaagccaaagtgcagtggaaggtcgataacgctctccagagtggcaattcacaggagagcgtgacagaacaggactccaaagattctacttatagtctgtctagtacactgactctgtccaaggcagactacgagaagcacaaagtgtatgcctgtgaagtcacccatcagggcctgtcaagccccgtgacaaagtcttttaacagaggggagtgt(SEQ ID NO:68)
MGWSWILLFLLSVTAGVHSQMQLVQSGAEVKKTGSSVKVSCKASGYTFTSYSINWVRQAPGKGLEWVAYFYVGNGYTDYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:59)
及びSEQ ID NO:60の軽鎖配列を含み、アミノ酸1〜19はリーダー配列である。
MGWSWILLFLLSVTAGVHSDIQMTQSPSSVSASVGDRVTITCKTSQDVNTAVAWYQQKPGQAPRLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYNTPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:60)
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagccagatgcagctggtccagtcaggcgcagaagtcaagaaaaccgggtcaagcgtcaaagtgtcatgtaaagcaagcggatataccttcacatcttacagcatcaactgggtgcggcaggcaccaggcaagggcctggagtgggtggcctacttctatgtgggcaacggctacaccgactataatgagaagtttaagggccgggtgaccatgacaagagatacctccacatctaccgtgtatatggagctgagctccctgaggagcgaggacacagccgtgtactattgcgcccgcggggggctgccatactactttgactattggggacagggaacactggtgaccgtctcatcagcctctacaaagggcccctccgtgtttccactggctccctgcagcaggtctacatccgagagcaccgctgctctgggatgtctggtgaaggattacttccctgagccagtgaccgtgagctggaactccggagctctgacatccggagtgcacacctttcctgctgtgctgcagagctctggcctgtacagcctgtccagcgtggtgacagtgccatcttccagcctgggcaccaagacatatacctgcaacgtggaccataagcccagcaataccaaggtggataagagagtggagtctaagtacggaccaccttgcccaccatgtccagctcctgagtttctgggaggaccatccgtgttcctgtttcctccaaagcctaaggacaccctgatgatctctcgcacacccgaggtgacctgtgtggtggtggacgtgtcccaggaggatcctgaggtgcagttcaactggtacgtggatggcgtggaggtgcacaatgctaagaccaagcctagggaggagcagtttaacagcacataccgggtggtgtctgtgctgaccgtgctgcatcaggactggctgaacggcaaggagtataagtgcaaggtgagcaataagggcctgccatcttccatcgagaagacaatctctaaggctaagggacagcctagggagccacaggtgtacaccctgcccccttcccaggaggagatgacaaagaaccaggtgagcctgacctgtctggtgaagggcttctatccttctgacatcgctgtggagtgggagtccaatggccagccagagaacaattacaagaccacaccacccgtgctggactccgatggcagcttctttctgtattccaggctgaccgtggataagagccggtggcaggagggcaatgtgttttcttgttccgtgatgcacgaagcactgcacaaccactacactcagaagtccctgtcactgtccctgggcaag(SEQ ID NO:69)
軽鎖は、SEQ ID NO:60に記載のアミノ酸配列と少なくとも約75%、少なくとも約80%、少なくとも約85%、少なくとも約90%、91%、92%、93%、94%、95%、96%、97%、98%、又は少なくとも約99%の同一性を有する配列、又はその対応するポリヌクレオチド配列SEQ ID NO:70を含む。
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgacattcagatgacccagtctccaagctcagtctcagccagtgtgggcgaccgagtgacaattacatgcaaaacaagccaggacgtgaacaccgcagtggcatggtaccagcagaagccaggacaggcacctaggctgctgatctattgggcatctaccaggcacacaggagtgccagacagattctctggcagcggctccggcacagattttaccctgacaatcagctccctgcaggcagaggacgtggcagtgtactattgccagcagcattacaatactcctctgacattcgggggcggaaccaaactggaaatcaaaaggaccgtggccgctcccagtgtcttcatttttccccctagcgacgaacagctgaaatccgggactgcttctgtggtctgtctgctgaacaatttctaccctcgcgaagccaaagtgcagtggaaggtcgataacgctctccagagtggcaattcacaggagagcgtgacagaacaggactccaaagattctacttatagtctgtctagtacactgactctgtccaaggcagactacgagaagcacaaagtgtatgcctgtgaagtcacccatcagggcctgtcaagccccgtgacaaagtcttttaacagaggggagtgt(SEQ ID NO:70)
MGWSWILLFLLSVTAGVHSQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYSINWVRQAPGKGLEWVAYFYVGNGYTDYNEKFKGRVTITTDESTSTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:61)
及びSEQ ID NO:62の軽鎖配列を含み、アミノ酸1〜19はリーダー配列である。
MGWSWILLFLLSVTAGVHSDIQMTQSPSSLSASVGDRVTITCKTSQDVNTAVAWYQQKPGQPPKLLIYWASTRHTGIPARFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYNTPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:62)
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagccaggtccagctggtccagtcaggggcagaagtgaaaaaacccggagcctcagtcaaagtgtcatgcaaagcaagcggatacacatttacctcttacagcatcaactgggtgaggcaggcaccaggcaagggcctggagtgggtggcctacttctatgtgggcaacggctacaccgactataatgagaagtttaagggccgggtgacaatcaccacagatgagtccacctctacagcctatatggagctgagctccctgcggagcgaggacacagccgtgtactattgcgccagaggcgggctgccttattattttgactattggggacaggggacactggtgaccgtctcttcagcctctacaaagggcccctccgtgtttccactggctccctgcagcaggtctacatccgagagcaccgctgctctgggatgtctggtgaaggattacttccctgagccagtgaccgtgagctggaactccggagctctgacatccggagtgcacacctttcctgctgtgctgcagagctctggcctgtacagcctgtccagcgtggtgacagtgccatcttccagcctgggcaccaagacatatacctgcaacgtggaccataagcccagcaataccaaggtggataagagagtggagtctaagtacggaccaccttgcccaccatgtccagctcctgagtttctgggaggaccatccgtgttcctgtttcctccaaagcctaaggacaccctgatgatctctcgcacacccgaggtgacctgtgtggtggtggacgtgtcccaggaggatcctgaggtgcagttcaactggtacgtggatggcgtggaggtgcacaatgctaagaccaagcctagggaggagcagtttaacagcacataccgggtggtgtctgtgctgaccgtgctgcatcaggactggctgaacggcaaggagtataagtgcaaggtgagcaataagggcctgccatcttccatcgagaagacaatctctaaggctaagggacagcctagggagccacaggtgtacaccctgcccccttcccaggaggagatgacaaagaaccaggtgagcctgacctgtctggtgaagggcttctatccttctgacatcgctgtggagtgggagtccaatggccagccagagaacaattacaagaccacaccacccgtgctggactccgatggcagcttctttctgtattccaggctgaccgtggataagagccggtggcaggagggcaatgtgttttcttgttccgtgatgcacgaagcactgcacaaccactacactcagaagtccctgtcactgtccctgggcaag(SEQ ID NO:71)
軽鎖は、SEQ ID NO:62に記載のアミノ酸配列と少なくとも約75%、少なくとも約80%、少なくとも約85%、少なくとも約90%、91%、92%、93%、94%、95%、96%、97%、98%又は少なくとも約99%の同一性を有する配列、又はその対応するポリヌクレオチド配列SEQ ID NO:72を含む。
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgacattcagatgacacagagccctagttcactgagcgccagcgtgggagatagagtcacaatcacatgcaaaacaagccaggacgtgaacaccgccgtggcctggtaccagcagaagccaggccagccccctaagctgctgatctattgggcatctaccaggcacacaggcatccccgcaagattctctggaagcggatccggcacagactttaccctgacaatcagctccctgcagcccgaggatttcgccgtgtactattgccagcagcactacaatacaccactgaccttcggcgggggaactaaactggaaatcaaaaggaccgtggccgctcccagtgtcttcatttttccccctagcgacgaacagctgaaatccgggactgcttctgtggtctgtctgctgaacaatttctaccctcgcgaagccaaagtgcagtggaaggtcgataacgctctccagagtggcaattcacaggagagcgtgacagaacaggactccaaagattctacttatagtctgtctagtacactgactctgtccaaggcagactacgagaagcacaaagtgtatgcctgtgaagtcacccatcagggcctgtcaagccccgtgacaaagtcttttaacagaggggagtgt(SEQ ID NO:72)
MGWSWILLFLLSVTAGVHSQVQLVQSGSELKKPGASVKVSCKASGYTFTSYSINWVRQAPGKGLEWVAYFYVGNGYTDYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK(SEQ ID NO:63)
及びSEQ ID NO:64の軽鎖配列を含み、アミノ酸1〜19はリーダー配列である。
MGWSWILLFLLSVTAGVHSDIQMTQSPSTLSASVGDRVTITCKTSQDVNTAVAWYQQKPGKAPKLLLYWASTRHTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQHYNTPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
(SEQ ID NO:64)
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagccaggtccagctggtccagagcggaagtgaactgaagaaacccggagcaagcgtcaaagtctcatgcaaagcaagcggctacacatttacctcttacagcatcaactgggtgaggcaggcaccaggcaagggcctggagtgggtggcctacttctatgtgggcaacggctacacagactataatgagaagtttaagggccgggtgaccatcacagccgatgagtccacctctacagcctatatggagctgagctccctgaggagcgaggacaccgccgtgtactattgcgccagaggagggctgccttattactttgattactggggacagggaacactggtgaccgtctcatccgcctctacaaagggcccctccgtgtttccactggctccctgcagcaggtctacatccgagagcaccgctgctctgggatgtctggtgaaggattacttccctgagccagtgaccgtgagctggaactccggagctctgacatccggagtgcacacctttcctgctgtgctgcagagctctggcctgtacagcctgtccagcgtggtgacagtgccatcttccagcctgggcaccaagacatatacctgcaacgtggaccataagcccagcaataccaaggtggataagagagtggagtctaagtacggaccaccttgcccaccatgtccagctcctgagtttctgggaggaccatccgtgttcctgtttcctccaaagcctaaggacaccctgatgatctctcgcacacccgaggtgacctgtgtggtggtggacgtgtcccaggaggatcctgaggtgcagttcaactggtacgtggatggcgtggaggtgcacaatgctaagaccaagcctagggaggagcagtttaacagcacataccgggtggtgtctgtgctgaccgtgctgcatcaggactggctgaacggcaaggagtataagtgcaaggtgagcaataagggcctgccatcttccatcgagaagacaatctctaaggctaagggacagcctagggagccacaggtgtacaccctgcccccttcccaggaggagatgacaaagaaccaggtgagcctgacctgtctggtgaagggcttctatccttctgacatcgctgtggagtgggagtccaatggccagccagagaacaattacaagaccacaccacccgtgctggactccgatggcagcttctttctgtattccaggctgaccgtggataagagccggtggcaggagggcaatgtgttttcttgttccgtgatgcacgaagcactgcacaaccactacactcagaagtccctgtcactgtccctgggcaag(SEQ ID NO:73)
軽鎖は、SEQ ID NO:64に記載のアミノ酸配列と少なくとも約75%、少なくとも約80%、少なくとも約85%、少なくとも約90%、91%、92%、93%、94%、95%、96%、97%、98%、又は少なくとも約99%の同一性を有する配列、又はその対応するポリヌクレオチド配列SEQ ID NO:74を含む。
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgatattcagatgacccagagcccaagcaccctgtccgcaagcgtcggggatagagtgaccattacctgtaaaacaagccaggatgtgaacaccgcagtggcatggtaccagcagaagccaggcaaggcccctaagctgctgctgtattgggcatctaccaggcacacaggcatccccgcaagattctctggaagcggatccggcacagagtttaccctgacaatcagctccctgcagagcgaggacttcgccgtgtactattgccagcagcattacaatacaccactgacattcgggggggggactaaactggaaatcaagaggaccgtggccgctcccagtgtcttcatttttccccctagcgacgaacagctgaaatccgggactgcttctgtggtctgtctgctgaacaatttctaccctcgcgaagccaaagtgcagtggaaggtcgataacgctctccagagtggcaattcacaggagagcgtgacagaacaggactccaaagattctacttatagtctgtctagtacactgactctgtccaaggcagactacgagaagcacaaagtgtatgcctgtgaagtcacccatcagggcctgtcaagccccgtgacaaagtcttttaacagaggggagtgt(SEQ ID NO:74)
別の態様では、本発明は、前述の抗体又はその抗原結合断片を含む医薬組成物を提供する。本発明の医薬組成物、方法及び用途は、そのため、以下に詳細するその他の活性剤との併用(共投与)の実施形態も含む。
別の態様では、本発明は、T細胞関連疾患又は免疫反応を増加、又は抑制又は延長することによって、改善又は予防することができる疾患をり患している対象を治療する方法に関し、対象に、(単独療法又は治療レジメンの組み合わせの何れかとして)本発明の抗体又はその抗原結合断片を治療有効量投与することを含む。様々な実施形態において、対象はヒト対象である。
「共投与」、「共投与される」、及び「併用して」という用語は、本明細書で使用する場合、本開示の抗体又はその抗原結合断片及び1つ以上の他の治療薬は、以下を意味し、まさに指し、含むことを意図する:本開示の抗体又はその抗原結合断片及び治療薬の組み合わせを治療を必要とする対象に同時投与し、このとき、成分は単一剤形に共に配合され、対象に実質的に同時に放出する;本開示の抗体又はその抗原結合断片及び治療薬の組み合わせを治療を必要とする対象に実質的に同時に投与し、このとき、成分は、対象によって実質的に同時に投与される別々の剤形に互いに分かれて配合され、成分は、対象に実質的に同時に放出される;本開示の抗体又はその抗原結合断片及び治療薬の組み合わせを治療を必要とする対象に連続投与し、このとき、成分は、各投与の間の重要な時間間隔で、対象によって連続して摂取される別々の剤形に互いに分かれて配合され、成分は、対象に実質的に異なる時間に放出される;本開示の抗体又はその抗原結合断片及び治療薬の組み合わせを治療を必要とする対象に連続投与し、このとき、成分は、制御されて放出される単一剤形に一緒に配合され、成分は、同時及び/又は異なる時間に同時に、連続的に、及び/又は重複的に放出され、各部分が同じ又は異なる経路によって投与され得る。
別の態様では、本発明は、例えば、ヒトPD−L1関連疾患を診断するために、試料のヒトPD−L1抗原の存在をin vitro又はin vivoに検出する方法を提供する。いくつかの方法において、抗体とヒトPD−L1の間で複合体を形成することができる条件下で、試験対象の試料を、コントロール試料と共に、本発明のヒト配列抗体又はヒトモノクローナル抗体、若しくはその抗原結合部分(又は二重特異性若しくは多特異性分子)に接触させることによって達成される。両方の試料において(ELISAを使用して)複合体の形成を検出し、試料間の複合体の形成における統計学的有意差は、試験試料のヒトPD−L1抗原の存在を示す。
本出願は、エフェクター分子に直接又は間接的に結合(又は連結する)本発明の抗体又はその抗原結合断片を含む免疫複合体を提供する。これについて、「結合される」又は「連結される」という用語は、1つの隣接するポリペプチド分子に2つのポリペプチドを作製することを指す。その結合は、化学的又は組み換え手段の何れかでよい。一実施形態において、結合は化学的であり、抗体部分とエフェクター分子との反応は、2つの分子間で形成される共有結合を生み出して、1つの分子を形成する。ペプチドリンカー(短ペプチド配列)が抗体とエフェクター分子の間に含まれていてもよい。様々な実施形態において、抗体又は抗原結合断片は、エフェクター分子に連結する。他の実施形態において、エフェクター分子に連結した抗体又は抗原結合断片は、さらに、脂質、タンパク質又はペプチドに連結して、身体における半減期を増加させる。したがって、様々な実施形態において、本開示の抗体は、様々なエフェクター分子を送達するために使用され得る。
別の態様では、本発明は、本発明の抗PD−L1抗体又はその抗原結合断片を含む二重特異性分子に注目する。本発明の抗体又はその抗原結合断片は、別の機能分子、例えば、別のペプチド又はタンパク質(例えば、別の抗体又は受容体のリガンド)に誘導体化又は結合して、少なくとも2つの異なる結合部位又は標的分子に結合する二重特異性分子を生成することができる。本発明の抗体は、実際には、1つ以上の他の機能分子に誘導体化又は結合して、2つ以上の異なる結合部位及び/又は標的分子に結合する多特異性分子を生成し得、このような多特異性分子は、また、本明細書で使用される「二重特異性分子」によって包含されることを意図する。本発明の二重特異性分子を作製するために、本発明の抗体は、別の抗体、別のフラグメント、ペプチド又は結合模倣物等の1つ以上のその他の結合分子に、(例えば、化学的カップリング、遺伝子的融合、非共有結合又はその他によって)機能的に結合することができ、二重特異性分子が生じる。様々な実施形態において、本発明は、FcγR又はFcαR発現エフェクター細胞(例えば、単球、マクロファージ又は多形核細胞(PMN))とPDを発現する標的細胞の両方に結合することができる二重特異性分子を含む。このような実施形態において、二重特異性分子はエフェクター細胞に対してPD−L1発現細胞を標的にし、Fc受容体媒介性エフェクター細胞活性、例えば、PD−L1発現細胞の食作用、抗体依存性細胞傷害(ADCC)、サイトカイン放出又はスーパーオキシドアニオンの生成を駆動する。本発明の二重特異性分子を調製する方法は、当該技術分野で周知である。
本出願は、抗PD−L1抗体又はその抗原結合断片をコードするヌクレオチド配列を含むポリヌクレオチドをさらに提供する。遺伝子的コードの縮重があるために、様々な核酸配列がそれぞれの抗体アミノ酸配列をコードする。本出願は、例えば本明細書に規定されるように、ストリンジェント又は低いストリンジェンシーハイブリダイゼーション条件下で、ヒトPD−L1に結合する抗体をコードするポリヌクレオチドにハイブリダイズするポリヌクレオチドをさらに提供する。
ヒトPD−L1に対するモノクローナル抗体の標的特異性の生成
C末端(PDL1/Fc融合タンパク質として示される)にヒトIgG1(Pro100−Lys330)タグを有するヒトPD−L1(NP_054862.1、Phe19−Thr239)が構築され、マウス骨髄腫細胞株(NSO)に発現し、タンパク質Aカラムによって精製され、免疫原として使用した。PDL1/Fcの推定の純度は、還元条件下でSDS−PAGEに基づいて90%より高く、銀色染色によって可視化した。
ヒトPD−L1に対するヒト化Fabの標的特異性の生成
mAb PDL1#10の重鎖及び軽鎖可変領域配列を使用して、コンビナトリアルヒト化ファージ表示ライブラリを構築した。端的には、PDL1#10に対して高い配列同一性を有するヒト抗体のフレームワークを選択し、オーバーラップPCRを使用して構築した。このヒト化Fabファージ表示ライブラリをPD−L1 Fc融合タンパク質に対してパニングした。個別の産出されたファージクローンを96ディープウェルプレートに増幅し、増幅されたファージをPD−L1 Fc融合タンパク質に対してELISAによって分析した。PD−L1タンパク質を結合する良好な割合のファージクローンが見使った場合、パニングを終了した。出力ファージのFabフラグメントをコードするDNAを増幅し、最良のヒト化抗体クローンをスクリーニングするために、pFASEBAベクター(Genscript)に挿入した。個別のFabクローンが96ディープウェルプレートに発現しE.coliによって培地に分泌された粗タンパク質の発現及び結合活性をそれぞれ、BSA及び抗原PD−L1タンパク質に対してELISAにより分析した。数千個のヒト化クローンをスクリーニングし、より遅い解離速度を有するクローンをいくつか識別し、そのうち最も高い結合親和性を有する14個のクローンをマルチサイクル親和性測定に供した。Hisタグ付けされたPD−L1タンパク質に対して14個の精製されたFabの結合親和性を表面プラズモン共鳴(SPR)バイオセンサーを使用して測定し、マルチサイクル親和性測定についてはBiacore T200(GE Healthcare)を使用して測定した。Fabをキャプチャー法によってセンサーチップに固定した。Hisタグ付けされた抗原PD−L1タンパク質を分析物として使用した。解離(kd)及び会合(ka)速度定数のデータをBiacore T200評価ソフトウェアを使用して処理した。kaに対するkdの比から、平衡解離定数(KD)を計算した。結果を以下の表4に記載する。
ヒトPD−L1に対するヒト化IgGの標的特異性の生成
親和性ランク及びマルチサイクル親和性ランク測定値の結果に基づいて、全長IgG発現、精製及び親和性測定についてクローンAS01814、AS01981、AS02013、AS01790及びAS01798を選択した。AS01814、AS01981、AS02013、AS01790及びAS01798をコードするDNA配列はリーダー配列を含み、増幅され、pTT5に挿入されて、全長IgGのプラスミドを発現した。重鎖及び軽鎖発現プラスミドを使用して、HEK293細胞を同時導入した(100Mlの細胞培養物)。培地に分泌された組み換えIgGをタンパク質A親和性クロマトグラフィーを使用して精製した。精製されたIgGは、非還元条件下でSDS−PAGEの約170kDaのバンドとして移動し、還元条件下で約55kDa及び約30kDaのバンドとして移動した。各ヒト化クローンの純度、収率及びエンドトキシンレベルを以下の表6に記載する。
混合リンパ球反応によるPD−L1 MAbの能力の評価
混合リンパ球反応(MLR)アッセイを実施して、T細胞活性についてキメラFab、AS01790、AS01814及びAS01981の能力を評価した。T細胞活性をT細胞によって分泌されたインターロイキン2(IL−2)の濃度によって測定した。ヒト末梢血単核球(PBMC)から樹状細胞(DC)及びCD4+T細胞を単離した。MLRのT細胞活性のKeytruda(登録商標)の能力を内部コントロールとして使用して、アッセイの性能をモニタリングした。50%効果濃度(HalfMaximal effective concentration(EC50))値をGraphPad Prismによるアゴニスト用量反応可変スロープ(4つのパラメータ)適合で分析した。T細胞活性について、キメラFabのEC50値は、1.048μg/ml、AS01790は0.174μg/ml、AS01814は0.089μg/ml、AS01981は0.106μg/mlであった。ネガティブコントロール、ヒトIgG4は、T細胞活性に効果を有しなかった。5つ全てのプレートの内部コントロール(MLRにおけるT細胞活性のKeytruda)からのT細胞活性データは、GenSriptの過去のデータ(.19μg/ml)に一致し、そのためこの試験を検証した。これは、ヒト化PD−L1抗体が、混合リンパ球反応において、T細胞の増殖及びIL−2の分泌を増加させることができることを実証している。
配列表
添付の配列表に挙げられた核酸及びアミノ酸配列は、ヌクレオチド塩基については標準的な文字略語を用いて示され、アミノ酸については米国特許法施行規則(37CFR)第1.822条に規定の3文字コードで示される。
SEQ ID NO:1はヒトPD−L1ポリペプチドのアミノ酸配列である。
SEQ ID NO:2は、PD−L1に特異的に結合するモノクローナル抗体の重鎖CDR1のアミノ酸配列である。
SEQ ID NO:3〜4は、PD−L1に特異的に結合するモノクローナル抗体の重鎖CDR2のアミノ酸配列である。
SEQ ID NO:5〜6は、PD−L1に特異的に結合するモノクローナル抗体の重鎖CDR3のアミノ酸配列である。
SEQ ID NO:7〜8は、PD−L1に特異的に結合するモノクローナル抗体の軽鎖CDR1のアミノ酸配列である。
SEQ ID NO:9は、PD−L1に特異的に結合するモノクローナル抗体の軽鎖CDR2のアミノ酸配列である。
SEQ ID NO:10〜11は、PD−L1に特異的に結合するモノクローナル抗体の軽鎖CDR3のアミノ酸配列である。
SEQ ID NO:12及び14は、PD−L1に特異的に結合するマウスモノクローナル抗体の重鎖可変領域のアミノ酸配列である。
SEQ ID NO:13及び15は、PD−L1に特異的に結合するマウスモノクローナル抗体の重鎖可変領域をコードする核酸配列である。
SEQ ID NO:16及び18は、PD−L1に特異的に結合するマウスモノクローナル抗体の軽鎖可変領域のアミノ酸配列である。
SEQ ID NO:17及び19は、PD−L1に特異的に結合するマウスモノクローナル抗体の軽鎖可変領域をコードする核酸配列である。
SEQ ID NO:20、22、24、26、28、30、32、34、36、38、40、42、44及び46は、PD−L1に特異的に結合するヒト化モノクローナル抗体の重鎖可変領域のアミノ酸配列である。
SEQ ID NO:21、23、25、27、29、31、33、35、37、39、41、43、45及び47は、PD−L1に特異的に結合するヒト化モノクローナル抗体の軽鎖可変領域のアミノ酸配列である。
SEQ ID NO:48及び49は、モノクローナル抗体の軽鎖定常領域のアミノ酸配列である。
SEQ ID NO:50は、モノクローナル抗体の重鎖定常領域のアミノ酸配列である。
SEQ ID NO:51は、PD−L1に特異的に結合するマウス−ヒトキメラ抗体の重鎖のアミノ酸配列である。
SEQ ID NO:52は、PD−L1に特異的に結合するマウス−ヒトキメラ抗体の重鎖の核酸配列である。
SEQ ID NO:53は、PD−L1に特異的に結合するマウス−ヒトキメラ抗体の軽鎖のアミノ酸配列である。
SEQ ID NO:54は、PD−L1に特異的に結合するマウス−ヒトキメラ抗体の軽鎖の核酸配列である。
SEQ ID NO:55、57、59、61及び63は、PD−L1に特異的に結合するヒト化モノクローナル抗体の重鎖のアミノ酸配列である。
SEQ ID NO:56、58、60、62及び64は、PD−L1に特異的に結合するヒト化モノクローナル抗体の軽鎖のアミノ酸配列である。
SEQ ID NO:65、67、69、71及び73は、PD−L1に特異的に結合するヒト化モノクローナル抗体の重鎖の核酸配列である。
SEQ ID NO:66、68、70、72及び74は、PD−L1に特異的に結合するヒト化モノクローナル抗体の軽鎖の核酸配列である。
配列表
SEQ ID NO:1−PD−L1抗原アミノ酸配列
MRIFAVFIFMTYWHLLNAFTVTVPKDLYVVEYGSNMTIECKFPVEKQLDLAALIVYWEME
DKNIIQFVHGEEDLKVQHSSYRQRARLLKDQLSLGNAALQITDVKLQDAGVYRCMISYGGADYKRITVKVNAPYNKINQRILVVDPVTSEHELTCQAEGYPKAEVIWTSSDHQVLSGKTTTTNSKREEKLFNVTSTLRINTTTNEIFYCTFRRLDPEENHTAELVIPELPLAHPPNERTHLVILGAILLCLGVALTFIFRLRKGRMMDVKKCGIQDTNSKKQSDTHLEET
SEQ ID NO:2−マウスモノクローナル抗体重鎖CDR1アミノ酸配列
SYSIN
SEQ ID NO:3−マウスモノクローナル抗体重鎖CDR2アミノ酸配列
YIYIGNGYTEYNEKFKG
SEQ ID NO:4−マウスモノクローナル抗体重鎖CDR2アミノ酸配列
YFYVGNGYTDYNEKFKG
SEQ ID NO:5−マウスモノクローナル抗体重鎖CDR3アミノ酸配列
WSLPNGMDY
SEQ ID NO:6−マウスモノクローナル抗体重鎖CDR3アミノ酸配列
GGLPYYFDY
SEQ ID NO:7−マウスモノクローナル抗体軽鎖CDR1アミノ酸配列
KASQDVGISVA
SEQ ID NO:8−マウスモノクローナル抗体軽鎖CDR1アミノ酸配列
KTSQDVNTAVA
SEQ ID NO:9−マウスモノクローナル抗体軽鎖CDR2アミノ酸配列
WASTRHT
SEQ ID NO:10−マウスモノクローナル抗体軽鎖CDR3アミノ酸配列
QQYSTYRT
SEQ ID NO:11−マウスモノクローナル抗体軽鎖CDR3アミノ酸配列
QQHYNTPLT
SEQ ID NO:12−マウスモノクローナル抗体重鎖可変領域アミノ酸配列
EVQLQQSGAELVRPGSSVKMSCKTSGYSFTSYSINWVKQRPGQGLEWVAYIYIGNGYTEYNEKFKGKATLTSDTPSSTAYMQLSSLTSEDSAIYFCARWSLPNGMDYWGQGTSVTVSS
SEQ ID NO:13−マウスモノクローナル抗体重鎖可変領域核酸配列
gaggtccagcttcagcagtctggagctgaactggtgaggcctgggtcctcagtgaagatgtcctgcaagacttctggatattcattcacaagttacagtataaactgggtgaagcagaggcctggacagggcctggaatgggttgcatatatttatattggaaatggttatactgaatataatgagaagttcaagggcaaggccacactgacttcagacacaccctccagcacagcctacatgcagctcagcagcctgacatctgaggattctgcaatctatttctgtgcaagatggtcactacccaatggaatggactactgggggcaaggaacctcagtcaccgtctcctca
SEQ ID NO:14−マウスモノクローナル抗体重鎖可変領域アミノ酸配列
EVQLQQSGAELVRPGSSVKMSCKTSGYTFTSYSINWVKQRPGQGLEWIAYFYVGNGYTDYNEKFKGKATLTSDTSSSTAYMQLSSLTSEDSAIYFCARGGLPYYFDYWGQGTTLTVSS
SEQ ID NO:15−マウスモノクローナル抗体重鎖可変領域核酸配列
gaggtccagcttcagcagtctggagctgaactggtgaggcctgggtcctcagtgaagatgtcctgcaagacttctggatatacattcacaagttacagtataaattgggtgaagcagaggcctggtcagggcctggaatggattgcatatttttatgttggaaatggttatactgactacaatgagaagttcaagggcaaggccacactgacttcagacacatcttccagcacagcctacatgcagctcagcagcctgacatctgaggactctgcaatctatttctgtgcacgagggggcctaccctactactttgactactggggccaaggcaccactctcacagtctcctca
SEQ ID NO:16−マウスモノクローナル抗体軽鎖可変領域アミノ酸配列
DIVMTQSHKLMSTSIGDRVNITCKASQDVGISVAWYQQKPGQSPKLLIYWASTRHTGVPDRFTGSGSGTDFTLTISNVQSEDLADYFCQQYSTYRTFGGGTKLENK
SEQ ID NO:17−マウスモノクローナル抗体軽鎖可変領域核酸配列
gacattgtgatgacccagtctcacaaactcatgtccacatcaataggagacagggtcaacatcacctgcaaggccagtcaggatgtgggtatttctgtagcctggtatcaacagaaaccaggacaatctcctaaactactgatttattgggcatccactcggcacactggagtccccgatcgcttcacaggcagtggatctgggacagatttcactctcaccattagtaatgtgcagtctgaggacttggcagattatttctgtcagcaatatagcacctatcggacgttcggtggaggcaccaagctggaaaacaaa
SEQ ID NO:18−マウスモノクローナル抗体軽鎖可変領域アミノ酸配列
DIVMTQSHKFMSTSVGDRVSITCKTSQDVNTAVAWYQQKPGHSPKLLFYWASTRHTGVPDRFTGGGSGTDYTLTISSVQAEDLALYYCQQHYNTPLTFGAGTRLELK
SEQ ID NO:19−マウスモノクローナル抗体軽鎖可変領域核酸配列
gacattgtgatgacccagtctcacaaattcatgtccacatcagttggagacagggtcagcatcacctgcaagaccagtcaggatgtgaatactgctgtagcctggtatcaacaaaaaccagggcattctcctaaactactgttttactgggcatccacccggcacactggagtccctgatcgcttcacaggcggtggatctgggacagattatactctcaccatcagcagtgtgcaggctgaagacctggcactttattactgtcagcaacattataacactccgctcacgttcggtgctgggaccaggctggagctgaaa
SEQ ID NO:20−ヒト化重鎖可変領域アミノ酸配列
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYSINWVRQMPGKGLEWMGYFYVGNGYTDYNEKFKGRVTMTRNTSISTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSS
SEQ ID NO:21−ヒト化軽鎖可変領域アミノ酸配列
DIQMTQSPSTLSASVGDRVTITCKTSQDVNTAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQHYNTPLTFGGGTKLEIK
SEQ ID NO:22−ヒト化重鎖可変領域アミノ酸配列
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYSINWVRQAPGKGLEWMGYFYVGNGYTDYNEKFKGRVTMTRNTSISTAYMELSSLRSEDTAVYYCARGGLPYYFDYGQGTLVTVSS
SEQ ID NO:23−ヒト化軽鎖可変領域アミノ酸配列
DIQLTQSPSSLSASVGDRVTITCKTSQDVNTAVAWYQQKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHYNTPLTFGGGTKLEIK
SEQ ID NO:24−ヒト化重鎖可変領域アミノ酸配列
QMQLVQSGAEVKKTGSSVKVSCKASGYTFTSYSINWVRQAPGKGLEWVAYFYVGNGYTDYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSS
SEQ ID NO:25−ヒト化軽鎖可変領域アミノ酸配列
DIQMTQSPSSLSASVGDRVTITCKTSQDVNTAVAWYQQKPGQPPKLLIYWASTRHTGIPARFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYNTPLTFGGGTKLEIK
SEQ ID NO:26−ヒト化重鎖可変領域アミノ酸配列
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYSINWVRQAPGKGLEWVAYFYVGNGYTDYNEKFKGRVTITTDESTSTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSS
SEQ ID NO:27−ヒト化軽鎖可変領域アミノ酸配列
DIQMTQSPSSVSASVGDRVTITCKTSQDVNTAVAWYQQKPGQAPRLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYNTPLTFGGGTKLEIK
SEQ ID NO:28−ヒト化重鎖可変領域アミノ酸配列
QVQLVQSGSELKKPGASVKVSCKASGYTFTSYSINWVRQAPGKGLEWVAYFYVGNGYTDYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSS
SEQ ID NO:29−ヒト化軽鎖可変領域アミノ酸配列
DIQMTQSPSTLSASVGDRVTITCKTSQDVNTAVAWYQQKPGKAPKLLLYWASTRHTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQHYNTPLTFGGGTKLEIK
SEQ ID NO:30−ヒト化重鎖可変領域アミノ酸配列
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYSINWVRQAPGQALEWMGYFYVGNGYTDYNEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCARGDLPFYFDYWGDGILVTVAS
SEQ ID NO:31−ヒト化軽鎖可変領域アミノ酸配列
DIVMTQSPDSLAVSLGERATINCKTSQDVNTAVAWYQQKPGQPPKLLIYWASTRHTGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCQQHYNTPLTFGGGTKLEIK
SEQ ID NO:32−ヒト化重鎖可変領域アミノ酸配列
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYSINWVRQAPGKGLEWMGYFYVGNGYTDYNEKFKGRVTMTRNTSISTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSS
SEQ ID NO:33−ヒト化軽鎖可変領域アミノ酸配列
DIQMTQSPSSVSASVGDRVTITCKTSQDVNTAVAWYQQKPGKAPKLLLYWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQHYNTPLTFGGGTKLEIK
SEQ ID NO:34−ヒト化重鎖可変領域アミノ酸配列
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYSINWVRQAPGKGLEWMGYFYVGNGYTDYNEKFKGRVTMTRNTSISTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSS
SEQ ID NO:35−ヒト化軽鎖可変領域アミノ酸配列
DIQMTQSPSSVSASVGDRVTITCKTSQDVNTAVAWYQQKPGQPPKLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYNTPLTFGGGTKLEIK
SEQ ID NO:36−ヒト化重鎖可変領域アミノ酸配列
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYSINWVRQAPGKGLEWMGYFYVGNGYTDYNEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSS
SEQ ID NO:37−ヒト化軽鎖可変領域アミノ酸配列
DIQLTQSPSFLSASVGDRVTITCKTSQDVNTAVAWYQQKPGQPPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHYNTPLTFGGGTKLEIK
SEQ ID NO:38−ヒト化重鎖可変領域アミノ酸配列
QVQLVQSGSELKKPGASVKVSCKASGYTFTSYSINWVRQAPGKGLEWVAYFYVGNGYTDYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSS
SEQ ID NO:39−ヒト化軽鎖可変領域アミノ酸配列
EIVMTQSPATLSVSPGERATLSCKTSQDVNTAVAWYLQKPGQSPQLLIYWASTRHTGVPSRFSGSGSGTDYTLTISSLQPEDFATYYCQQHYNTPLTFGGGTKLEIK
SEQ ID NO:40−ヒト化重鎖可変領域アミノ酸配列
QVQLVQSGSELKKPGASVKVSCKASGYTFTSYSINWVRQAPGKGLEWMGYFYVGNGYTDYNEKFKGRVTITRDTSASTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSS
SEQ ID NO:41−ヒト化軽鎖可変領域アミノ酸配列
DIQMTQSPSSVSASVGDRVTITCKTSQDVNTAVAWYQQKPDQSPKLLIKWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHYNTPLTFGGGTKLEIK
SEQ ID NO:42−ヒト化重鎖可変領域アミノ酸配列
QMQLVQSGAEVKKTGSSVKVSCKASGYTFTSYSINWVRQMPGKGLEWMGYFYVGNGYTDYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSS
SEQ ID NO:43−ヒト化軽鎖可変領域アミノ酸配列
DIQLTQSPSFLSASVGDRVTITCKTSQDVNTAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDVATYYCQQHYNTPLTFGGGTKLEIK
SEQ ID NO:44−ヒト化重鎖可変領域アミノ酸配列
QMQLVQSGAEVKKTGSSVKVSCKASGYTFTSYSINWVRQARGQRLEWIGYFYVGNGYTDYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSS
SEQ ID NO:45−ヒト化軽鎖可変領域アミノ酸配列
DIQMTQSPSSLSASVGDRVTITCKTSQDVNTAVAWYQQKPDQSPKLLIKWASTRHTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQHYNTPLTFGGGTKLEIK
SEQ ID NO:46−ヒト化重鎖可変領域アミノ酸配列
EVQLVQSGAEVKKPGESLKISCKGSGYSFTSYSINWVRQAPGKGLEWMGYFYVGNGYTDYNEKFKGRVTITTDESTSTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSS
SEQ ID NO:47−ヒト化軽鎖可変領域アミノ酸配列
DIQLTQSPSSLSASVGDRVTITCKTSQDVNTAVAWYQQKPDQSPKLLIKWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHYNTPLTFGGGTKLEIK
SEQ ID NO:48−軽鎖定常領域アミノ酸配列
TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:49−軽鎖定常領域アミノ酸配列
QPKAAPSVTLFPPSSEELQANKATLVCLISDFYPGAVTVAWKADSSPVKAGVETTTPSKQSNNKYAASSYLSLTPEQWKSHRSYSCQVTHEGSTVEKTVAPTECS
SEQ ID NO:50−重鎖定常領域アミノ酸配列
TKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREEQYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPSRDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK
SEQ ID NO:51−マウス−ヒトキメラ抗体の重鎖アミノ酸配列
MGWSWILLFLLSVTAGVHSEVQLQQSGAELVRPGSSVKMSCKTSGYTFTSYSINWVKQRPGQGLEWIAYFYVGNGYTDYNEKFKGKATLTSDTSSSTAYMQLSSLTSEDSAIYFCARGGLPYYFDYWGQGTTLTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO:52−マウス−ヒトキメラ抗体の重鎖核酸配列
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgaggtgcagctgcagcagagcggggcagaactggtgcggcctgggtcaagcgtgaagatgtcatgtaaaacaagcggctatactttcacatcctactctatcaactgggtgaagcagaggccaggacagggactggagtggatcgcctacttctatgtgggcaacggctacaccgactataatgagaagtttaagggcaaggccaccctgacaagcgatacaagctcctctaccgcctatatgcagctgagctccctgaccagcgaggactccgccatctacttctgcgcaaggggaggactgccatactattttgattattggggccagggcaccacactgacagtgtctagcgccagcaccaagggaccatccgtgttcccactggcaccatgcagcagatccacatctgagagcaccgccgccctgggatgtctggtgaaggactacttccctgagccagtgaccgtgtcttggaatagcggcgccctgacaagcggagtgcacacctttcctgccgtgctgcagtcctctggcctgtactccctgagctccgtggtgacagtgccctctagctccctgggcaccaagacatatacctgcaacgtggaccacaagccttctaataccaaggtggataagagggtggagagcaagtacggaccaccttgcccaccatgtccagcacctgagtttctgggaggaccaagcgtgttcctgtttcctccaaagcctaaggacacactgatgatcagccgcacacctgaggtgacctgcgtggtggtggacgtgtcccaggaggatccagaggtgcagttcaactggtacgtggatggcgtggaggtgcacaatgccaagaccaagcctagggaggagcagtttaactctacataccgcgtggtgagcgtgctgaccgtgctgcaccaggattggctgaacggcaaggagtataagtgcaaggtgtctaataagggcctgccatctagcatcgagaagacaatctccaaggcaaagggacagcctagggagccacaggtgtacaccctgcccccttcccaggaggagatgacaaagaaccaggtgtctctgacctgtctggtgaagggcttctatccaagcgacatcgccgtggagtgggagtccaatggccagcccgagaacaattacaagaccacaccacccgtgctggactccgatggctctttctttctgtattcccggctgaccgtggataagtctagatggcaggagggcaacgtgttcagctgttctgtgatgcacgaagcactgcacaaccattacactcagaagtccctgtccctgtccctgggcaaa
SEQ ID NO:53−マウス−ヒトキメラ抗体の軽鎖アミノ酸配列
MGWSWILLFLLSVTAGVHSDIVMTQSHKFMSTSVGDRVSITCKTSQDVNTAVAWYQQKPGHSPKLLFYWASTRHTGVPDRFTGGGSGTDYTLTISSVQAEDLALYYCQQHYNTPLTFGAGTRLELKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:54−マウス−ヒトキメラ抗体の軽鎖核酸配列
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgatatcgtgatgacccagagccacaagtttatgagcaccagcgtcggagacagagtcagtattacctgcaaaaccagccaggatgtgaacaccgccgtggcctggtaccagcagaagccaggccactctcccaagctgctgttctattgggcaagcaccaggcacacaggagtgccagaccgctttaccggaggaggatccggaacagattacaccctgacaatcagctccgtgcaggcagaggacctggccctgtactattgccagcagcactataatacccctctgacattcggcgcaggaaccaggctggagctgaagagaacagtggccgccccaagcgtgttcatctttcccccttccgacgagcagctgaagtccggcaccgcctctgtggtgtgcctgctgaacaacttctaccctcgggaggccaaggtgcagtggaaggtggataacgccctgcagtccggcaattctcaggagagcgtgaccgagcaggactccaaggattctacatatagcctgtctagcaccctgacactgtctaaggccgattacgagaagcacaaggtgtatgcctgcgaggtcactcaccaggggctgtcttcaccagtcaccaagtccttcaatcggggggaatgc
SEQ ID NO:55−ヒト化重鎖アミノ酸配列
MGWSWILLFLLSVTAGVHSEVQLVQSGAEVKKPGESLKISCKGSGYSFTSYSINWVRQMPGKGLEWMGYFYVGNGYTDYNEKFKGRVTMTRNTSISTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO:56−ヒト化軽鎖アミノ酸配列
MGWSWILLFLLSVTAGVHSDIQMTQSPSTLSASVGDRVTITCKTSQDVNTAVAWYQQKPGKAPKLLIYWASTRHTGVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQHYNTPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:57−ヒト化重鎖アミノ酸配列
MGWSWILLFLLSVTAGVHSEVQLVQSGAEVKKPGESLKISCKGSGYSFTSYSINWVRQAPGKGLEWMGYFYVGNGYTDYNEKFKGRVTMTRNTSISTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO:58−ヒト化軽鎖アミノ酸配列
MGWSWILLFLLSVTAGVHSDIQLTQSPSSLSASVGDRVTITCKTSQDVNTAVAWYQQKPGQAPRLLIYWASTRHTGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQHYNTPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:59−ヒト化重鎖アミノ酸配列
MGWSWILLFLLSVTAGVHSQMQLVQSGAEVKKTGSSVKVSCKASGYTFTSYSINWVRQAPGKGLEWVAYFYVGNGYTDYNEKFKGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO:60−ヒト化軽鎖アミノ酸配列
MGWSWILLFLLSVTAGVHSDIQMTQSPSSVSASVGDRVTITCKTSQDVNTAVAWYQQKPGQAPRLLIYWASTRHTGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQHYNTPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:61−ヒト化重鎖アミノ酸配列
MGWSWILLFLLSVTAGVHSQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYSINWVRQAPGKGLEWVAYFYVGNGYTDYNEKFKGRVTITTDESTSTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO:62−ヒト化軽鎖アミノ酸配列
MGWSWILLFLLSVTAGVHSDIQMTQSPSSLSASVGDRVTITCKTSQDVNTAVAWYQQKPGQPPKLLIYWASTRHTGIPARFSGSGSGTDFTLTISSLQPEDFAVYYCQQHYNTPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:63−ヒト化重鎖アミノ酸配列
MGWSWILLFLLSVTAGVHSQVQLVQSGSELKKPGASVKVSCKASGYTFTSYSINWVRQAPGKGLEWVAYFYVGNGYTDYNEKFKGRVTITADESTSTAYMELSSLRSEDTAVYYCARGGLPYYFDYWGQGTLVTVSSASTKGPSVFPLAPCSRSTSESTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTKVDKRVESKYGPPCPPCPAPEFLGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPVLDSDGSFFLYSRLTVDKSRWQEGNVFSCSVMHEALHNHYTQKSLSLSLGK
SEQ ID NO:64−ヒト化軽鎖アミノ酸配列
MGWSWILLFLLSVTAGVHSDIQMTQSPSTLSASVGDRVTITCKTSQDVNTAVAWYQQKPGKAPKLLLYWASTRHTGIPARFSGSGSGTEFTLTISSLQSEDFAVYYCQQHYNTPLTFGGGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC
SEQ ID NO:65−ヒト化重鎖核酸配列
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgaggtgcagctggtgcagagcggggcagaggtcaaaaagcctggcgaaagcctgaaaatctcctgtaagggaagcggatactcattcacctcttacagcatcaactgggtgcggcagatgccaggcaagggcctggagtggatgggctacttctatgtgggcaacggctacacagactataatgagaagtttaagggccgggtgaccatgacaagaaatacctccatctctacagcctatatggagctgagctccctgaggagcgaggataccgccgtgtactattgcgcccgcggggggctgccatactattttgactattggggacaggggactctggtgaccgtctcatccgcctctacaaagggcccctccgtgtttccactggctccctgcagcaggtctacatccgagagcaccgctgctctgggatgtctggtgaaggattacttccctgagccagtgaccgtgagctggaactccggagctctgacatccggagtgcacacctttcctgctgtgctgcagagctctggcctgtacagcctgtccagcgtggtgacagtgccatcttccagcctgggcaccaagacatatacctgcaacgtggaccataagcccagcaataccaaggtggataagagagtggagtctaagtacggaccaccttgcccaccatgtccagctcctgagtttctgggaggaccatccgtgttcctgtttcctccaaagcctaaggacaccctgatgatctctcgcacacccgaggtgacctgtgtggtggtggacgtgtcccaggaggatcctgaggtgcagttcaactggtacgtggatggcgtggaggtgcacaatgctaagaccaagcctagggaggagcagtttaacagcacataccgggtggtgtctgtgctgaccgtgctgcatcaggactggctgaacggcaaggagtataagtgcaaggtgagcaataagggcctgccatcttccatcgagaagacaatctctaaggctaagggacagcctagggagccacaggtgtacaccctgcccccttcccaggaggagatgacaaagaaccaggtgagcctgacctgtctggtgaagggcttctatccttctgacatcgctgtggagtgggagtccaatggccagccagagaacaattacaagaccacaccacccgtgctggactccgatggcagcttctttctgtattccaggctgaccgtggataagagccggtggcaggagggcaatgtgttttcttgttccgtgatgcacgaagcactgcacaaccactacactcagaagtccctgtcactgtccctgggcaag
SEQ ID NO:66−ヒト化軽鎖核酸配列
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgacattcagatgacacagagcccttcaacactgagcgcctccgtgggggatcgggtgactattacttgtaagaccagccaggacgtgaacaccgcagtggcatggtaccagcagaagccaggcaaggcccctaagctgctgatctattgggcctctacccggcacacaggcgtgccaagcagattctctggcagcggctccggcaccgagtttaccctgacaatcagctccctgcagcccgaggacttcgccacatactattgccagcagcattacaacacacccctgacattcggcggcgggacaaaactggaaatcaagaggaccgtggccgctcccagtgtcttcatttttccccctagcgacgaacagctgaaatccgggactgcttctgtggtctgtctgctgaacaatttctaccctcgcgaagccaaagtgcagtggaaggtcgataacgctctccagagtggcaattcacaggagagcgtgacagaacaggactccaaagattctacttatagtctgtctagtacactgactctgtccaaggcagactacgagaagcacaaagtgtatgcctgtgaagtcacccatcagggcctgtcaagccccgtgacaaagtcttttaacagaggggagtgt
SEQ ID NO:67−ヒト化重鎖核酸配列
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgaggtgcagctggtgcagagcggggcagaagtcaagaagcctggggaaagcctgaaaatctcctgtaagggaagcggatactcattcacctcttacagcatcaactgggtgcggcaggcaccaggcaagggcctggagtggatgggctacttctatgtgggcaacggctacacagactataatgagaagtttaagggccgggtgaccatgacaagaaatacctccatctctacagcctatatggagctgagctccctgaggagcgaggataccgccgtgtactattgcgcccgcgggggactgccttactattttgactactggggacagggaacactggtgaccgtctcctctgcctctacaaagggcccctccgtgtttccactggctccctgcagcaggtctacatccgagagcaccgctgctctgggatgtctggtgaaggattacttccctgagccagtgaccgtgagctggaactccggagctctgacatccggagtgcacacctttcctgctgtgctgcagagctctggcctgtacagcctgtccagcgtggtgacagtgccatcttccagcctgggcaccaagacatatacctgcaacgtggaccataagcccagcaataccaaggtggataagagagtggagtctaagtacggaccaccttgcccaccatgtccagctcctgagtttctgggaggaccatccgtgttcctgtttcctccaaagcctaaggacaccctgatgatctctcgcacacccgaggtgacctgtgtggtggtggacgtgtcccaggaggatcctgaggtgcagttcaactggtacgtggatggcgtggaggtgcacaatgctaagaccaagcctagggaggagcagtttaacagcacataccgggtggtgtctgtgctgaccgtgctgcatcaggactggctgaacggcaaggagtataagtgcaaggtgagcaataagggcctgccatcttccatcgagaagacaatctctaaggctaagggacagcctagggagccacaggtgtacaccctgcccccttcccaggaggagatgacaaagaaccaggtgagcctgacctgtctggtgaagggcttctatccttctgacatcgctgtggagtgggagtccaatggccagccagagaacaattacaagaccacaccacccgtgctggactccgatggcagcttctttctgtattccaggctgaccgtggataagagccggtggcaggagggcaatgtgttttcttgttccgtgatgcacgaagcactgcacaaccactacactcagaagtccctgtcactgtccctgggcaag
SEQ ID NO:68−ヒト化軽鎖核酸配列
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgacatccagctgacccagagcccaagtagcctgagcgcaagcgtcggggacagagtgactattacctgcaagacaagccaggacgtgaacaccgcagtggcatggtaccagcagaagccaggacaggcacctaggctgctgatctattgggcctctacccggcacacaggcgtgccaagcagattctctggcagcggctccggcaccgactttaccctgacaatcagctccctgcagcccgaggatttcgccacatactattgccagcagcattacaacactcctctgacattcgggggggggacaaaactggaaatcaaaaggaccgtggccgctcccagtgtcttcatttttccccctagcgacgaacagctgaaatccgggactgcttctgtggtctgtctgctgaacaatttctaccctcgcgaagccaaagtgcagtggaaggtcgataacgctctccagagtggcaattcacaggagagcgtgacagaacaggactccaaagattctacttatagtctgtctagtacactgactctgtccaaggcagactacgagaagcacaaagtgtatgcctgtgaagtcacccatcagggcctgtcaagccccgtgacaaagtcttttaacagaggggagtgt
SEQ ID NO:69−ヒト化重鎖核酸配列
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagccagatgcagctggtccagtcaggcgcagaagtcaagaaaaccgggtcaagcgtcaaagtgtcatgtaaagcaagcggatataccttcacatcttacagcatcaactgggtgcggcaggcaccaggcaagggcctggagtgggtggcctacttctatgtgggcaacggctacaccgactataatgagaagtttaagggccgggtgaccatgacaagagatacctccacatctaccgtgtatatggagctgagctccctgaggagcgaggacacagccgtgtactattgcgcccgcggggggctgccatactactttgactattggggacagggaacactggtgaccgtctcatcagcctctacaaagggcccctccgtgtttccactggctccctgcagcaggtctacatccgagagcaccgctgctctgggatgtctggtgaaggattacttccctgagccagtgaccgtgagctggaactccggagctctgacatccggagtgcacacctttcctgctgtgctgcagagctctggcctgtacagcctgtccagcgtggtgacagtgccatcttccagcctgggcaccaagacatatacctgcaacgtggaccataagcccagcaataccaaggtggataagagagtggagtctaagtacggaccaccttgcccaccatgtccagctcctgagtttctgggaggaccatccgtgttcctgtttcctccaaagcctaaggacaccctgatgatctctcgcacacccgaggtgacctgtgtggtggtggacgtgtcccaggaggatcctgaggtgcagttcaactggtacgtggatggcgtggaggtgcacaatgctaagaccaagcctagggaggagcagtttaacagcacataccgggtggtgtctgtgctgaccgtgctgcatcaggactggctgaacggcaaggagtataagtgcaaggtgagcaataagggcctgccatcttccatcgagaagacaatctctaaggctaagggacagcctagggagccacaggtgtacaccctgcccccttcccaggaggagatgacaaagaaccaggtgagcctgacctgtctggtgaagggcttctatccttctgacatcgctgtggagtgggagtccaatggccagccagagaacaattacaagaccacaccacccgtgctggactccgatggcagcttctttctgtattccaggctgaccgtggataagagccggtggcaggagggcaatgtgttttcttgttccgtgatgcacgaagcactgcacaaccactacactcagaagtccctgtcactgtccctgggcaag
SEQ ID NO:70−ヒト化軽鎖核酸配列
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgacattcagatgacccagtctccaagctcagtctcagccagtgtgggcgaccgagtgacaattacatgcaaaacaagccaggacgtgaacaccgcagtggcatggtaccagcagaagccaggacaggcacctaggctgctgatctattgggcatctaccaggcacacaggagtgccagacagattctctggcagcggctccggcacagattttaccctgacaatcagctccctgcaggcagaggacgtggcagtgtactattgccagcagcattacaatactcctctgacattcgggggcggaaccaaactggaaatcaaaaggaccgtggccgctcccagtgtcttcatttttccccctagcgacgaacagctgaaatccgggactgcttctgtggtctgtctgctgaacaatttctaccctcgcgaagccaaagtgcagtggaaggtcgataacgctctccagagtggcaattcacaggagagcgtgacagaacaggactccaaagattctacttatagtctgtctagtacactgactctgtccaaggcagactacgagaagcacaaagtgtatgcctgtgaagtcacccatcagggcctgtcaagccccgtgacaaagtcttttaacagaggggagtgt
SEQ ID NO:71−ヒト化重鎖核酸配列
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagccaggtccagctggtccagtcaggggcagaagtgaaaaaacccggagcctcagtcaaagtgtcatgcaaagcaagcggatacacatttacctcttacagcatcaactgggtgaggcaggcaccaggcaagggcctggagtgggtggcctacttctatgtgggcaacggctacaccgactataatgagaagtttaagggccgggtgacaatcaccacagatgagtccacctctacagcctatatggagctgagctccctgcggagcgaggacacagccgtgtactattgcgccagaggcgggctgccttattattttgactattggggacaggggacactggtgaccgtctcttcagcctctacaaagggcccctccgtgtttccactggctccctgcagcaggtctacatccgagagcaccgctgctctgggatgtctggtgaaggattacttccctgagccagtgaccgtgagctggaactccggagctctgacatccggagtgcacacctttcctgctgtgctgcagagctctggcctgtacagcctgtccagcgtggtgacagtgccatcttccagcctgggcaccaagacatatacctgcaacgtggaccataagcccagcaataccaaggtggataagagagtggagtctaagtacggaccaccttgcccaccatgtccagctcctgagtttctgggaggaccatccgtgttcctgtttcctccaaagcctaaggacaccctgatgatctctcgcacacccgaggtgacctgtgtggtggtggacgtgtcccaggaggatcctgaggtgcagttcaactggtacgtggatggcgtggaggtgcacaatgctaagaccaagcctagggaggagcagtttaacagcacataccgggtggtgtctgtgctgaccgtgctgcatcaggactggctgaacggcaaggagtataagtgcaaggtgagcaataagggcctgccatcttccatcgagaagacaatctctaaggctaagggacagcctagggagccacaggtgtacaccctgcccccttcccaggaggagatgacaaagaaccaggtgagcctgacctgtctggtgaagggcttctatccttctgacatcgctgtggagtgggagtccaatggccagccagagaacaattacaagaccacaccacccgtgctggactccgatggcagcttctttctgtattccaggctgaccgtggataagagccggtggcaggagggcaatgtgttttcttgttccgtgatgcacgaagcactgcacaaccactacactcagaagtccctgtcactgtccctgggcaag
SEQ ID NO:72−ヒト化軽鎖核酸配列
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgacattcagatgacacagagccctagttcactgagcgccagcgtgggagatagagtcacaatcacatgcaaaacaagccaggacgtgaacaccgccgtggcctggtaccagcagaagccaggccagccccctaagctgctgatctattgggcatctaccaggcacacaggcatccccgcaagattctctggaagcggatccggcacagactttaccctgacaatcagctccctgcagcccgaggatttcgccgtgtactattgccagcagcactacaatacaccactgaccttcggcgggggaactaaactggaaatcaaaaggaccgtggccgctcccagtgtcttcatttttccccctagcgacgaacagctgaaatccgggactgcttctgtggtctgtctgctgaacaatttctaccctcgcgaagccaaagtgcagtggaaggtcgataacgctctccagagtggcaattcacaggagagcgtgacagaacaggactccaaagattctacttatagtctgtctagtacactgactctgtccaaggcagactacgagaagcacaaagtgtatgcctgtgaagtcacccatcagggcctgtcaagccccgtgacaaagtcttttaacagaggggagtgt
SEQ ID NO:73−ヒト化重鎖核酸配列
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagccaggtccagctggtccagagcggaagtgaactgaagaaacccggagcaagcgtcaaagtctcatgcaaagcaagcggctacacatttacctcttacagcatcaactgggtgaggcaggcaccaggcaagggcctggagtgggtggcctacttctatgtgggcaacggctacacagactataatgagaagtttaagggccgggtgaccatcacagccgatgagtccacctctacagcctatatggagctgagctccctgaggagcgaggacaccgccgtgtactattgcgccagaggagggctgccttattactttgattactggggacagggaacactggtgaccgtctcatccgcctctacaaagggcccctccgtgtttccactggctccctgcagcaggtctacatccgagagcaccgctgctctgggatgtctggtgaaggattacttccctgagccagtgaccgtgagctggaactccggagctctgacatccggagtgcacacctttcctgctgtgctgcagagctctggcctgtacagcctgtccagcgtggtgacagtgccatcttccagcctgggcaccaagacatatacctgcaacgtggaccataagcccagcaataccaaggtggataagagagtggagtctaagtacggaccaccttgcccaccatgtccagctcctgagtttctgggaggaccatccgtgttcctgtttcctccaaagcctaaggacaccctgatgatctctcgcacacccgaggtgacctgtgtggtggtggacgtgtcccaggaggatcctgaggtgcagttcaactggtacgtggatggcgtggaggtgcacaatgctaagaccaagcctagggaggagcagtttaacagcacataccgggtggtgtctgtgctgaccgtgctgcatcaggactggctgaacggcaaggagtataagtgcaaggtgagcaataagggcctgccatcttccatcgagaagacaatctctaaggctaagggacagcctagggagccacaggtgtacaccctgcccccttcccaggaggagatgacaaagaaccaggtgagcctgacctgtctggtgaagggcttctatccttctgacatcgctgtggagtgggagtccaatggccagccagagaacaattacaagaccacaccacccgtgctggactccgatggcagcttctttctgtattccaggctgaccgtggataagagccggtggcaggagggcaatgtgttttcttgttccgtgatgcacgaagcactgcacaaccactacactcagaagtccctgtcactgtccctgggcaag
SEQ ID NO:74−ヒト化軽鎖核酸配列
atgggctggagctggatcctgctgttcctcctgagcgtgacagcaggagtgcacagcgatattcagatgacccagagcccaagcaccctgtccgcaagcgtcggggatagagtgaccattacctgtaaaacaagccaggatgtgaacaccgcagtggcatggtaccagcagaagccaggcaaggcccctaagctgctgctgtattgggcatctaccaggcacacaggcatccccgcaagattctctggaagcggatccggcacagagtttaccctgacaatcagctccctgcagagcgaggacttcgccgtgtactattgccagcagcattacaatacaccactgacattcgggggggggactaaactggaaatcaagaggaccgtggccgctcccagtgtcttcatttttccccctagcgacgaacagctgaaatccgggactgcttctgtggtctgtctgctgaacaatttctaccctcgcgaagccaaagtgcagtggaaggtcgataacgctctccagagtggcaattcacaggagagcgtgacagaacaggactccaaagattctacttatagtctgtctagtacactgactctgtccaaggcagactacgagaagcacaaagtgtatgcctgtgaagtcacccatcagggcctgtcaagccccgtgacaaagtcttttaacagaggggagtgt
Claims (27)
- ヒトプログラム死リガンド1(PD−L1)に特異的に結合し、(a)SEQ ID NO:10〜11から選択されるCDR3配列と同一、実質的に同一、又は実質的に類似する軽鎖CDR3配列、(b)SEQ ID NO:5〜6から選択されるCDR3配列と同一、実質的に同一、又は実質的に類似する重鎖CDR3配列、又は(c)(a)の軽鎖CDR3配列及び(b)の重鎖CDR3配列の何れかを含む単離された抗体又はその抗原結合断片。
- (d)SEQ ID NO:7〜8から選択されるCDR1配列と同一、実質的に同一、又は実質的に類似する軽鎖CDR1配列、(e)SEQ ID NO:9から選択されるCDR2配列と同一、実質的に同一、又は実質的に類似する軽鎖CDR2配列、(f)SEQ ID NO:2から選択されるCDR1配列と同一、実質的に同一、又は実質的に類似する重鎖CDR1配列、(g)SEQ ID NO:3〜4から選択されるCDR2配列と同一、実質的に同一、又は実質的に類似する重鎖CDR2配列、(h)(d)の軽鎖CDR1配列及び(f)の重鎖CDR1配列、並びに(i)(e)の軽鎖CDR2配列及び(g)の重鎖CDR2配列から選択されるアミノ酸配列をさらに含む請求項1に記載の単離された抗体又はその抗原結合断片。
- ヒトPD−L1に特異的に結合し、(a)SEQ ID NO:7〜8から選択されるCDR1配列と同一、実質的に同一、又は実質的に類似する軽鎖CDR1配列、(b)SEQ ID NO:9から選択されるCDR2配列と同一、実質的に同一、又は実質的に類似する軽鎖CDR2配列、(c)SEQ ID NO:10〜11から選択されるCDR3配列と同一、実質的に同一、又は実質的に類似する軽鎖CDR3配列、(d)SEQ ID NO:2から選択されるCDR1配列と同一、実質的に同一、又は実質的に類似する重鎖CDR1配列、(e)SEQ ID NO:3〜4から選択されるCDR2配列と同一、実質的に同一、又は実質的に類似する重鎖CDR2配列、及び(f)SEQ ID NO:5〜6から選択されるCDR3配列と同一、実質的に同一、又は実質的に類似する重鎖CDR3配列を含む単離された抗体又はその抗原結合断片。
- (a)SEQ ID NO:7と同一、実質的に同一、又は実質的に類似する軽鎖CDR1配列、(b)SEQ ID NO:9と同一、実質的に同一、又は実質的に類似する軽鎖CDR2配列、(c)SEQ ID NO:10と同一、実質的に同一、又は実質的に類似する軽鎖CDR3配列、(d)SEQ ID NO:2と同一、実質的に同一、又は実質的に類似する重鎖CDR1配列、(e)SEQ ID NO:3と同一、実質的に同一、又は実質的に類似する重鎖CDR2配列、及び(f)SEQ ID NO:5と同一、実質的に同一、又は実質的に類似する重鎖CDR3配列を含む請求項3に記載の単離された抗体又はその抗原結合断片。
- (a)SEQ ID NO:8と同一、実質的に同一、又は実質的に類似する軽鎖CDR1配列、(b)SEQ ID NO:9と同一、実質的に同一、又は実質的に類似する軽鎖CDR2配列、(c)SEQ ID NO:11と同一、実質的に同一、又は実質的に類似する軽鎖CDR3配列、(d)SEQ ID NO:2と同一、実質的に同一、又は実質的に類似する重鎖CDR1配列、(e)SEQ ID NO:4と同一、実質的に同一、又は実質的に類似する重鎖CDR2配列、及び(f)SEQ ID NO:6と同一、実質的に同一、又は実質的に類似する重鎖CDR3配列を含む請求項3に記載の単離された抗体又はその抗原結合断片。
- ヒトPD−L1に特異的に結合し、(a)重鎖及び/又は軽鎖可変領域であって、SEQ ID NO:7〜8、9、10〜11と同一、実質的に同一、又は実質的に類似する3つの軽鎖CDR1、CDR2及びCDR3の組を有する可変領域、及び/又はSEQ ID NO:2、3〜4及び5〜6と同一、実質的に同一、又は実質的に類似する3つの重鎖CDR1、CDR2、CDR3の組、並びに(b)ヒト免疫グロブリン(IgG)からの4つの可変領域フレームワーク領域の組を含む単離された抗体又はその抗原結合断片。
- 参照抗体と実質的に同じ又は大きいKdを有するヒトPD−L1に結合し、(b)前記参照抗体を有するヒトPD−L1との結合に競合し、又は(c)前記参照抗体よりヒト対象の免疫原性が低く、前記参照抗体が SEQ ID NO:14の重鎖可変領域配列及びSEQ ID NO:18の軽鎖可変領域配列を含む、単離された抗体又はその抗原結合断片。
- 少なくとも約1x10−6M、少なくとも約1x10−7M、少なくとも約1x10−8M、少なくとも約1x10−9M、少なくとも約1x10−10M、少なくとも約1x10−11M、又は少なくとも約1x10−12Mの解離定数(KD)でPD−L1タンパク質と結合する請求項1〜7の何れか一項に記載の単離された抗体又はその抗原結合断片。
- 前記単離された抗体又は抗原結合断片が、ヒト抗体、ヒト化抗体、キメラ抗体、モノクローナル抗体、ポリクローナル抗体、組み換え抗体、抗原結合抗体断片、一本鎖抗体、ダイアボディ、トリアボディ、テトラボディ、Fabフラグメント、Fab’フラグメント、Fab2フラグメント、F(ab)’2フラグメント、ドメイン抗体、IgD抗体、IgE抗体、IgM抗体、IgG1抗体、IgG2抗体、IgG3抗体、IgG4抗体、又はH鎖内ジスルフィド結合を形成する傾向を軽減するヒンジ領域に少なくとも1つの変異を有するIgG4抗体から選択される請求項1〜8の何れか一項に記載の単離された抗体又はその抗原結合断片。
- ヒトPD−L1に特異的に結合し、SEQ ID NO:20、22、24、26、28、30、32、34、36、38、40、42、44及び46と同一、実質的に同一、又は実質的に類似する重鎖可変領域配列並びにSEQ ID NO:21、23、25、27、29、31、33、35、37、39、41、43、45及び47と同一、実質的に同一、又は実質的に類似する軽鎖可変領域配列を含む単離されたヒト化抗体又はその抗原結合断片。
- ヒトPD−L1に特異的に結合し、a)SEQ ID NO:55、57、59、61及び63のアミノ酸20〜49から成る群から選択されるFR1、b)SEQ ID NO:55、57、59、61及び63のアミノ酸55〜68から成る群から選択されるFR2、c)SEQ ID NO:55、57、59、61及び63のアミノ酸86〜117から成る群から選択されるFR3、d)SEQ ID NO:55、57、59、61及び63のアミノ酸127−137から成る群から選択されるFR4を含む重鎖可変領域並びにe)SEQ ID NO:56、58、60、62及び64のアミノ酸20〜42から成る群から選択されるFR1、f)SEQ ID NO:56、58、60、62及び64のアミノ酸54〜68から成る群から選択されるFR2、g)SEQ ID NO:56、58、60、62及び64のアミノ酸76〜107から成る群から選択されるFR3、h)SEQ ID NO:56、58、60、62及び64のアミノ酸117〜126から成る群から選択されるFR4を含む軽鎖可変領域を含む単離されたヒト化抗体又はその抗原結合断片。
- ヒトPD−L1に特異的に結合し、SEQ ID NO:55に記載の重鎖配列及びSEQ ID NO:56に記載の軽鎖配列を含む単離されたヒト化抗体又はその抗原結合断片。
- ヒトPD−L1に特異的に結合し、SEQ ID NO:57に記載の重鎖配列及びSEQ ID NO:58に記載の軽鎖配列を含む単離されたヒト化抗体又はその抗原結合断片。
- ヒトPD−L1に特異的に結合し、SEQ ID NO:59に記載の重鎖配列及びSEQ ID NO:60に記載の軽鎖配列を含む単離されたヒト化抗体又はその抗原結合断片。
- ヒトPD−L1に特異的に結合し、SEQ ID NO:61に記載の重鎖配列及びSEQ ID NO:62に記載の軽鎖配列を含む単離されたヒト化抗体又はその抗原結合断片。
- ヒトPD−L1に特異的に結合し、SEQ ID NO:63に記載の重鎖配列及びSEQ ID NO:64に記載の軽鎖配列を含む単離されたヒト化抗体又はその抗原結合断片。
- 薬学的に許容される担体と混合した請求項1〜16の何れか一項に記載の単離された抗体又はその抗原結合断片を含む医薬組成物。
- T細胞関連疾患をり患している対象に請求項1〜16の何れか一項に記載の単離された抗体又はその抗原結合断片を治療有効量投与することを含む前記対象を治療する方法。
- 癌をり患している対象に請求項1〜16の何れか一項に記載の単離された抗体又はその抗原結合断片を治療有効量投与することを含む前記対象を治療する方法。
- 感染性疾患をり患している対象に請求項1〜16の何れか一項に記載の単離された抗体又はその抗原結合断片を治療有効量投与することを含む前記対象を治療する方法。
- a)T細胞関連疾患をり患している対象に請求項1〜16の何れか一項に記載の単離された抗体又はその抗原結合断片を治療有効量投与し、b)免疫療法、化学療法、小分子キナーゼ阻害剤標的治療、手術、放射線治療、ワクチン接種プロトコル及び幹細胞移植から成る群から選択される1つ以上の追加の治療法を含むT細胞関連疾患をり患している対象を治療する方法であって、前記併用療法によって腫瘍細胞の細胞殺傷が増加し、すなわち、共投与した場合に、前記単離された抗体又は抗原結合断片と前記追加の治療法との間に相乗作用が生じる、治療方法。
- a)感染性疾患をり患している対象に請求項1〜16の何れか一項に記載の単離された抗体又はその抗原結合断片を治療有効量投与し、b)免疫療法、化学療法、小分子キナーゼ阻害剤標的治療、手術、放射線治療、ワクチン接種プロトコル及び幹細胞移植から成る群から選択される1つ以上の追加の治療法を含むT細胞関連疾患をり患している対象を治療する方法であって、前記併用療法によって腫瘍細胞の細胞殺傷が増加し、すなわち、共投与した場合に、前記単離された抗体又は抗原結合断片と前記追加の治療法との間に相乗作用が生じる、治療方法。
- a)癌をり患している対象に請求項1〜16の何れか一項に記載の単離された抗体又はその抗原結合断片を治療有効量投与し、b)免疫療法、化学療法、小分子キナーゼ阻害剤標的治療、手術、放射線治療、ワクチン接種プロトコル及び幹細胞移植から成る群から選択される1つ以上の追加の治療法を含むT細胞関連疾患をり患している対象を治療する方法であって、前記併用療法によって腫瘍細胞の細胞殺傷が増加し、すなわち、共投与した場合に、前記単離された抗体又は抗原結合断片と前記追加の治療法との間に相乗作用が生じる、治療方法。
- エフェクター分子に結合した請求項1〜16の何れか一項に記載の抗体又はその抗原結合断片を含む単離された免疫複合体又は融合タンパク質。
- 請求項1〜16の何れか一項に記載の抗体又はその抗原結合断片をコードするポリヌクレオチド配列を含む単離された核酸。
- 請求項25に記載の単離された核酸を含む組み換え発現ベクター。
- 請求項26に記載のベクターを含む宿主細胞。
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