JP5817034B2 - Cd138を標的とする免疫複合体及びその使用 - Google Patents
Cd138を標的とする免疫複合体及びその使用 Download PDFInfo
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- JP5817034B2 JP5817034B2 JP2010540129A JP2010540129A JP5817034B2 JP 5817034 B2 JP5817034 B2 JP 5817034B2 JP 2010540129 A JP2010540129 A JP 2010540129A JP 2010540129 A JP2010540129 A JP 2010540129A JP 5817034 B2 JP5817034 B2 JP 5817034B2
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- PXSOHRWMIRDKMP-UHFFFAOYSA-N triaziquone Chemical compound O=C1C(N2CC2)=C(N2CC2)C(=O)C=C1N1CC1 PXSOHRWMIRDKMP-UHFFFAOYSA-N 0.000 description 1
- 230000005909 tumor killing Effects 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 238000011144 upstream manufacturing Methods 0.000 description 1
- 208000010570 urinary bladder carcinoma Diseases 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 239000008158 vegetable oil Substances 0.000 description 1
- 229960003048 vinblastine Drugs 0.000 description 1
- JXLYSJRDGCGARV-XQKSVPLYSA-N vincaleukoblastine Chemical compound C([C@@H](C[C@]1(C(=O)OC)C=2C(=CC3=C([C@]45[C@H]([C@@]([C@H](OC(C)=O)[C@]6(CC)C=CCN([C@H]56)CC4)(O)C(=O)OC)N3C)C=2)OC)C[C@@](C2)(O)CC)N2CCC2=C1NC1=CC=CC=C21 JXLYSJRDGCGARV-XQKSVPLYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000011592 zinc chloride Substances 0.000 description 1
- 235000005074 zinc chloride Nutrition 0.000 description 1
- 229960005502 α-amanitin Drugs 0.000 description 1
Classifications
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- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
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Description
(a)改変された標的抗体、及び
(b)エフェクタ分子
を含む免疫複合体であって、
均一にCD138発現標的細胞を標的とする免疫複合体に関する。
(i)CD138に対する非ヒト抗体の抗原結合領域(ABR)から本質的に成っていてもよい抗体、
(ii)CD138に対する非ヒト抗体の抗原結合領域(ABR)と、少なくとも一部がヒト抗体のものである、更なる抗体領域とを含んでいてもよい抗体。
(a)配列番号1で表されるアミノ酸配列のアミノ酸残基99〜111を含む重鎖可変領域CDR3、及び
(b)配列番号2で表されるアミノ酸配列のアミノ酸残基89〜97を含む軽鎖可変領域CDR3
を含んでいてもよい。
(a)配列番号1で表されるアミノ酸配列のアミノ酸残基31〜35を含む重鎖可変領域CDR1、及び配列番号1で表されるアミノ酸配列のアミノ酸残基51〜68を含む重鎖可変領域CDR2、
(b)配列番号2で表されるアミノ酸配列のアミノ酸残基24〜34を含む軽鎖可変領域CDR1、及び配列番号2で表されるアミノ酸配列のアミノ酸残基50〜56を含む軽鎖可変領域CDR2。
(a)配列番号1で表されるアミノ酸配列のアミノ酸残基123〜448、及び
(b)配列番号2で表されるアミノ酸配列のアミノ酸残基108〜214、の少なくともいずれかと、
以下の(i)及び(ii)の少なくともいずれかの突然変異を含んでいてもよい、
(i)改変された標的抗体の抗体依存性細胞傷害性及び補体依存性細胞傷害性の少なくともいずれかを、維持させる或いは低下させる突然変異、
(ii)改変された標的抗体を安定化させる突然変異。
CD138を標的とする標的剤が、免疫グロブリン重鎖及びその一部のいずれかのアミノ酸配列を含む単離ポリペプチドを含み、免疫グロブリン重鎖及びその一部のいずれかのアミノ酸配列が配列番号1で表されるアミノ酸配列と少なくとも70%の配列同一性を有する、免疫複合体に関する。免疫グロブリン重鎖及びその一部のいずれかの定常領域は、IgG4アイソタイプ定常領域であってもよい。
本明細書で特定する1以上の免疫複合体を提供する工程と、
多発性骨髄腫を治療するのに有効な量の免疫複合体を被験体に投与する工程と、
を含む方法に関する。
本明細書で特定する1以上の免疫複合体を提供する工程と、
治療に有効な量の免疫複合体を投与する工程であって、IgG4アイソタイプが、ADCC、補体依存性細胞傷害性、及び肝FcRのFc−媒介性標的の少なくともいずれかを緩和する工程と、
を含む、免疫複合体媒介薬物送達方法に関する。
腫瘍細胞の増殖の阻害、遅延、及び防止の少なくともいずれかに有効な量の本明細書で特定する1以上の免疫複合体を細胞培養物に接種する工程を含む方法に関する。有効な量により、CD138発現腫瘍細胞と、任意的にCD138を発現していない補助細胞、特に腫瘍間質細胞における、細胞死及び連続細胞周期停止のいずれかが誘導され得る。細胞培養物中の細胞は、癌患者から得ることができ、有効な量の免疫複合体の投与後、細胞培養物の細胞を、癌患者に再移植してもよい。
腫瘍の増殖及び腫瘍細胞の伝播の少なくともいずれかを阻害する或いは低減する量の、上記で特定した少なくとも1以上の免疫複合体を患者に投与する工程を含み、
免疫複合体が、腫瘍細胞の増殖及び伝播の少なくともいずれかの阻害、遅延、及び防止のいずれかを行う方法に関する。
(a)腫瘍量を減少させるのに有効な量の、1以上の細胞傷害性剤及び放射線の少なくともいずれかを患者に投与する工程と、
(b)腫瘍の増殖及び腫瘍細胞の伝播の少なくともいずれかの阻害、遅延、及び防止のいずれかを行う量の、本明細書で特定した免疫複合体の少なくとも1種を患者に投与する工程と、
を含む、
免疫複合体が、CD138発現細胞を含む腫瘍細胞の増殖及び伝播の少なくともいずれかの阻害、遅延、及び防止のいずれかを行う方法に関する。
(a)本明細書で特定する免疫複合体の少なくともいずれか1種を提供する工程と、
(b)被験体に免疫複合体を投与して、被験体の骨髄腫細胞の生存及び増殖のいずれかを選択的に減少させる工程と、
を含む方法に関する。
(a)免疫複合体を提供する工程であって、CD138に対する改変された標的抗体が切断可能なリンカーを介してエフェクタ分子に結合し、エフェクタ分子に対する立体障害がある工程と、
(b)腫瘍の増殖及び腫瘍細胞の伝播の少なくともいずれかの阻害、遅延、及び防止のいずれかを行う量の、(a)の免疫複合体を被験体に投与する工程であって、(a)の免疫複合体が、立体障害のない相当物の腫瘍増殖阻害活性を約10%、約20%、約30%、約40%、それ以上、上回る、腫瘍増殖阻害活性を提供する工程と、
を含む方法に関する。
(a)以下の(i)及び(ii)のいずれかである改変された標的抗体と、
(i)CD138に対する非ヒト抗体の抗原結合領域から本質的に成る抗体、
(ii)CD138に対する非ヒト抗体の抗原結合領域と、少なくとも一部がヒト抗体のものである、更なる抗体領域とを含む抗体、
(b)エフェクタ分子と、を含み、
免疫複合体がCD138に均一に結合する
免疫複合体を提供する。
CD138を標的とする標的剤が、免疫グロブリン重鎖及びその一部のいずれかのアミノ酸配列を含む単離ポリペプチドを含み、免疫グロブリン重鎖及びその一部のいずれかのアミノ酸配列が配列番号1で表されるアミノ酸配列と少なくとも70%の配列同一性を有する、免疫複合体を提供する。
(a)以下の(i)及び(ii)のいずれかである改変された標的抗体と、
(i)CD138に対する非ヒト抗体の抗原結合領域から本質的に成る抗体、
(ii)CD138に対する非ヒト抗体の抗原結合領域と、少なくとも一部がヒト抗体のものである、更なる抗体領域とを含む抗体、
(b)エフェクタ分子と、
を含む免疫複合体によって、細胞培養物中で治療されており、
免疫複合体がCD138に均一に結合する、
腫瘍細胞を提供する。
CD138を標的とする標的剤が、免疫グロブリン重鎖及びその一部のいずれかのアミノ酸配列を含む単離ポリペプチドを含み、免疫グロブリン重鎖及びその一部のいずれかのアミノ酸配列が配列番号1で表されるアミノ酸配列と少なくとも70%の配列同一性を有する、免疫複合体によって、細胞培養物中で治療されている腫瘍細胞を提供する。
(a)以下の(i)及び(ii)のいずれかである改変された標的抗体と、
(i)CD138に対する非ヒト抗体の抗原結合領域から本質的に成る抗体、
(ii)CD138に対する非ヒト抗体の抗原結合領域と、少なくとも一部がヒト抗体のものである、更なる抗体領域とを含む抗体、
(b)エフェクタ分子と、を含み、
免疫複合体がCD138に均一に結合する
免疫複合体を提供する。
CD138を標的とする標的剤が、免疫グロブリン重鎖及びその一部のいずれかのアミノ酸配列を含む単離ポリペプチドを含み、免疫グロブリン重鎖及びその一部のいずれかのアミノ酸配列が配列番号1で表されるアミノ酸配列と少なくとも70%の配列同一性を有する、免疫複合体を提供する。
(a)以下の(i)及び(ii)のいずれかである改変された標的抗体と、
(i)CD138に対する非ヒト抗体の抗原結合領域から本質的に成る抗体、
(ii)CD138に対する非ヒト抗体の抗原結合領域と、少なくとも一部がヒト抗体のものである、更なる抗体領域とを含む抗体、
(b)エフェクタ分子と、を含み、
免疫複合体がCD138に均一に結合し、
1以上の癌用薬物が腫瘍量を減少させることができる薬品を提供する。
CD138を標的とする標的剤が、免疫グロブリン重鎖及びその一部のいずれかのアミノ酸配列を含む単離ポリペプチドを含み、免疫グロブリン重鎖及びその一部のいずれかのアミノ酸配列が配列番号1で表されるアミノ酸配列と少なくとも70%の配列同一性を有し、
1以上の癌用薬物が、腫瘍量を減少させることができる薬品を提供する。
(a)以下の(i)及び(ii)のいずれかである改変された標的抗体と、
(i)CD138に対する非ヒト抗体の抗原結合領域から本質的に成る抗体、
(ii)CD138に対する非ヒト抗体の抗原結合領域と、少なくとも一部がヒト抗体のものである、更なる抗体領域とを含む抗体、
(b)エフェクタ分子と、を含み、
免疫複合体がCD138に均一に結合し、
薬品が、放射線で処理された患者に投与して腫瘍量を減少させるためのものである使用を提供する。
CD138を標的とする標的剤が、免疫グロブリン重鎖及びその一部のいずれかのアミノ酸配列を含む単離ポリペプチドを含み、免疫グロブリン重鎖及びその一部のいずれかのアミノ酸配列が配列番号1で表されるアミノ酸配列と少なくとも70%の配列同一性を有し、
薬品が、放射線で処理された患者に投与して腫瘍量を減少させるためのものである使用を提供する。
(a)以下の(i)及び(ii)のいずれかである改変された標的抗体と、
(i)CD138に対する非ヒト抗体の抗原結合領域から本質的に成る抗体、
(ii)CD138に対する非ヒト抗体の抗原結合領域と、少なくとも一部がヒト抗体のものである、更なる抗体領域とを含む抗体、
(b)エフェクタ分子と、を含み、
免疫複合体がCD138に均一に結合する、免疫複合体を提供する。
CD138を標的とする標的剤が、免疫グロブリン重鎖及びその一部のいずれかのアミノ酸配列を含む単離ポリペプチドを含み、免疫グロブリン重鎖及びその一部のいずれかのアミノ酸配列が配列番号1で表されるアミノ酸配列と少なくとも70%の配列同一性を有する、免疫複合体を提供する。
ターゲティング変動[%]=Ts−Tf/Tm×100
丸括弧内の(K)は、配列番号1の一部ではない。
腫瘍増殖阻害活性=100×(TGDnBT062−DM1/TGDBT062)、
より一般的には、
腫瘍増殖阻害活性=100×(TGDサンプル/TGDリファレンス)。
(*)処理群が所定の大きさ(160mm3)に達する平均時間(日)から、対照群がこの所定の大きさに達する平均時間を引いたときの、腫瘍増殖遅延(TGD)(日)
(**)腫瘍増殖阻害活性=100×(TGDサンプル/TGDBT062)。BT062の活性を100%であると定義する。
キメラ抗体の構築(cB−B4:nBT062)
B−B4
既に特性評価されているマウス抗体B−B4(Wijdenes et al.,Br J Haematol.,94(1996),318)を、これらの実験で用いた。
J.Sambrook;Molecular Cloning,A Laboratory Manual;2nd Ed.(1989),Cold Spring Harbor Laboratory Press,USAなどのテキストブックに詳述されているように、或いはキットを用いる場合は製造業者の取扱説明書により推奨されているように、標準的な組み換えDNA技術を実施した。マウス可変領域のPCR−クローニング及び修飾は、標準的なPCR法を用いて実施した。用いたプライマーはそれぞれの結果のセクションに示した。
10%のFCS、580μg/mLのL−グルタミン、50ユニット/mLのペニシリン、及び50μg/mLのストレプトマイシンを添加したDMEM中で培養した、対数増殖期のCOS細胞を、トリプシン処理により回収し、遠心分離して、PBSで洗浄した。最終濃度が1×107細胞/mLになるように、細胞をPBSに再懸濁した。700μLのCOS細胞懸濁液を、Gene Pulserキュベットに移し、重鎖及びカッパ軽鎖発現ベクターDNA(それぞれ10μg、及び13μgのいずれかのSupervector)と混合した。Bio−Rad Gene Pulserを用いて、1900V、25μFで細胞を電気穿孔処理した。形質転換された細胞を、10%のガンマグロブリン遊離FBS、580μg/mLのL−グルタミン、50ユニット/mLのペニシリン、及び50μg/mLのストレプトマイシンを添加したDMEM中で72時間培養し、その後、抗体含有細胞培養上清を回収した。
96ウェルプレートを、PBSで希釈した0.4μg/mLのヤギ抗ヒトIgG抗体の100μLのアリコートでコーティングした(4℃、一晩)。プレートを、200μL/ウェルの洗浄緩衝液(PBS+0.1%のTween−20)で3回洗浄した。ウェルを、0.2%BSA−PBS溶液、0.02%Tween−20−PBS溶液でブロッキングして、その後分泌された抗体を含有する200μLの細胞培養上清(37℃で1時間インキュベート)を添加した。ウェルを、洗浄バッファーで6回洗浄し、その後ヤギ抗ヒトカッパ軽鎖ペルオキシダ−ゼ複合体と結合した抗体を検出した。
製造業者の推奨に従って、Protein A ImmunoPure Plus kit(Pierce,Rockford,IL)を用いて、形質転換されたCOS7細胞の上清から、cB−B4抗体を精製した。
B−B4及びcB−B4のCD138への結合活性の分析を、Diaclone(Besancon,France)sCD138 kitを用いて、製造業者の推奨に従って、結果のセクションに記載した変化を考慮して実施した。
ハイブリドーマB−B4細胞を増殖させ、Qiagen Midi kit(Hilden,Germany)を用いて処理して、製造業者のプロトコルに従ってRNAを単離した。約5μgのB−B4 RNAを逆転写させて、Amersham Biosciences(Piscataway,NJ)1st strand synthesis kitを用いて、製造業者のプロトコルに従ってB−B4 cDNAを作製した。
免疫グロブリン重鎖(IgH)cDNAを、IgHプライマーMHV7(5’−ATGGGCATCAAGATGGAGTCACAGACCCAGG−3’)(配列番号3)、及びIgG1定常領域プライマーMHCG1(5’−CAGTGGATAGACAGATGGGGG−3’)(配列番号4)を用いて、PCRにより増幅した。同様に、免疫グロブリン軽鎖(IgL)を、それぞれプライマーMKC(5’−ACTGGATGGTGGGAAGATGG−3’)(配列番号8)と組み合わせた、3種の異なるIgKプライマーMKV2(5’−ATGGAGACAGACACACTCCTGCTATGGGTG−3’)(配列番号5)、MKV4(5’−ATGAGGGCCCCTGCTCAGTTTTTTGGCTTCTTG−3’)(配列番号6)、及びMKV9(5’−ATGGTATCCACACCTCAGTTCCTTG−3’)(配列番号7)を用いて増幅した。全ての増幅産物を、製造業者の取扱説明書に従って、TOPO−TA cloning kit(Invitrogen,Carlsbad,CA)を用いて、pCR2.1−TOPOベクターと直接ライゲーションした。
BigDye Termination v3.0 Cycle Sequencing Ready Reaction Kit(ABI,Foster City,CA)を用いて、プラスミドの配列を決定した。選択された各プラスミドを、1210及び1233プライマーを用いて、GeneAmp9600PCR装置で増幅させ(cycle)両方向に配列決定した。電気泳動配列分析を、ABIキャピラリシーケンサで行った。
1st strand synthesisを3つの独立な反応で実施した。プライマーMKC及びMKV2(上記配列)を用いて作製したRCP産物を、製造業者の取扱説明書に従ってpCR2.1−TOPOベクターにライゲーションした。RT−PCR反応のそれぞれの独立なセットから得られたクローンを、両方向に配列決定した。MKV−2プライマーを用いた産物の配列は、MOPC−21、SP2、及びAg8のような骨髄腫融合パートナーを起源とする無菌カッパ転写産物に非常に類似していたため((Carroll et al.,Mol Immunol.,25(1988),991;Cabilly et al.,Gene,40(1985);157)、無視した。
1st strand合成を3つの独立な反応において実施し、PCR産物を各1st strand産物からクローニングおよび配列決定した。5つのクローンを各1st strandから配列決定した。
キメラ発現ベクターの構築は、VH及びVKに、BamHI制限酵素部位及びKozak配列が先行する、好適なリーダー配列を付加することを必要とする。Kozak共通配列は、可変領域配列の効率的翻訳にとって極めて重要である。Kozak共通配列は、そこからリボソームが翻訳を開始することができる正確なAUGコドンを規定し、1つの最も重要な塩基は、AUG開始の上流、−3の位置にあるアデニン(或いはそれ程好ましくはないが、グアニン)である。リーダー配列は、Kabatデータベースにおいて最も類似する配列として選択される(Kabat et al.,NIH National Technical Information Service,1991)。これらの付加は、フォワード(For)プライマー内にコードされる(両方、配列5’−AGAGAAGCTTGCCGCCACCATGATTGCCTCTGCTCAGTTCCTTGGTCTCC−3’(配列番号9)を有する;制限酵素部位には下線をひき、GCCGCCACCはKozak配列である)。更に、キメラ発現ベクターの構築は、B−B4のJ領域の3’末端に隣接する、天然ApaI制限酵素部位に至るまで、ヒトガンマ1定常領域の5’断片を導入し、軽鎖には、スプライス供与部位及びHindIII部位を付加することを必要とする。スプライス供与部位は、可変領域配列を、適切な定常領域へ正確にインフレームで結合させ、V:Cイントロンを切り出すのに重要である。カッパイントロン+CKは、B−B4のVK配列の下流の発現コンストラクトにコードされる。同様に、ガンマ−4 CHは、B−B4 VH配列の下流の発現コンストラクトにコードされる。
非多義性B−B4 VKリーダー配列(PCRプライマー配列とは独立)を、Kabatデータベースにおけるマウスリーダー配列と整列させた。B−B4 VHリーダー配列に最もよく一致していたのは、VK−10 ARS−Aであった(Sanz et al.,PNAS,84(1987),1085)。このリーダー配列は、SignalPアルゴリズムにより正確に切断されることが予測される(Nielsen et al.,Protein Eng,10(1997);1)。pKN100発現ベクターにクローニングするために、プライマーCBB4Kfor(上記参照)及びg2258(5’−CGCGGGATCCACTCACGTTTGATTTCCAGCTTGGTGCCTCC−3’(配列番号12);制限酵素部位に下線を引く)を設計して、この完全リーダー、B−B4 VK領域、並びにHindIII及びBamHI末端制限酵素部位を含むPCR産物を作製した。フォワードプライマーCBB4Kは、HindIII制限酵素部位、Kozak翻訳開始部位、及びVK−10 ARS−Aリーダー配列を導入する。リバースプライマーg2258は、スプライス供与部位、及びBamHI制限酵素部位を導入する。得られた断片を、pKN100のHindIII/BamHI制限酵素部位にクローニングした。
非多義性B−B4 VHリーダー配列(PCRプライマー配列とは独立)を、Kabatデータベースにおけるマウスリーダー配列と整列させた。B−B4 VKリーダーに最もよく一致したのは、VH17−1A(Sun et al.,PNAS,84(1987),214)であった。このリーダー配列は、SignalPアルゴリズムにより正確に切断されことが予測される。pG4D200発現ベクターにクローニングするために、プライマーcBB4Hfor(上記参照)及びg22949(5’−CGATGGGCCCTTGGTGGAGGCTGAGGAGACGGTGACTGAGGTTCC−3’(配列番号13);制限酵素部位に下線を引く)を設計して、VH17−1Aリーダー、B−B4のVH領域、並びに末端HindIII及びApaI制限酵素部位を含むPCR産物を作製した。フォワードプライマーCBBHForは、HindIII制限酵素部位、Kozak翻訳開始部位、及びVK−17 1Aリーダー配列を導入する。リバースプライマーg22949は、ガンマ4 C領域の5’末端、及び天然ApaI制限酵素部位を導入する。得られた断片を、pG4D200のHindIII/ApaI制限酵素部位にクローニングし、ベクターpG4D200cBB4を得た。
バイアル瓶1本分のCOS7細胞を解凍し、抗生物質を含む10%の胎児クローンI血清を添加したDMEM中で増殖させた。1週間後、細胞(107細胞/mLで0.7mL)を、pG4D200cBB4+pKN100cBB4(それぞれ10μgのDNA)を用いて、或いはDNAを用いずに電気穿孔処理した。細胞を4日間8mLの増殖培地にプレーティングした。電気穿孔処理を7回繰り返した。
サンドイッチELISAを用いて、COS7上清中の抗体濃度を測定した。一過性に形質転換されたCOS7細胞は、約6,956ng/mLの抗体を分泌した(データは示さず)。
COS7培養上清におけるcB−B4の結合活性を検定するために、Diaclone sCD138キットを用いた(固相サンドイッチELISA)。sCD138に特異的なモノクローナル抗体で、提供されたマイクロタイターストリップのウェルをコーティングした。最初のインキュベート中、sCD138及びビオチン化B−B4(bio−B−B4)抗体を、非標識試験抗体(B−B4及びcB−B4のいずれか)の希釈系列とともに同時にインキュベートした。
キメラB−B4を、製造業者の推奨に従って、Protein A ImmunoPure Plus kit(Pierce)を用いて、COS7細胞上清から精製した(データは示さず)。
可溶性CD138の精製
U−266細胞培養上清由来の可溶性CD138抗原を、B−B4にカップリングした1mLの「HiTrap NHS−活性化HP」カラムを用いて、FPLCにより精製した。細胞培養上清を、カラム上のPBS緩衝液(pH7.4)にロードし、その後CD138抗原を、50mMのトリエチルアミン(pH11)で、2mLの画分に溶出させた。溶出したCD138を、375μLの1M Tris−HCl(pH3)で直ちに中和して、構造的損傷及び機能的損傷の少なくともいずれかを防いだ。
スルホ−NHS−LC(Pierce)を用いて、CD138を標識した。NHS−活性化ビオチンは、pH7〜9の緩衝液中で、リジン残基のような一級アミノ基と効率よく反応して、安定なアミド結合を形成する。
BIACORE検定で用いるセンサチップ(SENSOR CHIP SA、BIACORE AB)を、BIACOREシステムにおける相互作用分析のためにビオチン化分子に結合するよう設計した。表面は、ストレプトアビジンで予め固定化されたカルボキシメチル化デキストランマトリックスから成り、ビオチン化リガンドの高親和性捕捉の準備が整っている。手動注入により、10μL/分の流速を用いて、SENSOR CHIP SA上で、bCD138の固定化を実施した。50mMのNaOH中の1MのNaClを、3回連続して1分間注入することにより、チップ表面を調整した。次いで、ビオチン化CD138を1分間注入した。
BIACORE Cのソフトウェアは、異なる実験に対して、ある設計のみを変化させることができる、予め規定されたマスク、いわゆる「ウィザード」を用いる。BIACORE Cは、元々濃度を測定するために開発されたため、親和性測定を実行するよう設計されたウィザードが存在しない。しかしながら、適切な設定を行えば、「非特異的結合」のためのウィザードを用いて、親和性速度定数を測定することができたため、KD−決定に用いた。このウィザードでは、BIACOREランニング緩衝液を用いて「再生(Regeneration)1」を実施することにより、2つのフローセルを測定し、解離相を90秒に設定した。真の再生に相当する「再生2」を、10mMのグリシン−HCl(pH2.5)を用いて実施した。この工程後、リガンドCD138は、再び結合競合状態になった。全手順の間、HBS−EPをランニング及び希釈緩衝液として用いた。様々な抗体(〜150kDa)のCD138への結合を決定するために、会合及び解離を様々な濃度(100nM、50nM、25nM、12.5nM、6.25nM、及び3.13nM)で分析した。速度定数ka及びkdを計算することにより、解離平衡定数を決定した。その後、BIAevaluationソフトウェアでkd及びkaの商を求めることにより、分析物のKD−値を計算した。結果を表4に示す。
各抗体の平均KD値を、3つの独立な実験から計算した。結果は、全ての実験において、nBT062が、B−B4に比べて僅かに低いKD値を呈することを示す(それぞれ、平均KD値は1.4nM及び1.6nMであった)。
nBT062−DM1及びhuC242−DM1
チオール含有マイタンシノイドDM1を、Chari(Chari et al.,Cancer Res.1(1992),127)により既に記載されているように、微生物の発酵産物であるアンサマイトシンP−3から合成した。ヒト化C242(huC242)の調製((Roguska et al.,PNAS,91(1994),969)は、既に記載されている。抗体−薬物複合体を、既に記載されているように調製した(Liu et al.,PNAS,93(1996),8618)。抗体分子1つ当たり、平均3.5個のDM1分子が結合した。
BT062は、nBT062キメラ化モノクローナル抗体に、リンカーを介して、ジスルフィド結合で結合した、細胞傷害性マイタンシノイド薬であるDM4から構成される、抗体−薬物複合体である。マイタンシノイドは、チューブリン重合及び微小管の組み立てを阻害する有糸分裂阻害剤である(Remillard et al.,Science 189(1977),1002)。BT062(nBT062−DM4)の化学的及び模式的表現を図1及び2に示す。
DM4は、周知の誘導体マイタンシノールから調製される(Kupchan et al.,J. Med. Chem.,21(1978),31)。マイタンシノールは、微生物の発酵産物である、アンサマイトシンP3のエステル部分を、リチウムトリメトキシアルミニウム水素化物で還元的に切断することにより調製される(図3参照)。
nBT062−DM4の調製手順を図5に概説する。nBT062抗体を、N−スクシニミジル−4−(2−ピリジルジチオ)ブチラート(SPDBリンカー)で修飾して、ジチオピリジル基を導入する。DM4を、ジチオピリジル基の等量を超える濃度で、修飾された抗体と混合する。DM4のチオール基と、リンカーを介して抗体に導入されたジチオピリジル基との間のジスルフィド交換反応により、BT062複合体を形成する。クロマトグラフィー及び透析ろ過により精製して、低分子量反応体(DM4)及び反応産物(チオピリジン)、並びに複合体化抗体の凝集物を除去し、バルク原体を作製する。
FACS分析
OPM−2細胞は、CD138を高発現している形質細胞白血病細胞株である。OPM−2細胞を、様々な濃度のnBT062、nBT062−SPDB−DM4、nBT062−SPP−DM1、及びnBT062−SMCC−DM1のいずれかとともにインキュベートした(図6に示す)。細胞を洗浄し、CD138に結合した抗体及び複合体のいずれかを、FACS分析において蛍光標識された二次抗体を用いて検出した。これらの実験で測定された平均蛍光を、抗体濃度に対してプロットした。
CD138+MOLP−8細胞を、3,000細胞/ウェルで平底プレートに播種した。CD138−BJAB対照細胞を1,000細胞/ウェルで播種した。細胞を、様々な濃度のnBT062−SPDB−DM4、nBT062−SPP−DM1、及びnBT062−SMCC−DM1のいずれか(図7A〜Dに示す)で5日間処理した。製造業者の取扱説明書(ROCHE)に従って、細胞生存性を測定するために、WST試薬(水溶性テトラゾリウム塩、ROCHE)を添加した。試薬をMOLP−8細胞上で7.5時間、及びBJAB細胞上で2時間インキュベートした。標準的な手順を用いてマイクロタイターリーダープレートで測定した光学密度に基づいて、生存細胞の割合を計算した。
nBT062−SPDB−DM4、nBT062−SPP−DM1、nBT062−SMCC−DM1、及びnBT062のいずれかの結合をFACSにより分析した。標的細胞として、CD138+OPM−2を、nBT062及び免疫複合体のいずれかとともにインキュベートし、細胞に結合した分子を、蛍光標識された二次抗体を用いて検出した。図6では、細胞に結合した抗体の量の尺度として平均蛍光を、様々な抗体及び複合体のいずれかの濃度に対してプロットした。結果は、nBT062−SPDB−DM4、nBT062−SPP−DM1、及びnBT062−SMCC−DM1は、非常に類似する結合特性を示すことを示す。更に、結果は、複合体化していない抗体の結合特性が、複合体化した毒素により影響を受けないことを強く示唆する。
B−B4抗体のヒトキメラバージョンであるnBT062の抗体−マイタンシノイド複合体の抗腫瘍活性に対する、CD138標的の重要性を評価するために、異種移植マウス実験を実施した。ジスルフィド結合の化学的安定性の異なる可能性のある、nBT062−マイタンシノイド複合体の2つのバージョンを調製した(nBT062−SPP−DM1及びnBT062−SPDB−DM4)。これらの抗体−薬物複合体の抗腫瘍活性を、B−B4−SPP−DM1複合体(マウス親抗体を含む)、並びに複合体化していない遊離マイタンシノイド(DM4)、ネイティブな非修飾nBT062抗体、及び標的ではない(無関係な)IgG1−マイタンシノイド複合体の活性と比較した。重症複合型免疫不全症(SCID)マウスにおいて、ヒト多発性骨髄腫のCD138陽性異種移植モデル(MOLP−8)で、複合体を評価した。
マウス
雌CB.17 SCIDマウス(5週齢)を、Charles River Laboratoriesから入手した。
MOLP−8(ヒト多発性骨髄腫細胞株)は、ATCCから供給された。MOLP−8細胞(その細胞表面上でCD138抗原を発現し、SCIDマウスにおいて異種移植腫瘍を発達させる)を、4mMのL−グルタミン(Biowhittaker,Walkersville,MD)、10%のウシ胎児血清(Hyclone,Logan,Utah)、及び1%のストレプトマイシン/ペニシリンを添加したRPMI−1640培地で、5%のCO2を含む湿気のある大気中にて、37℃で維持した。
マウスにおける腫瘍増殖
各マウスの右肩下の領域に、1×107個のMOLP−8細胞を皮下接種した。総体積はマウス当たり0.2mLであり、ここで血清を含有しない培地の、マトリゲル(BD Bioscience,Bedford,MA)に対する比は1/1(v/v)であった。処理前に、異種移植腫瘍を毎日モニタし、確立を可能にした。腫瘍体積は、腫瘍細胞接種後約11日で、およそ113mm3に達した。CB.17 SCIDマウスの腫瘍発現率(take rate)は100%であった。
第2の実験セットでは、血清を含有しない培地及びマトリゲルの50:50混合物に懸濁したMOLP−8細胞(マウス当たり1.5×107細胞)を、右肩下の領域に100μL皮下注射した。腫瘍体積は、細胞接種後11日目に約80mm3に達し、対照の平均は25日目で約750mm3であった。腫瘍の倍加時間は、4.58日であると推定された。対照群の各マウス(n=6)には、0.2mLの滅菌PBSを、ボーラス注射で外側尾静脈に投与した(i.v.)。全ての処理用量は、複合体化マイタンシノイドに基づいた。それぞれ、450μg/kg、250μg/kg、及び100μg/kgの用量で、nBT062−SMCC−DM1、nBT062−SPDB−DM4、及びnBT062−SPP−DM1のいずれかを単回静脈内注射することにより、9群(n=6)を処理した。追加群(n=6)には、反復投与(週1回5週間)で250μg/kgのnBT062−SMCC−DM1を投与した。LabCatプログラムを用いて、腫瘍体積により、マウスを11群(n=6)に無作為に分けた。腫瘍体積は、40.0mm3〜152.5mm3の範囲であった。マウスには、個体の体重に基づいて投薬した。
体積=長さ×幅×高さ×1/2
Log10細胞死滅=(T−C)/Td×3.32
式中、(T−C)、即ち腫瘍増殖遅延は、処理群(T)及び対照群(C)の腫瘍が、所定の大きさ(600mm3)に達するのに必要な日数の中央時間である。Tdは、対照マウスの中央腫瘍体積に基づいた、腫瘍倍加時間であり、3.32は、細胞増殖の対数当たりの細胞倍加数である。
個々のマウスにおける腫瘍増殖を図8A〜9Dに示す。各群の平均(+/−SD)腫瘍増殖を図10に示す。
実験動物における3種のCD138標的複合体の分析結果は、抗腫瘍活性にいとって、標的送達が重要であることを示す。ヒトキメラnBT062及びマウスB−B4抗体のマイタンシノイド複合体は、対数細胞死滅により測定したとき、非常に高い活性を示すが、複合体化していないDM4、修飾されていないネイティブなhuBT062抗体、及び非標的対照複合体(huC242−DM4)のいずれかによる処理は、腫瘍増殖に対してそれ程影響を与えなかった。
CD138+OPM2細胞及びCD138−ナマルバ細胞を、丸底プレートの別々のウェルにに播種した、或いは共培養した。細胞を、1×10−8M〜1×10−9Mの範囲の濃度の、nBT062−SPDB−DM4で処理した。製造業者の取扱説明書(ROCHE)に従って、WST試薬(水溶性テトラゾリウム塩;ROCHE)を用いて、生存細胞の割合を検出した。生存細胞の割合を、標準的な手順を用いてマイクロタイターリーダー内で測定した光学密度に基づいて計算した。
nBT062−SPDB−DM4処理時に、多発性骨髄腫に非常に近接している(丸底ウェルに存在するような)非標的細胞のバイスタンダーキリングを、CD138陽性OPM2細胞をCD138陰性ナマルバ細胞と共培養で培養したインビトロ研究において分析した(図13)。一般に、CD138陽性細胞は、nBT062−SPDB−DM4によって効率的に死滅するが、CD138陰性細胞は、複合体により影響を受けなかった。しかしながら、丸底ウェルにおける共培養では、nBT062−SPDB−DM4は、抗原陽性細胞に非常に近接している抗原陰性細胞も死滅させた(バイスタンダーキリングと称されることが多い効果)。Kovtunら(2006)は、マイタンシノイド複合体により媒介されるバイスタンダーキリングは、抗原陽性細胞に非常に近接するときにのみ生じると考察した。Kovtunら(2006)(全文が本明細書に援用される)はまた、免疫複合体のリンカーの重要性についても考察している。インビボにおけるバイスタンダーキリングは、1)CD138を不均一に発現する腫瘍細胞の根絶、2)腫瘍間質細胞の死滅による腫瘍微小環境の破壊、及び3)CD138陰性nBT062−SPDB−DM4耐性細胞の選択の妨害に寄与する可能性がある。
この実験セットでは、85匹のマウスの右肩にMOLP−8細胞(1.5×107細胞/マウス)を皮下接種した。腫瘍発現率は100%であった。平均腫瘍体積が約80mm3である、嵩高いMOLP−8腫瘍を有する66匹のSCIDマウスを、11の処理群(n=6)に無作為に分けた。マウスを、3種の複合体(nBT062−SMCC−DM1、nBT062−SPDB−DM4、及びnBT062−SPP−DM1のいずれか)のうち1種の単回用量で処理した。追加群には、週用量のnBT062−SMCC−DM1を5回投与し、対照群には単回用量のPBSを投与した。平均腫瘍体積を図11Aに示す。各複合体について、用量反応が確立された。PBS処理した動物では、25日目に中央腫瘍体積が750mm3に達した。対照腫瘍増殖の対数線形プロット上において最も適合した線形回帰曲線適合により決定された腫瘍倍加時間は、4.58日であった。450μg/kgのnBT062−SPDB−DM4で処理した動物が、最高の対数細胞死滅(LCK=2.89)を有し、続いて、250μg/kgの週用量のnBT062−SMCC−DM1で処理した動物(LCK=2.1;表5を参照)であった。ダネットの多重比較試験を実施してANOVAを反復測定することによる、処理群の平均腫瘍体積曲線の比較は、PBS対照群と、450μg/kgのnBT062−SPDB−DM4(p<0.01)、250μg/kgのnBT062−SPDB−DM4(p<0.05)、及び250μg/kgの週用量5回のnBT062−SMCC−DM1(p<0.05)との間に有意な差を示した。接種後85日目までに腫瘍が部分的に縮小した、450μg/kgのnBT062−SPDB−DM4を投与した動物を除いて、いずれの処理群でも、部分的腫瘍縮小及び完全な腫瘍縮小のいずれも生じなかった。
ヒト胎児骨移植片を有するSCIDマウスの調製
ヒト胎児長骨(ヒト胎児骨片)を、既に記載されているように(Urashima et al.,1997)、CB17 SCID−マウス(SCID−hu)の上体に移植し、それによりヒトMM細胞のヒトBM細胞へのホーミングについてのマウスモデルを提供した。
骨移植の4週間後、最終体積100μLのRPMI−1640細胞培養培地中、2.5×106個のINA−6細胞を、上記SCID−huマウスのヒト骨髄腔に直接注入した。可溶性ヒトIL−6受容体(shuIL−6R)(これはINA−6細胞により放出される)のレベル上昇を、MM細胞増殖及び疾患負担のパラメータとして用いた。
インターロイキン6(IL−6)は、多発性骨髄腫の増殖及び生存因子である。INA−6は、IL−6依存性ヒト骨髄腫細胞株であり、これはまた、増殖に骨髄間質細胞(BMSC)を必要とする。INA−6細胞株は、可溶性IL−6受容体(shuIL−6R)を産生する。shuIL−6Rのレベル上昇は、MM細胞増殖及び疾患負担のパラメータとして用いることができる。
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Claims (50)
- (a)重鎖の可変領域が、配列番号1で表されるアミノ酸配列のアミノ酸残基31〜35である重鎖可変領域CDR1と、配列番号1で表されるアミノ酸配列のアミノ酸残基51〜68である重鎖可変領域CDR2と、配列番号1で表されるアミノ酸配列のアミノ酸残基99〜111である重鎖可変領域CDR3とを含み、軽鎖の可変領域が、配列番号2で表されるアミノ酸配列のアミノ酸残基24〜34である軽鎖可変領域CDR1と、配列番号2で表されるアミノ酸配列のアミノ酸残基50〜56である軽鎖可変領域CDR2と、配列番号2で表されるアミノ酸配列のアミノ酸残基89〜97である軽鎖可変領域CDR3とを含み、IgG4アイソタイプであるCD138を標的とする標的抗体と、
(b)エフェクタ分子と、を含み、
CD138発現細胞を標的とすることを特徴とする免疫複合体。 - エフェクタ分子が、標的抗体にリンカーを介して結合する、請求項1に記載の免疫複合体。
- リンカーが、切断可能なリンカーである、請求項2に記載の免疫複合体。
- 切断可能なリンカーが、ジスルフィド結合を含む、請求項3に記載の免疫複合体。
- エフェクタ分子が、標的抗体と前記エフェクタ分子との間に立体障害をもたらす、請求項1から4のいずれかに記載の免疫複合体。
- 免疫複合体が2.6nM未満のKD値を有する、請求項1に記載の免疫複合体。
- エフェクタ分子が、少なくとも1種のマイタンシノイド、タキサン、及びCC1065のいずれかである、請求項1から6のいずれかに記載の免疫複合体。
- エフェクタ分子が、少なくとも1種のマイタンシノイドである、請求項7に記載の免疫複合体。
- 少なくとも1種のマイタンシノイドが、DM1、DM3、及びDM4のいずれかである、請求項8に記載の免疫複合体。
- エフェクタ分子がDM4である、請求項5に記載の免疫複合体。
- 免疫複合体が、150%未満のターゲティング変動でCD138に結合する、請求項1から10のいずれかに記載の免疫複合体。
- CD138を標的とする標的抗体が、
(a)配列番号1で表されるアミノ酸配列のアミノ酸残基123〜448、及び
(b)配列番号2で表されるアミノ酸配列のアミノ酸残基108〜214、の少なくともいずれかと、以下の(i)及び(ii)の少なくともいずれかの突然変異とを含む、請求項1から11のいずれかに記載の免疫複合体、
(i)CD138を標的とする標的抗体の抗体依存性細胞傷害性及び補体依存性細胞傷害性の少なくともいずれかを、維持させる或いは低下させる突然変異、
(ii)CD138を標的とする標的抗体を安定化させる突然変異。 - (a)配列番号1で表されるアミノ酸配列を有する重鎖と、配列番号2で表されるアミノ酸配列を有する軽鎖とを含むCD138を標的とする標的抗体と、
(b)エフェクタ分子と、を含み、
CD138発現細胞を標的とすることを特徴とする免疫複合体。 - 被験体における多発性骨髄腫を治療するための免疫複合体であって、
前記免疫複合体が、請求項1から13のいずれかに記載の免疫複合体であることを特徴とする免疫複合体。 - 免疫複合体媒介薬物送達のための免疫複合体であって、
前記免疫複合体が、請求項1から13のいずれかに記載の免疫複合体であり、
IgG4アイソタイプが、ADCC、補体依存性細胞傷害性、及び肝FcRのFc−媒介性標的の少なくともいずれかを緩和することを特徴とする免疫複合体。 - 細胞培養物中の腫瘍細胞の増殖の阻害、遅延、及び防止の少なくともいずれかを行う方法であって、
前記腫瘍細胞の増殖の阻害、遅延、及び防止の少なくともいずれかに有効な量の、請求項1から13のいずれかに記載の免疫複合体を前記細胞培養物に接種する工程、
を含むことを特徴とする方法。 - 免疫複合体の有効な量の接種により、CD138発現腫瘍細胞における、細胞死及び連続細胞周期停止のいずれかが誘導される、請求項16に記載の方法。
- CD138腫瘍細胞を含む腫瘍の増殖及び該腫瘍の腫瘍細胞の伝播の少なくともいずれかの阻害、遅延、及び防止の少なくともいずれかを、それを必要とする患者において行うための免疫複合体であって、
前記免疫複合体が、請求項1から13のいずれかに記載の免疫複合体であることを特徴とする免疫複合体。 - 患者が、CD138発現細胞を含む血液悪性疾患及び固形腫瘍の少なくともいずれかに罹患している、請求項18に記載の免疫複合体。
- 患者が、多発性骨髄腫、卵巣癌の細胞腫、腎臓癌腫、胆嚢癌腫、乳癌腫、前立腺癌、肺癌、結腸癌腫、ホジキンリンパ腫、非ホジキンリンパ腫、慢性リンパ球性白血病(CLL)、急性リンパ球性白血病(ALL)、急性骨髄芽球性白血病(AML)、及び固形組織肉腫のいずれか1種に罹患している、請求項19に記載の免疫複合体。
- 患者が罹患している疾患が、多発性骨髄腫である、請求項20に記載の免疫複合体。
- 免疫複合体のエフェクタ分子が、毒素、細胞傷害性酵素、低分子量細胞傷害性薬物、ポア形成剤、生物学的反応調節物質、プロドラッグ活性化酵素、抗体、サイトカイン、及び放射性核種のいずれかである、請求項18に記載の免疫複合体。
- 免疫複合体を、5mg/m 2 〜300mg/m 2 の単回用量で投与する、請求項18に記載の免疫複合体。
- 免疫複合体が、5mg/m 2 〜300mg/m 2 の単回用量で、少なくとも2回投与する、請求項18に記載の免疫複合体。
- 免疫複合体を、1時間、1日、1週間間隔及びこれらを組み合わせた間隔のいずれかで、少なくとも2回投与する、請求項24に記載の免疫複合体。
- CD138発現細胞を含む悪性腫瘍細胞の増殖及び該悪性腫瘍細胞の伝播の少なくともいずれかの阻害、遅延、及び防止の少なくともいずれかを、それを必要とする患者において行うための免疫複合体であって、
前記免疫複合体が、請求項1から13のいずれかに記載の免疫複合体であり、
前記患者が、腫瘍量を減少させる量の、1以上の細胞傷害性剤及び放射線の少なくともいずれかで処理されていることを特徴とする免疫複合体。 - 細胞傷害性剤が、メルファラン、ビンクリスチン、ドキソルビシン、デキサメサゾン、シクロホスファミド、エトポシド、シタラビン、シスプラチン、プレドニゾン、サリドマイド、ボルテゾミブ、レナリドマイド、ソラフェニブ、ロミデプシン、及びこれらの組み合わせのいずれかである、請求項26に記載の免疫複合体。
- 細胞傷害性剤が、抗体に基づくものである、請求項26に記載の免疫複合体。
- 骨髄腫細胞の生存を抑制することによって利益を得る状態を有する被験体を治療するための免疫複合体であって、
前記免疫複合体が、請求項1から13のいずれかに記載の免疫複合体であり、
前記免疫複合体が、前記被験体の前記骨髄腫細胞の生存及び増殖のいずれかを選択的に減少させることが可能であることを特徴とする免疫複合体。 - 請求項1から13のいずれかに記載の免疫複合体と、1種以上の薬学的に許容される賦形剤と、を含むことを特徴とする医薬組成物。
- 少なくとも1種の細胞傷害性剤を更に含む、請求項30に記載の医薬組成物。
- 細胞傷害性剤が、メルファラン、ビンクリスチン、ドキソルビシン、デキサメサゾン、シクロホスファミド、エトポシド、シタラビン、シスプラチン、プレドニゾン、サリドマイド、ボルテゾミブ、レナリドマイド、ソラフェニブ、ロミデプシン、及びこれらの組み合わせのいずれかである、請求項31に記載の医薬組成物。
- 細胞傷害性剤が、抗体に基づくものである、請求項31に記載の医薬組成物。
- 腫瘍の増殖及び腫瘍細胞の伝播の少なくともいずれかの阻害、遅延、及び防止の少なくともいずれかを行うために組み合わせて用いられる医薬組成物を別々の容器に含むキットであって、1つの容器が、有効な量の請求項30に記載の医薬組成物を含み、別の容器が、腫瘍の増殖及び腫瘍細胞の伝播の少なくともいずれかの阻害、遅延、及び防止の少なくともいずれかを行うための有効な量の更なる薬剤を含む第2の医薬組成物と、1種以上の薬学的に許容される賦形剤とを含むことを特徴とするキット。
- 第2の医薬組成物中の薬剤が、細胞障害性剤である、請求項34に記載のキット。
- 第2の医薬組成物中の薬剤が、メルファラン、ビンクリスチン、ドキソルビシン、デキサメサゾン、シクロホスファミド、エトポシド、シタラビン、シスプラチン、プレドニゾン、サリドマイド、ボルテゾミブ、レナリドマイド、ソラフェニブ、ロミデプシン、及びこれらの組み合わせから成る群から選択されるか、或いは抗体に基づくものである、請求項34に記載のキット。
- CD138腫瘍細胞を含む腫瘍の増殖及び該腫瘍の腫瘍細胞の伝播の少なくともいずれかの阻害、遅延、及び防止の少なくともいずれかを、それを必要とする被験体において行うための免疫複合体であって、
前記免疫複合体が、請求項1から13のいずれかに記載の免疫複合体であり、
CD138を標的とする標的抗体が立体障害のあるエフェクタ分子に切断可能なリンカーを介して結合していて、
前記免疫複合体が、立体障害のないエフェクタ分子に切断可能なリンカーを介して結合しているCD138を標的とする標的抗体を含む免疫複合体の腫瘍増殖阻害活性を10%以上、上回る腫瘍増殖阻害活性を提供することを特徴とする免疫複合体。 - 切断可能なリンカーが、ジスルフィド結合を含む、請求項37に記載の免疫複合体。
- エフェクタ分子がDM4である、請求項37に記載の免疫複合体。
- 免疫複合体を、5mg/m 2 〜300mg/m 2 の量で、少なくとも1回被験体に投与する、請求項37に記載の免疫複合体。
- 免疫複合体を、複数回投与で被験体に投与し、そのように投与された前記免疫複合体が、立体障害のないエフェクタ分子に切断可能なリンカーを介して結合しているCD138を標的とする標的抗体を含む免疫複合体の腫瘍増殖阻害活性を20%以上、上回る腫瘍増殖阻害活性を提供する、請求項37に記載の免疫複合体。
- 切断可能なリンカーが、ジスルフィド結合を含む、請求項41に記載の免疫複合体。
- エフェクタ分子がDM4である、請求項41に記載の免疫複合体。
- 複数回投与を、5時間、6時間、7時間、8時間、9時間、10時間、11時間、12時間、13時間、14時間、15時間、16時間、17時間、18時間、19時間、20時間、21時間、22時間、23時間、1日、2日、3日、4日、5日、6日、7日、1週間、2週間、3週間、4週間、5週間、6週間、7週間、及び8週間のいずれかの間隔で行う、請求項41に記載の免疫複合体。
- 免疫複合体を、5mg/m 2 〜300mg/m 2 の用量で投与する、請求項41に記載の免疫複合体。
- CD138発現腫瘍細胞と直接的或いは間接的に接触する細胞の数を、それを必要とする被験体において減少させるための免疫複合体であって、
前記免疫複合体が、請求項1から13のいずれかに記載の免疫複合体であることを特徴とする免疫複合体。 - CD138発現腫瘍細胞と直接的或いは間接的に接触する細胞が、不均一にCD138を発現する細胞、CD138を発現しない細胞、及び有効量の少なくとも1種の免疫複合体に接近不可能な細胞の少なくともいずれかから成る、請求項46に記載の免疫複合体。
- 細胞が、CD138発現腫瘍細胞と直接接触する、或いは結合する細胞である、請求項46に記載の免疫複合体。
- 試験管内において、CD138発現腫瘍細胞と直接的或いは間接的に接触する細胞の数を減少させる方法であって、
前記腫瘍細胞、及び前記腫瘍細胞に直接的或いは間接的に接触する前記細胞に、CD138発現腫瘍細胞と直接的或いは間接的に接触する前記細胞の数を減少させるのに有効な量の、請求項1から13のいずれかに記載の少なくとも1種の免疫複合体を投与する工程を含むことを特徴とする方法。 - 重鎖の可変領域が、配列番号1で表されるアミノ酸配列のアミノ酸残基31〜35である重鎖可変領域CDR1と、配列番号1で表されるアミノ酸配列のアミノ酸残基51〜68である重鎖可変領域CDR2と、配列番号1で表されるアミノ酸配列のアミノ酸残基99〜111である重鎖可変領域CDR3とを含み、
軽鎖の可変領域が、配列番号2で表されるアミノ酸配列のアミノ酸残基24〜34である軽鎖可変領域CDR1と、配列番号2で表されるアミノ酸配列のアミノ酸残基50〜56である軽鎖可変領域CDR2と、配列番号2で表されるアミノ酸配列のアミノ酸残基89〜97である軽鎖可変領域CDR3とを含み、
IgG4アイソタイプであることを特徴とするCD138を標的とする標的抗体。
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