JP5848863B2 - 抗cldn6抗体 - Google Patents
抗cldn6抗体 Download PDFInfo
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- JP5848863B2 JP5848863B2 JP2009548907A JP2009548907A JP5848863B2 JP 5848863 B2 JP5848863 B2 JP 5848863B2 JP 2009548907 A JP2009548907 A JP 2009548907A JP 2009548907 A JP2009548907 A JP 2009548907A JP 5848863 B2 JP5848863 B2 JP 5848863B2
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Description
[非特許文献1] Mikio Furuse and Shoichiro Tsukita: Claudins in occluding junctions of human and flies. TRENDS in Cell Biology 2006, 16:181
[非特許文献2] Edward R. Wilcox, Quianna L. Burton, Sadaf Naz, Saima Riazuddin, Tenesha N. Smith, Barbara Ploplis, Inna Belyantseva, Tamar Ben-Yosef, NikkiA. Liburd, Robert J. Morell, Bechara Kachar, Doris K. Wu, Andrew J. Griffith, Sheikh Riazuddin, and Thomas B. Friedman: Mutations in the Gene Encoding Tight Junction Claudin-14 Cause Autosomal Recessive Deafness DFNB29. Cell 2001, 104: 165
[非特許文献3] Christoph Rahner, Laura L. Mitic, and James M. Anderson: Heterogeneity in Expression and Subcellular Localization of Claudin 2, 3, 4, and 5 in the Rat Liver, Pancreas, and Gut. GASTROENTEROLOGY 2001, 120: 411
[非特許文献4] Kazumasa Morita, Mikio Furuse, Kazushi Fujimoto, and Shoichiro Tsukita: Claudin multigene family encoding four-transmembrane domain protein components of tight junction strands. Proc. Natl. Acad. Sci. USA 1999, 96: 511
[非特許文献5] Kyle J Hewitt, Rachana Agarwal and Patrice J Morin: The claudin gene family: expression in normal and neoplastic tissues. BMC Cancer 2006, 6:186
[非特許文献6] Makoto Osanai, Masaki Murata, Hideki Chiba, Takashi Kojima and Norimasa Sawada: Epigenetic silencing of claudin-6 promotes anchorage-independent growth of breast carcinoma cells. Cancer Sci 2007, 98: 1557
[非特許文献7] Azadeh Arabzadeh, Tammy-Claire Troy and Kursad Turksen: Changes in the distribution pattern of Claudin tight junction proteins during the progression of mouse skin tumorigenesis. BMC Cancer 2007, 7: 196
[非特許文献8] Chengshi Quan and Shi-Jiang Lu: Identification of genes preferentially expressed in mammary epithelial cells of Copenhagen rat using subtractive hybridization and microarrays. Carcinogenesis 2003, 24:1593
[非特許文献9] Kohls MD, Lappi DA: Mab-ZAP: A tool for evaluating antibody efficacy for use in an immunotoxin. BioTechniques 2000, 28 (1): 162
[非特許文献10] Nimmerjahn F, Ravetch JV.: Divergent immunoglobulin G subclass activity through selective Fc receptor binding. Science. 2005, 310: 1510
[非特許文献11] Nimmerjahn F, Ravetch JV.: Fcγ Receptors: Old friends and new family members. Immunity. 2006, 24: 19
今回、本発明者らはhuman CLDN6 mRNAが成体のあらゆる正常組織でその発現が認められないのに対して、腫瘍組織(肺腺癌、胃癌、卵巣癌)で発現亢進していることを見出した。
(a) 配列番号24に記載のアミノ酸配列を有するCDR1、配列番号25に記載のアミノ酸配列を有するCDR2、配列番号26に記載のアミノ酸配列を有するCDR3を有する重鎖可変領域を含む抗体(AB3-1重鎖)、
(b) 配列番号27に記載のアミノ酸配列を有するCDR1、配列番号28に記載のアミノ酸配列を有するCDR2、配列番号29に記載のアミノ酸配列を有するCDR3を有する軽鎖可変領域を含む抗体(AB3-1軽鎖)、
(c) (a)に記載の重鎖可変領域および(b)に記載の軽鎖可変領域を有する抗体(AB3-1)、
(d) 配列番号30に記載のアミノ酸配列を有するCDR1、配列番号31に記載のアミノ酸配列を有するCDR2、配列番号32に記載のアミノ酸配列を有するCDR3を有する重鎖可変領域を含む抗体(AE1-16、AE49-11重鎖)、
(e) 配列番号33に記載のアミノ酸配列を有するCDR1、配列番号34に記載のアミノ酸配列を有するCDR2、配列番号35に記載のアミノ酸配列を有するCDR3を有する軽鎖可変領域を含む抗体(AE1-16、AE49-11軽鎖)、
(f) (d)に記載の重鎖可変領域および(e)に記載の軽鎖可変領域を有する抗体(AE1-16、AE49-11)、
(g) 配列番号40に記載のアミノ酸配列を有するCDR1、配列番号41に記載のアミノ酸配列を有するCDR2、配列番号42に記載のアミノ酸配列を有するCDR3を有する重鎖可変領域を含む抗体(AE3-20重鎖)、
(h) 配列番号43に記載のアミノ酸配列を有するCDR1、配列番号44に記載のアミノ酸配列を有するCDR2、配列番号45に記載のアミノ酸配列を有するCDR3を有する軽鎖可変領域を含む抗体(AE3-20軽鎖)、
(i) (g)に記載の重鎖可変領域および(h)に記載の軽鎖可変領域を有する抗体(AE3-20)、
(j) (a)〜(i)のいずれかに記載の抗体が認識するエピトープと同じエピトープを認識する抗体、
を提供する。
(a) 被験者から採取された試料を提供する工程、
(b) (a)の試料に含まれるCLDN6タンパク質を検出する工程、
を含む。好ましくは、CLDN6タンパク質は抗CLDN6抗体により検出される。
Claudin6(CLDN6)のアミノ酸配列およびこれをコードする遺伝子配列は、GenBank登録番号NP_067018.1およびNM_021195.3(配列番号:22及び配列番号:23)、またはGenBank登録番号NP_067018.2およびNM_021195.4(配列番号:46及び配列番号:47)に開示されている。
本発明の抗CLDN6抗体はCLDN6に結合する限り如何なる抗体でもよく、その由来(マウス、ラット、ヒト、等)、種類(モノクローナル抗体、ポリクローナル抗体)および形状(改変抗体、低分子化抗体、修飾抗体、など)等は問われない。
(1)エフェクター細胞の調製
CBA/Nマウスなどから脾臓を摘出し、RPMI1640培地(Invitrogen社製)中で脾臓細胞が分離される。10%ウシ胎児血清(FBS、HyClone社製)を含む同培地で洗浄後、細胞濃度を5×106/mlに調製することによって、エフェクター細胞が調製できる。
Baby Rabbit Complement(CEDARLANE社製)を10% FBS含有培地(Invitrogen社製)にて10倍希釈し、補体溶液が調製できる。
CLDN6タンパク質を発現する細胞を0.2 mCiの51Cr-クロム酸ナトリウム(GEヘルスケアバイオサイエンス社製)とともに、10% FBS含有DMEM培地中で37℃にて1時間培養することにより該標的細胞を放射性標識できる。CLDN6タンパク質を発現する細胞としては、CLDN6タンパク質をコードする遺伝子で形質転換された細胞、癌細胞(肺線癌細胞、胃癌細胞など)等を利用することができる。放射性標識後、細胞を10% FBS含有RPMI1640培地にて3回洗浄し、細胞濃度を2×105/mlに調製することによって、該標的細胞が調製できる。
(a) 配列番号24に記載のアミノ酸配列を有するCDR1、配列番号25に記載のアミノ酸配列を有するCDR2、配列番号26に記載のアミノ酸配列を有するCDR3を有する重鎖可変領域を含む抗体(AB3-1重鎖)、
(b) 配列番号27に記載のアミノ酸配列を有するCDR1、配列番号28に記載のアミノ酸配列を有するCDR2、配列番号29に記載のアミノ酸配列を有するCDR3を有する軽鎖可変領域を含む抗体(AB3-1軽鎖)、
(c) (a)に記載の重鎖可変領域および(b)に記載の軽鎖可変領域を有する抗体(AB3-1)、
(d) 配列番号30に記載のアミノ酸配列を有するCDR1、配列番号31に記載のアミノ酸配列を有するCDR2、配列番号32に記載のアミノ酸配列を有するCDR3を有する重鎖可変領域を含む抗体(AE1-16、AE49-11重鎖)、
(e) 配列番号33に記載のアミノ酸配列を有するCDR1、配列番号34に記載のアミノ酸配列を有するCDR2、配列番号35に記載のアミノ酸配列を有するCDR3を有する軽鎖可変領域を含む抗体(AE1-16、AE49-11軽鎖)、
(f) (d)に記載の重鎖可変領域および(e)に記載の軽鎖可変領域を有する抗体(AE1-16、AE49-11)、
(g) 配列番号40に記載のアミノ酸配列を有するCDR1、配列番号41に記載のアミノ酸配列を有するCDR2、配列番号42に記載のアミノ酸配列を有するCDR3を有する重鎖可変領域を含む抗体(AE3-20重鎖)、
(h) 配列番号43に記載のアミノ酸配列を有するCDR1、配列番号44に記載のアミノ酸配列を有するCDR2、配列番号45に記載のアミノ酸配列を有するCDR3を有する軽鎖可変領域を含む抗体(AE3-20軽鎖)、
(i) (g)に記載の重鎖可変領域および(h)に記載の軽鎖可変領域を有する抗体(AE3-20)、
(j) (a)〜(i)のいずれかに記載の抗体が認識するエピトープと同じエピトープを認識する抗体。
疎水性アミノ酸(A、I、L、M、F、P、W、Y、V)、
親水性アミノ酸(R、D、N、C、E、Q、G、H、K、S、T)、
脂肪族側鎖を有するアミノ酸(G、A、V、L、I、P)、
水酸基含有側鎖を有するアミノ酸(S、T、Y)、
硫黄原子含有側鎖を有するアミノ酸(C、M)、
カルボン酸及びアミド含有側鎖を有するアミノ酸(D、N、E、Q)、
塩基含有側鎖を有するアミノ酸(R、K、H)、
芳香族含有側鎖を有するアミノ酸(H、F、Y、W)
(括弧内はいずれもアミノ酸の一文字標記を表す)。
本発明の抗CLDN6抗体は、公知の手段を用いて取得できる。本発明の抗CLDN6抗体として、特に哺乳動物由来のモノクローナル抗体が好ましい。哺乳動物由来のモノクローナル抗体は、ハイブリドーマにより産生されるもの、および遺伝子工学的手法により抗体遺伝子を含む発現ベクターで形質転換した宿主により産生されるもの等を含む。
本発明の抗体は、抗体産生細胞からクローニングされた抗体遺伝子を利用して作成することができる組換え抗体であってもよい。クローニングした抗体遺伝子は、適当なベクターに組み込んで宿主に導入することによって、抗体を発現させることができる。抗体遺伝子の単離と、ベクターへの導入、そして宿主細胞の形質転換のための方法は既に確立されている(例えば、Vandamme, A. M. et al., Eur.J. Biochem.(1990)192, 767-775参照)。
本発明の抗CLDN6抗体は糖鎖が改変された抗体であってもよい。抗体の糖鎖を改変することにより抗体の細胞傷害活性を増強できることが知られている。
本発明の抗体の好ましい他の態様としてキメラ抗体またはヒト化抗体を挙げることができる。キメラ抗体は、互いに由来の異なる領域同士を連結した抗体を言う。一般にキメラ抗体は、ヒト以外の動物由来抗体のV領域とヒト抗体由来のC領域とから構成される。例えば、マウス抗体の重鎖、軽鎖の可変領域と、ヒト抗体の重鎖、軽鎖の定常領域からなる抗体は、マウス−ヒト異種キメラ抗体である。
本発明の抗CLDN6抗体には、CLDN6タンパク質に結合する限り、IgGに代表される二価抗体だけでなく、一価抗体、若しくはIgMに代表される多価抗体も含まれる。本発明の多価抗体には、全て同じ抗原結合部位を有する多価抗体、または、一部もしくは全て異なる抗原結合部位を有する多価抗体が含まれる。
本発明は上述の抗CLDN6抗体を有効成分として含有する医薬組成物を提供する。又、本発明は上述の抗CLDN6抗体を有効成分として含有する抗癌剤に関する。本発明の抗癌剤は、癌を罹患している対象または再発する可能性がある対象に投与されることが好ましい。
本発明はさらに抗CLDN6抗体を用いた癌の診断方法を提供する。本発明の方法により診断される癌はCLDN6を発現している限り特に限定されないが、肺線癌、胃癌または卵巣癌が好ましい。
(a) 被験者から採取された試料を提供する工程、
(b) (a)の試料に含まれるCLDN6タンパク質を検出する工程。
human CLDN6 mRNAの臨床癌、癌細胞株、各種正常臓器における発現分布について明らかにするために、元来はスプライスバリアント解析を行うために開発されたHuman Exon 1.0 ST Array (Affymetrix社) を用いた発現解析を実施した。Human Exon 1.0 ST Arrayによって発現解析を実施する利点は、基本的に一遺伝子につき3’側に一つのプローブセットしかなかったこれまでのAffymetrix社の発現アレイと比較して、Human Exon 1.0 ST Arrayでは遺伝子のエクソン毎に少なくとも一つのプローブセットが設定されているので、本アレイを用いて遺伝子毎の発現解析を行った場合、一遺伝子について複数のプローブセットの発現データを得ることができることになり、遺伝子毎の発現データの信頼性が上がると言える。
癌細胞株におけるhuman CLDN6タンパク質の発現解析は、細胞株ライセートに対するウエスタンブロット法を用いて実施した。
実施例1、2において示した通り、human CLDN6蛋白の発現とmRNAの発現は良く相関しており、また、成体の正常組織でのhuman CLDN6 mRNAの発現は腫瘍組織と比較してかなり少ないか、ほぼ無いことが明らかとなった。従って、成体の正常組織でのhuman CLDN6蛋白の発現も腫瘍組織と比較して、ほぼ無いものと推測された。このことは、癌細胞表面上に発現するhuman CLDN6タンパク質を認識する抗体は、極めて腫瘍特異性の高い抗体であることを意味している。そのような抗体を抗腫瘍剤として使用する場合、薬効と副作用の極めて大きな乖離を期待することができ、抗腫瘍剤の標的としてhuman CLDN6が極めて高いポテンシャルを有していることを意味している。
Human CLDN6に対する抗体を作製するにあたり、human CLDN6 (Refseq Accession No. NM_021195.3) cDNAのオープンリーディングフレームを含む配列のクローニングを実施した。Human CLDN6のcDNAは、Marathon-Ready cDNA Fetal Lung (Clontech社 Code.639333)をテンプレートとして、配列番号1、及び配列番号2で表されるプライマーを用いてクローニングした。詳細には、KOD plus DNA polymerase (TOYOBO社)を用いて、5μL の10 x KOD Buffer, 5uLの2mM dNTPs, 3uLの25mM MgSO4, 1.5uLの10μM 配列番号1 のプライマー, 1.5uLの10μMの配列番号2 のプライマー, 2uLのTemplate fetal lung cDNA, 1uLのKOD plus DNA polymerase, 31uLのヌクレアーゼフリー水を含む溶液を調製し、94℃ 2min、{94℃ 15秒、58℃ 30秒、68℃ 1分} x30サイクルでPCR増幅を行った。次に、本増幅産物をテンプレートとして、配列番号3、及び配列番号4で表されるプライマーを用い、同酵素でもって、同上の組成で、94℃ 2min、{94℃ 15秒、58℃ 30秒、68℃ 1分} x20サイクルで更に再増幅した。増幅断片をHindIII、NheIで消化し、pMCN-flag ベクターのHind III、Nhe Iサイトにクローニングした。
human CLDN6発現CHO細胞(DG44 、Invitrogen社より購入)、及びhuman CLDN6発現Ba/F3細胞作製のための哺乳動物での発現ベクターとしてはpCOS2ベクターを用いた。pCOS2ベクターは、ベクター上に目的遺伝子の発現誘導のためのプロモーターとして、EF1α プロモーター−エンハンサー配列が組み込まれており、本プロモーター−エンハンサー下に目的遺伝子cDNA配列を挿入することにより、ベクター導入細胞において、目的遺伝子の発現を誘導することができる。また、本ベクターには、ネオマイシン耐性遺伝子が組み込まれているので、ベクター導入細胞をネオマイシンで選抜することが可能である。
抗human CLDN6抗体の作製にあたり、マウスへの免疫はHelios Gene Gun (BIO-RAD社)によるDNA免疫とhuman CLDN6強制発現Ba/F3細胞の細胞免疫の組み合わせで実施し、モノクローナル抗体のスクリーニングは、human CLDN6発現CHO(DG44)細胞を用いたフローサイトメトリーで実施した。
[実施例 3-3]において記載した、精製抗human CLDN6モノクローナル抗体18種類のhCLDN6強制発現Ba/F3細胞、及び親株であるBa/F3への結合性について、抗体濃度を振ってフローサイトメトリーによって評価した。
human CLDN6のC末細胞内ペプチド配列を認識するポリクローナル抗体は知られているが、癌細胞膜表面上のネイティブな形をとっているhuman CLDN6の細胞外部分を認識する抗体は未だ存在しなかった。そこで、[実施例3-3]において作製した本発明の抗human CLDN6モノクローナル抗体を用いて、これらの抗体がhuman CLDN6 強制発現細胞株の細胞ライセートだけでなく、実際の癌細胞膜表面上のhuman CLDN6をも認識するか否かについてフローサイトメトリーを用いて評価した。
本発明の抗human CLDN6モノクローナル抗体の肺腺癌細胞株ABC-1および胃癌細胞株AGSに対するADCC活性をクロム放出法で調べた。ABC-1またはAGSを96ウェルプレートに播種し付着させた後、クロム51を添加して培養を数時間続けた。培養液を除去、培養液で細胞を洗浄したのちに新しい培養液を添加した。続いて抗体を添加し、各ウェルにターゲット細胞に比べて約5倍量のエフェクター細胞(NK-92 (ATCC, CRL-2407)にマウスFc-ガンマ受容体3(NM_010188)の細胞外領域およびヒトガンマ鎖(NM_004106)の膜貫通領域と細胞内領域を含むキメラタンパク質を強制発現させた組換え細胞(特願2007-20155))を添加し、プレートを5% CO2インキュベーター中で37℃にて4時間静置した。静置後プレートを遠心し、各ウェルより一定量の上清を回収してガンマカウンターWallac 1480を用いて放射活性を測定し、以下の式を用いて特異的クロム遊離率(%)を求めた。
特異的クロム遊離率(%) = (A-C)×100/(B-C)
ここで、Aは各ウェルにおける放射活性、Bは終濃度1% Nonidet P-40で細胞溶解して培地へ放出される放射活性平均値、Cは培地のみ添加した場合における放射活性平均値である。
抗human CLDN6モノクローナル抗体の肺腺癌細胞株ABC-1に対するCDC活性をクロム放出法で調べた。ABC-1を96ウェルプレートに播種し付着させた後、Chromium-51を添加して培養を数時間続けた。培養液を除去、培養液で細胞を洗浄したのちに新しい培養液を添加した。続いて本発明の抗human CLDN6モノクローナル抗体(AB3-1、AC2-40、AD12-47、AE1-16、AE2-4、AE3-20、AE49-11)およびコントロールマウスIgG1抗体(Cat. No. 553453、BD Biosciences Pharmingen)を終濃度10μg/mLになるように添加した。続いて幼令ウサギ補体(Cat. No. CL3441、Cederlane)を終濃度25%、5%、または1%になるように添加した。プレートを5% CO2インキュベーター中で37℃にて1.5時間静置した。静置後プレートを遠心し、各ウェルより一定量の上清を回収してガンマカウンターWallac 1480を用いて放射活性を測定し、3-6.と同様に特異的クロム遊離率(%)を求めた。
Human CLDN6を標的としたイムノトキシンが抗腫瘍活性を示すことができるかについて、Mab-ZAP (Advanced Targeting Systems社) を用いて評価した。Mab-ZAPはヤギ抗マウスIgGのサポリン(saporin)標識体である。サポリンはリボソームにおけるタンパク質合成阻害を作用機作とするタンパク質性の毒素である。全ての抗体がイムノトキシンを作製するのに適している訳ではなく、イムノトキシンとして薬効の強い抗体もあればそうでないものもあることが知られている(非特許文献9;Kohls and Lappi, BioTechniques 2000, 28 (1): 162)。そこで、今回取得した抗human CLDN6結合抗体18種類のイムノトキシンとしてのポテンシャルについて、Mab-ZAPを用いて評価した。
以上の結果から、今回取得した抗human CLDN6抗体のうち、ADCC、CDC、及びMab-ZAP共存在下によるイムノトキシンとしての抗腫瘍活性の強かった抗体3種類(AB3-1、AE1-16、AE49-11、AE3-20)を選択し、抗体の可変領域の核酸配列、及びアミノ酸配列を決定した。それぞれの抗体を産生するハイブリドーマを培養し、1 x 106 個の細胞からRNeasy (QIAGEN社)を用いてtotal RNAを精製した。精製したtotal RNA 1μgを使用し、SMART RACE cDNA Amplification Kit (Clontech社)とマウスIgG1定常領域配列に相補的な合成オリゴヌクレオチドMHC-IgG1(配列番号7)またはマウスIgG2b定常領域配列に相補的な合成オリゴヌクレオチドMHC-IgG2b(配列番号8)またはマウスκ鎖定常領域塩基配列に相補的な合成オリゴヌクレオチドmCKappaR(配列番号9)を用い、3種類の抗体のH鎖、L鎖cDNAの定常領域の上述のオリゴヌクレオチド配列に相当する位置から5’ - cDNA末端までの配列をPCR増幅した。増幅断片をpTA2ベクター(TOYOBO)にクローニングし、cDNA配列を決定した。AB3-1のH鎖可変領域の塩基配列を配列番号10、アミノ酸配列を配列番号11、L鎖可変領域の塩基配列を配列番号12、アミノ酸配列を配列番号13に示す。AE1-16のH鎖可変領域の塩基配列を配列番号14、アミノ酸配列を配列番号15、L鎖可変領域の塩基配列を配列番号16、アミノ酸配列を配列番号17に示す。AE49-11のH鎖可変領域の塩基配列を配列番号18、アミノ酸配列を配列番号19、L鎖可変領域の塩基配列を配列番号20、アミノ酸配列を配列番号21に示す。AE3-20のH鎖可変領域の塩基配列を配列番号36、アミノ酸配列を配列番号37、L鎖可変領域の塩基配列を配列番号38、アミノ酸配列を配列番号39に示す。
[実施例4]において、可変領域アミノ酸配列を決定した抗human CLDN6モノクローナル抗体4種類(AB3-1、AE1-16、AE49-11、AE3-20)の human CLDN1、CLDN3、CLDN4、CLDN9分子に対する結合性について、各分子の強制発現Ba/F3細胞株を作製し、抗体濃度を振ってフローサイトメトリーによって評価した。
肺腺癌組織におけるCLDN6タンパク質発現、癌細胞膜上への局在を免疫組織染色で確認した。免疫組織染色においては、肺腺癌臨床組織から抽出した全RNAを用いて、Real Time PCRによるCLDN6転写産物の定量をまず実施し、CLDN6転写産物が高発現の症例を用いた。凍結切片は4% PFA固定後、一般的なLSAB法にて、Ventana HX Discovery System (Ventana Medical Systems社)を用いて免疫組織染色を行った。免疫組織染色における1次抗体は、ヤギ抗CLDN6ポリクローナル抗体(Santa Cruz社Code.No. sc-17669 Lot. H2605)を12.5μg/mLとして使用した。結果、肺腺癌の腫瘍組織において、細胞膜および細胞質内に陽性反応が認められた。一方、非腫瘍組織においては、マクロファージ、2型肺胞上皮および細気管支上皮に陽性反応が認められたが、いずれも染色強度は軽微であり、腫瘍組織で認められた細胞膜への陽性反応は認められなかった。肺腫瘍組織における細胞膜の染色強度は、正常肺組織よりも高かった。ヒト腫瘍組織の細胞膜におけるタンパク質レベルでの発現検出は、本発明によって初めて示された。
AE49-11抗体の抗腫瘍活性の評価
AE49-11抗体のサブクラスはIgG2bであるが、先行研究において、IgG2aの方がADCC活性が強いとの報告(非特許文献[10]、[11])があったことから、薬効増強を意図して、抗体のFc領域をIgG2aに変換したAE49-11抗体(「AE49-11/mIgG2a」と命名、H鎖アミノ酸配列(配列番号[52])、L鎖アミノ酸配列(配列番号[53])を発現するベクターを構築し、CHO-DG44細胞にて発現、精製した。本AE49-11/mIgG2a抗体の結合活性が元のIgG2b抗体とほぼ同等であることは、フローサイトメトリーにて確認し、本抗体を用いて、in vivo抗腫瘍実験を以下の通り実施した。
PA-1細胞をHanks’ Balanced Salt Solution (HBSS)にて5 x 107 cell/mlに調製し、前日に抗アシアロGM1抗体100 μl (和光純薬社、1バイアルを1 mlの注射用蒸留水で溶解後、4 mlの生理的食塩水を添加)を腹腔内投与したSCIDマウス(メス、9週齢、日本チャールス・リバー社)の腹部皮下へ200 μl移植した。移植後23日目よりAE49-11/mIgG2a抗体を週1回、4週間、尾静脈より投与した。抗体は生理食塩液にて5 mg/mlに調製し50 mg/kgにて投与した。陰性対照として生理食塩液 (vehicle)を同様に投与した。1群5匹にて試験を行った。抗腫瘍活性は腫瘍体積で評価した。腫瘍体積 (mm3)、腫瘍体積変化量、及び腫瘍増殖抑制効果(%)は以下のように算出した。
腫瘍体積 (mm3) = 腫瘍長径 × 腫瘍短径 × 腫瘍短径 × 1/2
腫瘍体積変化量 (mm3) = 測定時の腫瘍体積 - 投与開始時の腫瘍体積
腫瘍増殖抑制率 (%)= {1-(薬剤投与群の腫瘍体積変化量の平均値 /
vehicle投与群の腫瘍体積変化量の平均値)} × 100
引き続いて、NUGC-3皮下移植モデルでの薬効を検討した。本モデルにおける薬効試験を行うにあたっては、フコーストランスポーターをノックアウトしたCHO-DXB11S細胞でAE49-11/mIgG2a抗体を発現、精製した抗体(低フコース型AE49-11/mIgG2a抗体)を用いて薬効試験を行った。
試験の結果、低フコース型AE49-11/mIgG2a抗体はvehicle投与群に対して延命効果を有することが示された。
以上から抗CLDN6抗体がヒト臨床において抗腫瘍活性を示す可能性が示唆された。
Claims (7)
- 細胞膜上に発現したClaudin6(CLDN6)に結合し、Claudin9(CLDN9)には実質的に結合しない、細胞障害活性を有するモノクローナル抗体であって、以下の(a)または(b)に記載のモノクローナル抗体:
(a) 配列番号40に記載のアミノ酸配列を有するCDR1、配列番号41に記載のアミノ酸配列を有するCDR2、配列番号42に記載のアミノ酸配列を有するCDR3を有する重鎖可変領域および配列番号43に記載のアミノ酸配列を有するCDR1、配列番号44に記載のアミノ酸配列を有するCDR2、配列番号45に記載のアミノ酸配列を有するCDR3を有する軽鎖可変領域を含む抗体
(b) (a)に記載の抗体が認識するエピトープに対する結合が競合する抗体。 - ADCC活性を有する請求項1に記載のモノクローナル抗体。
- CDC活性を有する請求項1に記載のモノクローナル抗体。
- 細胞障害性物質が結合していることを特徴とする請求項1〜3いずれかに記載のモノクローナル抗体。
- 請求項1〜4いずれかに記載のモノクローナル抗体を含有する医薬組成物。
- 細胞増殖抑制剤である請求項5に記載の医薬組成物。
- 抗癌剤である請求項6に記載の医薬組成物。
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Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
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JPWO2011155607A1 (ja) * | 2010-06-11 | 2013-08-15 | 協和発酵キリン株式会社 | 抗tim−3抗体 |
WO2023054421A1 (ja) | 2021-09-29 | 2023-04-06 | 中外製薬株式会社 | がんの治療に用いるための細胞傷害誘導治療剤 |
Also Published As
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EP4282428A3 (en) | 2024-03-20 |
BRPI0907237A2 (pt) | 2015-07-14 |
AU2009203464A1 (en) | 2009-07-16 |
US9274119B2 (en) | 2016-03-01 |
KR20100116179A (ko) | 2010-10-29 |
EP2241578B1 (en) | 2016-04-20 |
JPWO2009087978A1 (ja) | 2011-05-26 |
US20110059469A1 (en) | 2011-03-10 |
EP2241578A1 (en) | 2010-10-20 |
RU2010133547A (ru) | 2012-02-20 |
EP3064512A2 (en) | 2016-09-07 |
WO2009087978A1 (ja) | 2009-07-16 |
EP3064512B1 (en) | 2023-08-30 |
EP4282428A2 (en) | 2023-11-29 |
EP3064512A3 (en) | 2016-10-19 |
MX2010007500A (es) | 2010-10-20 |
SG187457A1 (en) | 2013-02-28 |
CN101918450A (zh) | 2010-12-15 |
EP3064512C0 (en) | 2023-08-30 |
EP2241578A4 (en) | 2012-09-12 |
CA2711557A1 (en) | 2009-07-16 |
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