JP7249696B2 - 抗cldn抗体並びにその医薬組成物および検出方法 - Google Patents
抗cldn抗体並びにその医薬組成物および検出方法 Download PDFInfo
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Description
抗CLDN抗体であって、
重鎖と軽鎖とを含み、
ここで、抗体の重鎖は、一つまたは一つ以上のCDRを含み、重鎖のCDRは、SEQ ID No.1~SEQ ID No.7またはSEQ ID No.15~SEQ ID No.30のいずれか一つのCDR配列との差は、三つ以下のアミノ酸であり、
抗体の軽鎖は、一つまたは一つ以上のCDRを含み、軽鎖のCDRは、SEQ ID No.8~SEQ ID No.14またはSEQ ID No.31~SEQ ID No.46のいずれか一つのCDR配列との差は、三つ以下のアミノ酸であることを特徴とする。
SEQ ID No.1およびSEQ ID N0.8、SEQ ID No.2およびSEQ ID N0.9、SEQ ID No.3およびSEQ ID No.10、
SEQ ID No.4およびSEQ ID No.11、SEQ ID No.5およびSEQ ID No.12、SEQ ID No.6およびSEQ ID No.13、
SEQ ID No.7およびSEQ ID No.14、SEQ ID No.15およびSEQ ID No.31、SEQ ID No.16およびSEQ ID No.32、
SEQ ID No.17およびSEQ ID No.33、SEQ ID No.18およびSEQ ID No.34、SEQ ID No.19およびSEQ ID No.35、
SEQ ID No.20およびSEQ ID No.36、SEQ ID No.21およびSEQ ID No.37、SEQ ID No.22およびSEQ ID No.38、
SEQ ID No.23およびSEQ ID No.39、SEQ ID No.24およびSEQ ID No.40、SEQ ID No.25およびSEQ ID No.41、
SEQ ID No.26およびSEQ ID No.42、SEQ ID No.27およびSEQ ID No.43、SEQ ID No.28およびSEQ ID No.44、
SEQ ID No.29およびSEQ ID No.45、SEQ ID No.30およびSEQ ID No.46があるという特徴をさらに有する。
本発明は、上記のいずれか1項に記載の抗体を含む医薬組成物をさらに提供する。
本発明は、生物学的サンプルに上記のいずれか1項に記載の抗体を投与する工程、ここで、前記抗体は、検出可能なマーカーを有し、および前記検出可能なマーカーが存在するかどうかを検出するか、または前記検出可能なマーカーの含有量を検出する工程を含むことを特徴とする、生物学的サンプル中にCLDNが存在するかどうかを検出するための方法をさらに提供する。
本発明の抗体は、ヒト抗体を含むが、これらに限定されない。本発明で提供される様々な抗体のスクリーニング方法は、通常、好ましくは、より便利なハイブリドーマによってスクリーニングされた抗体を好むが、この標的抗原(claudin18.2)は、入手が難しいため、同時にファージライブラリーを使用して抗体をスクリーニングする。本実施形態でスクリーニングされた抗claudin18.2抗体の配列は、次のとおりである。
>QP189
QVQLQQSGAELVKPGASVKLSCKASGYTFTSYGINWVRQRPEQGLEWIGWLFPGDGTIKYNENFKGKATLTTDRSSSAAYMQLSRLTSEDSAVYFCARGGYYGNAMDYWGQGTSVTVSS
>QP191
EVKLVESGGGLVKPGGSLKLSCAASGFTFSNYAMSWVRQTPEKRLEWVASIISGGRTYYLDSEKGRFTISRDNARNNLYLQMSSLRSEDTAMYYCTRIYYGNSFDYWGQGTTLTVSS
>QD193
QVQLQQSGAELVRPGSSVKISCKASGYAFSSYWMNWVKQRPGQGLEWIGQIYPGNGDTTYNGKFKGQATLTADKSSSTVYMQLSSLTSEDSAVYFCARFVKGNAMDYWGQGTSVTVSS
>QD198
QVQLKESGPGLVAPSQSLSITCTVSGFSLTIYGVHWVRQPPGRGLEWLGVIWAGGSTNYNSALMSRLSISKDNSKSQVFLKVNSLQTDDTAMYYCARDYYYGSGFDYWGQGTTLTVSS
>QD200
DVQLVESGGGLVQPGGSRKLSCAASGFTFSSFGMHWVRQAPEKGLEWVAYISSGSNSIYYVDTVKGRFTISRDNPKNTLFLQMTSLKSEDTAMYYCARNAYYGNSFDYWGQGTTLTVSS
>QD202
EVQLQQSGPELVKPGASVKMSCKASGYTFTNYFVHWVKQKPGQGLEWIGYINPYNDDTKYNEKFKGKATLTSDKSSSTAYMDLSSLTSEDSAVYYCLSLRFFAYWGQGTLVTVSA
>QD208
EVQLQQSGPELVKPGASVKMSCKASGYTFTSYIMHWVKQKPGQGLEWIGYINPYNDGTKYNEKFKGKATLTSDKSSSTVYMELSSLTSEDSAVYCCARLGFTTRNAMDYWGQGTSVTVSS
ここで、軽鎖可変領域(VL)のCDRは、配列中の下線部分に示される。
>QD188
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKSYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYFCQNDYFYPYTFGGGTKLEIK
>QD190
DIVMTQSPSSQTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTDFTLTISNMQAEDLAVYYCQNDYSYPFTFGSGTKLEIK
>QD192
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQNPGQPPKMLIYWASTRESGVPDRFTGSGSGIDFSLTISSVQAEDLALYYCQNAYSYPFTFGSGTKLEIK
>QD196
DIVMTQSPSSLSVSAGEKVTMSCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYGASTRESGVPDRFTGSGSGTDFTLTISSVRAEDLAVYYCQNDHYYPFTFGSGTKLEIK
>QD199
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQPPKLLIYWASTRESGVPDRFTGSGSGTVFTLTISSVQAEDLAVYFCQNNYYYPLTFGAGTKLELK
>QD201
DIVMTQSPSSLTVTAGEKVTMSCKSSQSLLNSGNQKNYLTWYQQKPGQAPKLLIYWASTRESGVPDRFIGSGSGTDFTLTISHVQAEDLAVYFCQNDYSYPLTFGAGTNLELK
>QD207
DIVMTQSPSSLSVSAGEKVTMNCKSSQSLLNSGNQKNYLAWYQQKPGQPPKLLIYGASTRESGVPDRFTGSGSGTDFTLTISSVQAEDLAVYYCQNDHSYPFTFGSGTKLEIK
>QD1045
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARDYAFTGFDYWGQGTLVTVSS
>QD1047
QVQLVQSGAEVKKPGASVKVSCKASGYTFTSYYMHWVRQAPGQGLEWMGIINPSGGSTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARSSAYGTYSMDYWGQGTLVTVSS
>QD1073
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTGVYYCARGSGSWFGPYFDYWGQGTTVTVSS
>QD1079
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARTDGATPFDYWGQGTTVTVSS
>QD1085
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARRSYYGTGAFDYWGQGTTVTVSS
>QD1091
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARSLGYFSGLAFDYWGQGTTVTVSS
>QD1097
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGYNWSFGMDYWGQGTTVTVSS
>QD1099
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARAGYFPRSLDYWGQGTTVTVSS
>QD1103
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGYSWYWLFGFDYWGQGTTVTVSS
>QD1105
QVQLVQSGAEVKKPGSSVKVSCKASGGTFSSYAISWVRQAPGQGLEWMGGIIPIFGTANYAQKFQGRVTITADKSTSTAYMELSSLRSEDTAVYYCARGGDWGGYMDYWGQGTTVTVSS
>QD1107
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDYYYYFWFDYWGQGTLVTVSS
>QD1109
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDYYYYYWFDYWGQGTLVTVSS
>QD1111
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKGYYYYFWFDYWGQGTLVTVSS
>QD1113
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKSAAYYYFWFDYWGQGTLVTVSS
>QD1115
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDSYYYYFWYDYWGQGTLVTVSS
>QD1117
EVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVRQAPGKGLEWVSAISGSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKAIDYYTFDYWGQGTLVTVSS
ここで、軽鎖可変領域(VL)のCDRは、配列中の下線部分に示されるとおりである。
>QD1046
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALMTPTFGQGTKVEIK
>QD1048
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQDLWPRTFGQGTKVEIK
>QD1074
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQAAQSPTFGQGTKVEIK
>QD1080
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALNTPPTFGQGTKVEIK
>QD1086
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVTDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALMTPTFGQGTKVEIK
>QD1092
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGRQFPTFGQGTKVEIK
>QD1098
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQGLNTFTFGQGTKVEIK
>QD1100
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQWDTFGQGTKVEIK
>QD1104
DIVMTQSPLSLPVTPGEPASISCRSSQSLLHSNGYNYLDWYLQKPGQSPQLLIYLGSNRASGVPDRFSGSGSGTDFTLKISRVEAEDVGVYYCMQALQTGTFGQGTKVEIK
>QD1106
DIVMTQSPDSLAVSLGERATINCKSSQSVLYSSNNKNYLAWYQQKPGQPPKLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVAVYYCQQYYTTPFTFGQGTKVEIK
>QD1108
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYSTFGQGTKVEIK
>QD1110
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYSSYSPTFGQGTKVEIK
>QD1112
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTKFTLTISSLQPDDFATYYCQQYSTYPLTFGQGTKVEIK
>QD1114
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYLSYPPTFGQGTKVEIK
>QD1116
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYNSYPLTFGQGTKVEIK
>QD1118
DIQMTQSPSTLSASVGDRVTITCRASQSISSWLAWYQQKPGKAPKLLIYDASSLESGVPSRFSGSGSGTEFTLTISSLQPDDFATYYCQQYSTYPLTFGQGTKVEVK
実験1:FACSの腫瘍細胞株に対する抗体の結合能力の検出
a)1.96ウェルプレートに細胞をプレートし、ウェルあたり2×105細胞であり、1000×rpmで5分間遠心分離し、1×PBSで細胞を1回洗浄し、上清から過剰な液体を吸引する。
b)3%BSA-PBS溶液を加えて細胞をブロックし、4℃で60分間ブルックする。
c)被験抗体をブロッキング溶液で5ug/mlに希釈し、ウェルに加え、4℃で60分間インキュベートする。
e)ウェルあたり50ulのPE-抗ヒト(anti-human)FC(1:200希釈)二次抗体を加え、暗所で4℃で40分間インキュベートする。
g)オンボードで検出する。
実験2:FACSのPDX組織腫瘍細胞に対する抗体の結合能力の検出
a)各腫瘍に一つのgentleMACS<商標>Cチューブ(Tube)および3mlの消化液を準備し、消化液は、腫瘍解離キット(Tumor Dissociation Kit)(miltenyibiotech、130-096-730)の取扱説明書に従って調製され、調製してすぐに使用する。
d)組織ブルx得をgentleMACS<商標>Cチューブに入れ、残留消化液でウェルプレートを洗浄し、一緒に消化管に転移して、氷上に置く。
j)2mlのFACS洗浄緩衝液(wash buffer)を加え、細胞を穏やかに再懸濁し、300×gで5分間遠心分離し、上清を除去し、2回繰り返す。
m)細胞を200ulのFACS洗浄緩衝液で再懸濁し、オンボードで検出する。
図2a~図2h、図3a~図3hおよび図4a~図4dは、CHOS細胞に対するファージによってスクリーニングされた抗体の結合能力を示す。
CHOS細胞株の図において、各パネル(panel)は、三つのCHOS細胞株に対する被験抗体のFACS検出結果の組み合わせで構成され、ここで、
1.赤い曲線3(丸付き数字)は、空のベクターをトランスフェクトしたCHOS細胞株(CHOS)に対する被験抗体の結合能力、即ち、陰性対照を示す。
図6a~図6hおよび図7a~図7fは、CHOS細胞に対するファージによってスクリーニングされた抗体の結合能力を示す。
293T-QD010:293T-CLDN18.2で細胞を一過性的にトランスフェクトする
実験目的:293-T細胞株でclaudin18.1(非特異的結合)およびclaudin18.2に対する抗体の結合能力を検証する。
1.赤い曲線5(丸付き数字)は、空のベクターを一過性的にトランスフェクトする293T細胞株に対する被験抗体の結合能力、即ち、陰性対照を示す。
別の実施形態において、本発明は、上記に記載の抗体をコードするポリヌクレオチドをさらに提供し、本発明によって提供される抗体をコードするこれらのポリヌクレオチドがDNAの形態で提供される場合、その後の転写および編集プロセスで除去される非コード配列を含み得るか、または、本発明の実施例で提供される抗体をコードする配列およびタンパク質発現に必要な配列のみを含み得る。
生物学的サンプルに上記のいずれか1項に記載の抗体を投与する工程、ここで、前記抗体は、検出可能なマーカーを有し、および前記検出可能なマーカーが存在するかどうかを検出するか、または前記検出可能なマーカーの含有量を検出する工程を含むことを特徴とする。
a)胃がん異種移植モデルGA0006担癌マウスから腫瘍組織を収集し、直径が2~3mmである腫瘍ブロックに切り、Balb/cヌードマウスの右前肩甲骨の皮下に接種する。
表1および表2の抗体番号の意味、例えば、QP190191は、一つの重鎖および一つの軽鎖の組み合わせを意味する。
Claims (7)
- 重鎖と軽鎖とを含む、抗CLDN18.2抗体であって、
ここで、前記抗CLDN18.2抗体の前記重鎖は、HCDR1、HCDR2、及びHCDR3によりそれぞれ表される3つのCDRを含み、
前記抗CLDN18.2抗体の前記軽鎖は、LCDR1、LCDR2、及びLCDR3によりそれぞれ表される3つのCDRを含み、
前記抗CLDN18.2抗体のアミノ酸配列は、HCDR1がSYIMHであり、HCDR2がYINPYNDGTKYNEKFKGであり、HCDR3がLGFTTRNAMDYであり、LCDR1がKSSQSLLNSGNQKNYLAであり、LCDR2がGASTRESであり、LCDR3がQNDHSYPであるCDRの組合せを含む、抗CLDN18.2抗体。 - 前記抗CLDN18.2抗体の前記重鎖は、SEQ ID No.7に示され、前記軽鎖は、SEQ ID No.14に示される、
請求項1に記載の抗CLDN18.2抗体。 - 請求項1又は2に記載の抗CLDN18.2抗体をコードするポリヌクレオチド。
- 請求項1又は2に記載の抗CLDN18.2抗体を含む医薬組成物。
- 抗腫瘍薬の調製における請求項1又は2に記載の抗CLDN18.2抗体の使用。
- 生物学的サンプル(ヒトを除く。)中にCLDN18.2が存在するかどうかを検出するための方法であって、
生物学的サンプルに請求項1又は2に記載の抗CLDN18.2抗体を投与する工程、ここで、前記抗CLDN18.2抗体は、検出可能なマーカーを有し、及び
前記検出可能なマーカーが存在するかどうかを検出するか、又は前記検出可能なマーカーの含有量を検出する工程、
を含む、前記生物学的サンプル中にCLDN18.2が存在するかどうかを検出するための方法。 - 請求項1又は2に記載の抗CLDN18.2抗体を投与する工程を有する対象(ヒトを除く。)の腫瘍を治療する方法。
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