JP4959136B2 - 細胞内で開裂可能な結合を有する免疫接合体 - Google Patents
細胞内で開裂可能な結合を有する免疫接合体 Download PDFInfo
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- JP4959136B2 JP4959136B2 JP2004559895A JP2004559895A JP4959136B2 JP 4959136 B2 JP4959136 B2 JP 4959136B2 JP 2004559895 A JP2004559895 A JP 2004559895A JP 2004559895 A JP2004559895 A JP 2004559895A JP 4959136 B2 JP4959136 B2 JP 4959136B2
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- 125000002987 valine group Chemical group [H]N([H])C([H])(C(*)=O)C([H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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Description
本発明は、様々な癌細胞、感染性疾患生物をターゲットし、自己免疫疾患を治療するための改善された能力を有する治療接合体であって、ターゲッティング残基および治療残基を含む接合体に関する。ターゲッティングと治療残基とは、治療効力を増強する、細胞内で開裂可能な結合を介して結合している。
長年にわたり、ヒト癌に毒性因子を特異的に送達するためのモノクローナル抗体(mAb)の使用は、特異的にターゲッティングした薬物療法の分野における科学者の目標となっている。腫瘍関連mAbと適当な毒性因子との接合体が開発され、癌の治療において複合的に成功しているが、他の疾患には実質的に応用されていない。毒性因子は、最も一般的には化学療法薬であるが、粒子放射放射性核種や、細菌性または植物性毒素もmAbに接合されている。
(a) ターゲッティング残基、
(b) 化学療法薬残基、および
(c) チオール基を介してターゲッティング残基へ結合し、かつヒドラゾン以外の細胞内で開裂可能な残基を介して化学療法薬残基へ結合するリンカー
を含んでなる、免疫接合体に関する。他の態様によれば、本発明は、
(a) ターゲッティング残基、
(b) 化学療法薬残基、および
(c) チオール基を介してターゲッティング残基へ結合し、かつヒドラゾン以外の細胞内で開裂可能な残基を介して化学療法薬残基へ結合するリンカー
を含んでなる、免疫接合体であって、上記リンカーがアミノ酸残基とチオール反応性残基とを含んでなり、アミノ酸残基を介して化学療法薬残基におよびチオール反応性残基を介してターゲッティング残基に結合している免疫接合体に関する。
癌細胞は、好ましくは造血腫瘍(hematopoietic tumor)、癌、肉腫、黒色腫、またはグリア腫瘍由来の細胞である。
本発明の好ましい態様の一側面によれば、本発明は、ターゲッティング残基、化学療法薬残基、およびチオール基を介してターゲッティング残基へ、およびヒドラゾン以外の細胞内で開裂可能な残基を介して化学療法薬残基へ結合するリンカーを含んでなる、免疫接合体に関する。
を伴う治療薬接合体によってこれらB細胞を涸渇させることは、特にB細胞抗体をある情況においてHLA-DR抗体および/またはT細胞抗体(抗TAC抗体のようなIL-2を抗原としてターゲットとするものなど)と結合させるときには、自己免疫疾患治療において好ましい方法である。
実施例
実施例1:10ヒドロキシカンプトテシンのC-20-O-(N-'MCC')グリシネート誘導体であって、MCCが4-(N-マレイミドメチル)-シクロヘキサン-l-カルボニル残基であるものの調製
抗体を、20-40倍モル過剰量のジチオトレイトールおよびエチレンジアミン四酢酸(EDTA)(約5mM最終濃度)でpH 7.4で処理し、アルゴンを流し、37℃で45分間インキュベーションした。冷却した内容物を、遠心分離溶出条件(遠心分離SEC)下にて50mM酢酸ナトリウム-150mM塩化ナトリウム, pH 5.3(「ABS緩衝液」)中Sephadex G50/80の2本の連続した3mlカラムで精製した。溶出液を280nmでの吸光度を用いてタンパク質濃度について分析し、チオール含量をEllman分析法によって分析した。還元抗体は7-9チオール基を含んでいた。還元抗体を20倍モル過剰量のCPT誘導体とDMF中で反応させ、接合混合物中のDMFの最終濃度が≦5%v/vとなるようにし、氷上(約4℃)で20-30分間インキュベーションした。Sephadex G50/80上ABS緩衝液で2回連続して遠心分離-SEC精製を行った後、溶出液を疎水性カラムを通過させて非共有結合CPT誘導体を除去し、最終的接合体を得た。7を用いる接合体の場合には、さらに30K MWCO遠心分離フィルター上での限外濾過による精製が必要であった。総ての調製物において、反応混合物並びに精製接合体は透明溶液であり、CPT誘導体の水溶性が用いられたことを示していた。SE-HPLCによる分析は、ガードカラムとイン・ライン吸光度検出器を備えた分析用SEC250カラム上で溶離剤として0.2Mリン酸ナトリウムpH 6.8および流速として1ml/分を用いて行った。生成物は、260-540nmの領域で分光光度法による吸光度掃引によっても分析した。360nmでの吸光度をCPT-11標準品で得られた吸光度で補正して、接合体におけるCPT濃度を決定した。CPT誘導体からのスピルオーバー(spillover)について補正した280nmでの吸光度を用いて、抗体濃度を計算した。この方法で、CPT誘導体対IgGのモル比を決定した。生成物を10 %(v/v)の1Mスクロースと混合し、1mgおよび0.1mgずつのロットに等分し、凍結乾燥した。凍結乾燥した調製物をアルゴン置換した後、冷凍庫に保管した。
接合体は、実施例4に記載の方法で調製した。下記のものは、様々な接合体に関するデーターである。
接合体は、実施例4に記載の方法で調製した。下記のものは、様々な接合体に関するデーターである。
接合体は、実施例4に記載の方法で調製した。下記のものは、様々な接合体に関するデーターである。
一般的方法は、図4に示す。簡単に説明すれば、CPTおよび10-ヒドロキシ-CPTをSingerの方法(上記引用)によって相当するC-20-O-グリシネートに転換した。平行合成において、イソチオシアナトベンジルDTPAペンタ第三ブチルエステルを相当するアミン前駆体から生成させた後、S-トリチルシステインにカップリングした。フラッシュクロマトグラフィー精製により、中間体11(質量スペクトル: M+Na m/e 1207; M-H:1183)を得た。
SN-38は、プロドラッグCPT-11からイン・ビボで代謝により転換される活性薬剤である(Liehr, Giovanella, Verschraegen (監修)(上記引用))。SN-38は、トポイソメラーゼI活性の阻害においてCPT-11より3桁強力な活性化学療法薬である。抗体接合に適する二官能価SN-38は、下記の通りに簡単に調製される。すなわち、[CPT-11]-20-O-バリネートを、そのバリンN末端をBOCとして保護したものを、水酸化物のような塩基1当量を用いてそのC-10-カルバメートで選択的に開裂させる。カリウム第三ブトキ2当量と水1当量とから誘導されるような「無水水酸化物」(Gassman and Schenk, J. Org. Hem., 42:918-920 (1977))は、この目的に有利に用いられる。CPTのバリネートエステルは、1N水酸化ナトリウム水溶液の1当量に少なくとも1時間安定であることが示されている。この方法により、C-10-カルバメートを選択的に開裂する。次に、バリン残基のアミノ基をイソチオシアネートに転換し、ペプチド鋳型MCC-Gly-Lys-Lys(R')-NHにカップリングする。あるいは、SN-38自身を、最初にメトキシトリチル誘導体のような酸感受性誘導体としてC10-ヒドロキシル基を保護することによって誘導体形成する。次に、C20-ヒドロキシル基をバリネートエステルに転換する。この時点で、C-10位のメトキシトリチル基を除去する。別の方法は、最初に相当する「BOC」エステルとしてC-10ヒドロキシルを保護し、20-ヒドロキシル基を誘導体形成し、脱保護することによってすることによってSN-38の20-バリネートエステル(または任意の他のエステル)誘導体を調製する。次に、これに続いてトリメチルシリルクロリドで処理して、C-10ヒドロキシルとC-20のエステルのアミノ基を誘導体形成させ、マレイミド-PEG-NHSのようなアミン反応性のヘテロ二官能価架橋剤と反応させ、C-10位のトリメチルシリル基を脱保護する。
Claims (17)
- (a) 抗体、
(b) ヒドロキシル基を含む化学療法薬残基、および
(c) (i)前記抗体のチオール基に結合するチオール反応性基であって、マレイミドまたはビニルスルホンである、チオール反応性基と、
(ii)エチレンジアミン四酢酸 (EDTA)、 ジエチレントリアミン五酢酸 (DTPA)、トリエチレンテトラミン六酢酸 (TTHA)、ベンジル-DTPA、1,4,7,10-テトラアザシクロドデカン-N,N',N",N"'-四酢酸 (DOTA)、ベンジル-DOTA、1,4,7-トリアザシクロノナン-N,N', N"-三酢酸 (NOTA)、ベンジル-NOTAおよび1,4,8,11-テトラアザシクロテトラデカン-1,4,8, 11-四酢酸 (TETA)、N,N'-ジアルキル置換ピペラジンからなる群から選択される水可溶化残基であって、前記チオール反応性基と直接またはスペーサーを介して結合してなる水可溶化残基と、
(iii)前記水可溶化残基と直接またはスペーサーを介して結合してなるアミノ基を含むアミノ酸と
を含んでなる、リンカー
を含んでなる、免疫接合体であって、
前記化学療法薬残基が、細胞内で開裂可能な残基を介してリンカーと結合し、
前記細胞内で開裂可能な残基が、細胞内エステラーゼによって開裂可能でありかつ前記アミノ酸のα-カルボン酸と前記化学療法薬残基のヒドロキシル基とから形成されるエステルである、免疫接合体。 - (a) 抗体、
(b) ヒドロキシル基を含む水溶性化学療法薬残基、および
(c) 前記抗体のチオール基に結合するチオール反応性基とα-アミノ酸とを含んでなる、リンカー
を含んでなる、免疫接合体であって、
前記化学療法薬残基が、細胞内で開裂可能な残基を介してリンカーと結合し、
前記細胞内で開裂可能な残基が、細胞内エステラーゼによって開裂可能でありかつ前記アミノ酸のα-カルボン酸と前記化学療法薬残基のヒドロキシル基とから形成されるエステルであり、
前記リンカーが、下式に示されるものである、免疫接合体:
- (a) 抗体、
(b) ヒドロキシル基を含む化学療法薬残基、および
(c) (i)前記抗体のチオール基に結合するチオール反応性基と、
(ii) エチレンジアミン四酢酸 (EDTA)、 ジエチレントリアミン五酢酸 (DTPA)、トリエチレンテトラミン六酢酸 (TTHA)、ベンジル-DTPA、1,4,7,10-テトラアザシクロドデカン-N,N',N",N"'-四酢酸 (DOTA)、ベンジル-DOTA、1,4,7-トリアザシクロノナン-N,N', N"-三酢酸 (NOTA)、ベンジル-NOTAおよび1,4,8,11-テトラアザシクロテトラデカン-1,4,8, 11-四酢酸 (TETA)、N,N'-ジアルキル置換ピペラジンからなる群から選択され、前記チオール反応性基と直接またはスペーサーを介して結合してなる水可溶化残基と、
(iii)前記水可溶化残基と直接またはスペーサーを介して結合してなるアミノ基を含んでなるペプチドと
を含んでなる、リンカー
を含んでなる、免疫接合体であって、
前記化学療法薬残基が、細胞内で開裂可能な残基を介してリンカーと結合し、
前記細胞内で開裂可能な残基が、細胞内エステラーゼによって開裂可能でありかつ前記ペプチドのC末端のアミノ酸のα-カルボン酸と前記化学療法薬残基のヒドロキシル基とから形成されるエステルである、免疫接合体。 - 前記化学療法薬残基が、ドキソルビシン(DOX)、エピルビシン、モルホリノドキソルビシン(モルホリノ-DOX)、シアノモルホリノ-ドキソルビシン(シアノモルホリノ-DOX)、2-ピロリノ-ドキソルビシン(2-PDOX)、CPT、CPT-11、SN-38、トポテカン、タキサン、ゲルダナマイシン、アンサマイシン、およびエポチロンからなる群から選択されるものである、請求項1〜3のいずれか一項に記載の免疫接合体。
- 前記抗体がモノクローナル抗体(mAb)である、請求項1〜3のいずれか一項に記載の免疫接合体。
- 前記抗体が、多価および/または多重特異性である、請求項1〜3のいずれか一項に記載の免疫接合体。
- 前記抗体が、ネズミ、キメラ、ヒト化、またはヒトモノクローナル抗体であり、前記抗体が完全な、断片(Fab、Fab'、F(ab')2)または小断片(一本鎖構築物)形態である、請求項1〜3のいずれか一項に記載の免疫接合体。
- 前記抗体が、癌または悪性細胞上で発現した、抗原または抗原のエピトープと反応性のモノクローナル抗体である、請求項1〜3のいずれか一項に記載の免疫接合体。
- 前記癌細胞が、造血腫瘍、癌、肉腫、黒色腫、またはグリア腫瘍由来の細胞である、請求項1〜3のいずれか一項に記載の免疫接合体。
- 前記抗体が、B細胞系抗原、T細胞系抗原、骨髄系抗原、およびHLA-DR抗原からなる群から選択される抗原に結合するモノクローナル抗体である、請求項1〜3のいずれか一項に記載の免疫接合体。
- 前記抗体が、CD74、CD22、上皮糖タンパク質-1、MUC1、癌胎児性抗原 (CEAまたはCD66e)、結腸特異性抗原-p、α-フェトプロテイン、前立腺特異性膜抗原、カルボニックアンヒドラーゼIX、HER-2/neu、BrE3抗原、CD19、CD20、CD21、CD23、CD33、CD45、CD80、VEGF、EGF受容体、P1GF、MUC2、MUC3、MUC4、ガングリオシド、HCG、EGP-2、CD37、HLA-DR、CD30、Ia、A3、A33抗原、Ep-CAM、KS-1、Le(y)、S100、PSA、テネイシン、葉酸受容体、Thomas-Friedreich抗原、腫瘍壊死抗原、腫瘍血管新生抗原、Ga 733、IL-2、IL-6、T101、MAGE、CD66a (BGP)、CD66b (CGM6)、CD66c (NCA)、CD66d (CGM1)、TAC、およびそれらの組合せからなる群から選択される抗原に結合するモノクローナル抗体である、請求項1〜3のいずれか一項に記載の免疫接合体。
- 前記抗体が少なくとも1つの化学療法薬残基に結合するものである、請求項1〜3のいずれか一項に記載の免疫接合体。
- 前記抗体が約7〜12個の前記化学療法薬残基に結合するものである、請求項1〜3のいずれか一項に記載の免疫接合体。
- 非経口投与に適した形態である、請求項1〜3のいずれか一項に記載の免疫接合体。
- 前記抗体が、二重特異性および/または二価抗体構築物である、請求項1〜3のいずれか一項に記載の免疫接合体。
- 前記抗体が、LL1、hA20、RS7、PAM-4、Mu-9、AFP-31、MN-14、hLL1、hRS7、hPAM-4およびhMu-9からなる群から選択されるものである、請求項1〜3のいずれか一項に記載の免疫接合体。
- 前記抗体が、LL1、hA20、RS7、PAM-4、Mu-9、AFP-31、MN-14、hLL1、hRS7、hPAM-4およびhMu-9からなる群から選択される1種類以上の抗体を含んでなる二重特異性および/または二価抗体構築物である、請求項1〜3のいずれか一項に記載の免疫接合体。
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- 2003-12-15 WO PCT/GB2003/005454 patent/WO2004054622A1/en active Application Filing
- 2003-12-15 EP EP03780388.9A patent/EP1572242B1/en not_active Expired - Lifetime
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JP2006511526A (ja) | 2006-04-06 |
EP1572242B1 (en) | 2014-04-16 |
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US8268319B2 (en) | 2012-09-18 |
US20160287722A1 (en) | 2016-10-06 |
US20040185053A1 (en) | 2004-09-23 |
US7585491B2 (en) | 2009-09-08 |
IL169045A (en) | 2010-12-30 |
US9388237B2 (en) | 2016-07-12 |
AU2003288467A1 (en) | 2004-07-09 |
WO2004054622A1 (en) | 2004-07-01 |
US9133268B2 (en) | 2015-09-15 |
US10280220B2 (en) | 2019-05-07 |
US20120328634A1 (en) | 2012-12-27 |
US20140004078A1 (en) | 2014-01-02 |
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