JP2018502824A - 新規なイメージング組成物およびその使用 - Google Patents
新規なイメージング組成物およびその使用 Download PDFInfo
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- JP2018502824A JP2018502824A JP2017521145A JP2017521145A JP2018502824A JP 2018502824 A JP2018502824 A JP 2018502824A JP 2017521145 A JP2017521145 A JP 2017521145A JP 2017521145 A JP2017521145 A JP 2017521145A JP 2018502824 A JP2018502824 A JP 2018502824A
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- radionuclide
- dfosq
- trastuzumab
- conjugate
- imaging
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Abstract
Description
の化合物(本明細書では「DFO−スクアルアミド(DFO−squaramide)」または「DFOSq」とも称す)、およびその生体分子とのコンジュゲート体(89Zrなどの放射性核種を錯体化した場合)が、有効なPETイメージング剤であることを発見した。一実施形態では、LはORである。Rは、それぞれ任意選択により置換されているC1〜C10アルキル、C1〜C10ヘテロアルキル、C2〜C10アルケン、C2〜C10アルキンおよびアリールから選択されてもよい。Rは、C1〜C10アルキル(例えば、メチル、エチル、プロピルまたはブチルなどのC1〜C6アルキル)であってもよい。Rはメチルでもエチルでもよい。Rはエチルでもよい。
の化合物またはその薬学的に許容される塩の放射性核種錯体に関する。LはORでもよい。Rは、それぞれ任意選択により置換されているC1〜C10アルキル、C1〜C10ヘテロアルキル、C2〜C10アルケン、C2〜C10アルキンおよびアリールから選択されてもよい。Rは、アルキル(例えば、メチル、エチル、プロピルまたはブチルなどのC1〜C6アルキル)であってもよい。Rはメチルでもエチルでもよい。Rはエチルでもよい。
− 式(I):
の化合物またはその薬学的に許容される塩と、
− 標的分子と
のコンジュゲート体にも関する。
− 式(I):
の化合物またはその薬学的に許容される塩と、
− 標的分子と、
− 式(I)の化合物またはその薬学的に許容される塩に錯体化された放射性核種と
の放射性核種で標識されたコンジュゲート体に関する。
− 上記に定義した放射性核種で標識されたコンジュゲート体を患者に投与するステップと、
− 患者をイメージングするステップと
を含む、患者をイメージングする方法に関する。
− 上記に定義した放射性核種で標識されたコンジュゲート体を細胞またはin vitro生検サンプルに投与するステップと、
− 細胞またはin vitro生検サンプルをイメージングするステップと
を含む、細胞またはin vitro生検サンプルをイメージングする方法に関する。
1.標的分子のホウ酸緩衝液溶液を、pH9、反応混合物の最終緩衝濃度が0.5Mになるような濃度で調製する。
2.DFOSqの4%DMSO溶液のMilliQ水溶液(DFOSqが十分に溶解していることを確実にするためにDMSOを最初に添加すべきである)を調製する。
3.DFOSq溶液を必要に応じて標的分子に添加し、反応混合物を室温で終夜静置すべきである(反応時間が短いと、標的分子当たりの平均キレーター量が低くなる)。
4.コンジュゲート体は、スピンフィルターを適切な分画分子量(少なくとも1kDa)で使用して精製することができる。初期濾過後、コンジュゲート体をスピンフィルター上でMilliQ中4%DMSOを用いて少なくとも2回洗浄し、過剰な全てのDFOSqを除去するべきである。
5.スピンフィルターを使用しての緩衝液交換ステップにより、その後、コンジュゲート体の保管が可能になる(0.9%NaCl溶液がDFOSq−ハーセプチンに推奨される)。
− 式(I):
の化合物またはその薬学的に許容される塩と、
− 標的分子と、
− 式(I)の化合物またはその薬学的に許容される塩に錯体化された放射性核種と
の放射性核種で標識されたコンジュゲート体、ならびに1種または複数種の薬学的に許容される担体物質、添加剤および/または補助剤を含む医薬組成物にも関する。
− 上記に定義した放射性核種で標識されたコンジュゲート体を患者に投与するステップと、
− 前記患者をイメージングするステップと
を含む、患者をイメージングする方法にも関する。
− 本明細書に定義した放射性核種で標識されたコンジュゲート体を細胞またはin vitro生検サンプルに投与するステップと、
− 細胞またはin vitro生検サンプルをイメージングするステップと
を含む、細胞またはin vitro生検サンプルをイメージングする方法に関する。
Na2CO3水溶液(2M、4.5μL)を、89Zrの1Mシュウ酸(10MBq、10μL)溶液に、pHが増加して10になるまで添加した。次いでHEPES緩衝液(0.5M、pH7、50μL)を添加し、この溶液を5分間静置した。中性pHを確認し、次いでDFOSqのDMSO(1μL、0.18μmol)溶液を添加した。1時間後、反応完了をラジオ−iTLC(シリカ注入ガラス繊維プレート、20mM pH5クエン酸緩衝液、生成物Rf=0)およびSEHPLC(BioSuite 125、5μm HR SEC 7.8×300mmカラム、溶離液として5%i−PrOHを含む20mM pH7ダルベッコPBS、0.6mL/分、生成物保持時間21.80分)によって確認した。
対照(即ちDFOSqなし)のクロマトグラムが図4に示されている。これは、DFOSqが存在しない場合、ジルコニウムを含有する溶液が溶媒先端とともに動く(予測どおり)ことを示している。
対照のUV−Visクロマトグラム(280および254nmの2つの異なる吸収波長での)および放射線クロマトグラム(検出器としてガイガー計数管を使用して取得)が図6に示されている。
DFOSq(5mg、7μmol)のDMSO(35μL)溶液をpH9ホウ酸緩衝液(0.5M、965μL)中cRGDfK(3mg、5μmol)に添加した。反応混合物を室温で5日間静置し、次いでセミ分取HPLC(ProteCol C18カラム)で精製してDFOSq−cRGDfKを白色固体(0.002g、32%)として得た。
DFOSq(0.17mg、0.25μmol)のDMSO/H2O(1:10、26μL)溶液をヒトホロ−トランスフェリン(1.0mg、0.013μmol)のpH9ホウ酸緩衝液(0.5M、974μL)溶液に添加した。反応混合物を室温で17時間静置し、次いでAmicon 10kDa遠心分離フィルターを使用して濾過した。粗生成物をNaCl溶液(0.9%w/v、2×400μL)で洗浄し、濃縮物を回収してDFOSq−トランスフェリン(1.25mg、0.012μmol)を得た。生成物をLCMS(Agilent Poroshell C18 5μm 2.1 75mmカラム)で分析し、その分析により、トランスフェリン(Tf)と2〜8個のキレーターとの混合物および平均4.5個のキレーター/タンパク質が示された(図9を参照)。
DFOSq(0.46mg、0.67μmol)のDMSO/H2O(1:10、228μL)溶液を臨床グレードのトラスツズマブ(5.0mg、0.034μmol)の溶液に添加し、反応混合物を周囲温度でpH9ホウ酸緩衝液(0.5M、総体積1.0mL)に入れて静置した。16時間後、この溶液を、Amicon 50kDa遠心分離フィルターを使用して濃縮した。次いでフィルターを使用して、粗生成物をNaCl/DMSO溶液(0.9%w/v NaCl、5%DMSO、4×400μL)で洗浄し、次いでNaCl溶液(0.9%w/v、400μL)で洗浄し、濃縮物を回収して、DFOSq−ハーセプチン(1.4mg、0.0093μmol、28%)を得た。生成物をLCMS(Agilent Poroshell C18 5μm 2.1 75mmカラム)で分析し、その分析により、ハーセプチン(Herc)と2〜7個のキレーターとの混合物および平均4.5個のキレーター/抗体が示された(図12を参照)。
5%ゲンチジン酸ナトリウム(200μL、6.0MBqずつ)を含む89ZrDFOSq−ハーセプチンの20mM PBS(pH7)溶液を2用量調製し、BT474腫瘍担持マウスに尾静脈注射によって投与した。PET画像を、投与後22時間、46時間、94時間および8日の間隔で取得した(図17および18を参照)。
トラスツズマブ(2mg)をpH9.0ホウ酸緩衝液(0.5M、355μL)に希釈し、DFOSqのDMSO(1mg/mL、45μL、5当量)溶液を添加した。この混合物を周囲温度で40時間インキュベートし、50kDa Amiconスピンフィルターを使用して精製し、4%DMSOの生理食塩水溶液(3×300μL)で洗浄し、次いで生理食塩水のみ(300uL)で洗浄した。精製したコンジュゲート体のESI MS分析により、0〜5個のキレーターの結合および平均2個のキレーター/mAbが示された。精製したDFOSq−トラスツズマブ溶液を直ちに使用して放射標識した。
89Zrの1Mシュウ酸(150MBq、112μL)溶液をMilliQ水(250μL)で希釈し、pHが増加して7になるまでNa2CO3水溶液(2M、32.5μL)を少量ずつ添加した。次いでHEPES緩衝液(0.5M、pH7、120μL)を添加し、この溶液を5分間静置した。0.9%NaCl(56μL、675μg)中DFOSq−トラスツズマブを添加した。30分後、反応完了をラジオ−iTLC(シリカ注入ガラス繊維プレート、溶離液として0.1M pH6クエン酸緩衝液、生成物Rf=0)によって確認した。反応混合物を、PD−10サイズ排除カラムにおいて、溶離液としてpH7ダルベッコPBS(20mM、5%ゲンチジン酸ナトリウムを含む)を使用して精製した。カラム充填後、素通り画分を廃棄し、2つの画分(画分A:0.5mL、画分B:1.0mL、90.2MBq)を回収した。画分BをSE−HPLC(BioSuite 125、5μm HR SEC 7.8×300mmカラム、溶離液として5%iPrOHを含む20mM pH7ダルベッコPBS、生成物保持時間約12.5分)で分析した。
4用量(7.5MBqずつ)を、精製したmAb溶液から引き上げ、BT474腫瘍担持NOD/SCIDマウスに投与した。PETイメージングを24時間、48時間および96時間時点で行った。96時間で生体内分布データを取るためにマウスを処分した。
DFOSqのトラスツズマブへのコンジュゲート
トラスツズマブ(10mg)をpH9.0ホウ酸緩衝液(0.5M、1.5mL)に希釈し、DFOSqのDMSO(2mg/mL、455μL、16当量)溶液を添加した。この混合物を周囲温度で終夜インキュベートし、50kDa Amiconスピンフィルターを使用して精製し、4%DMSOの生理食塩水(2×300μL)溶液で洗浄し、次いで生理食塩水のみ(300uL)で洗浄した。精製したコンジュゲート体のESI MS分析により、1〜6個のキレーターの結合および平均3.4個のキレーター/mAbが示された。精製したDFOSq−トラスツズマブ溶液を4℃で8〜9日間保管してから放射標識した。
89Zrの1Mシュウ酸(150MBq、195μL)溶液をMilliQ水(350μL)で希釈し、pHが増加して8になるまでNa2CO3水溶液(2M、65μL)を少量ずつ添加した。次いでHEPES緩衝液(0.5M、pH7、200μL)を添加し、この溶液を5分間静置した。0.9%NaCl(8μL、675μg)中DFOSq−トラスツズマブを添加した。1時間後、反応完了をラジオ−iTLC(シリカ注入ガラス繊維プレート、溶離液として0.1M pH6クエン酸緩衝液、生成物Rf=0)によって確認した。反応混合物を、PD−10サイズ排除カラムにおいて、溶離液としてpH7ダルベッコPBS(20mM、5%ゲンチジン酸ナトリウムを含む)を使用して精製した。カラム充填後、素通り画分を廃棄し、第1の画分(1.0mL、54MBq)を回収した。生成物をSEHPLC(BioSuite 125、5μm HR SEC 7.8×300mmカラム、溶離液として5%iPrOHを含む20mM pH7ダルベッコPBS、生成物保持時間約12.5分)によって分析した。
3用量(7.5MBqずつ)を、精製したmAb溶液から引き上げ、SKOV3腫瘍担持NOD/SCIDマウスに投与した。PETイメージングを24時間、48時間および96時間時点で行った。96時間で生体内分布データを取るためにマウスを処分した。
3用量(7.5MBqずつ)を、精製したmAb溶液から引き上げ、LS174T腫瘍担持BALB/cヌードマウスに投与した。PETイメージングを24時間、48時間および96時間時点で行った。96時間で生体内分布データを取るためにマウスを処分した。
DFOPhNCSの合成
手順はVosjan,M.J.W.D.;Perk,L.R.;Visser,G.W.M.;Budde,M.;Jurek,P.;Kiefer,G.E.;van Dongen,G.A.M.S.,Nat.Protocols 2010,5(4),739−743のとおりに従った。
手順はVosjan、M.J.W.D.et al(上記)のとおりに従った。
3用量(3.5MBqずつ)を、精製したmAb溶液から引き上げ、SKOV3腫瘍担持NOD/SCIDマウスに投与した。PETイメージングを24時間、48時間および96時間時点で行った。96時間で生体内分布データを取るためにマウスを処分した。
DFO−cRGDfK誘導体の合成
炭酸ナトリウム溶液を使用して、cRGDfK(100uL、2mg、2μmol)の水溶液のpHを9まで増加させた。DMSO(100uL、2当量)中DFOSqのpH9ホウ酸緩衝液(0.5M、100μL)溶液である。反応混合物を室温で終夜静置し、次いでセミ分取HPLC(ProteCol C18カラム、H2O/MeCN、0.1%TFA)によって精製し、凍結乾燥して、DFOSq−cRGDfKを白色固体として得た。同様の手順を使用してDFOPhNCS−cRGDfKをDFO−Ph−NCSから調製したが、沈殿したため、精製する前にこれを遠心分離し、可溶性の物質のみを精製した。各DFO−cRGDfK誘導体の水溶液を等濃度で調製し、これをFe3+滴定によってUV−Vis分光法(425nm)を使用して確認した。
89Zr(2uL、約2MBq)の1Mシュウ酸溶液をH2O(50uL)で希釈し、2M Na2CO3(1uL)を使用して中和し、次いでpH7.4のHEPES緩衝液(5uL)で緩衝した。次いで、緩衝したZr溶液少量(5uL)を各DFO−cRGDfK溶液(50uLずつ)に添加した。20分後、反応完了をラジオ−iTLCで確認した。各サンプルを標準としてHPLC(Phenomenex Lunaカラム)に供した。DFOPhNCS−cRGDfK配位子は20.1分で溶出し、Zr錯体は18.5分で溶出する(図39)。DFOSq−cRGDfK配位子は18.0分で溶出し、Zr錯体は15.5分で溶出する(図40)。DFOSq−cRGDfK配位子溶液中の未同定の不純物も18.0分で溶出したが、これにZrは結合していなかった。
DFO−SO3H誘導体の合成:DFOSqTaur
各配位子、即ちDFOPhSO3HおよびDFOSqTaurの3mMストック溶液をH2OとMeOHとの混合液中で調製した(希釈する前に、濃度をUV−Vis H2O中Fe3+滴定によって確認した、430nm)。両溶液(25uLずつ)の混合物を完全に混合し、50℃まで加熱した。ZrCl4(THF)2のH2O/MeOH(3mM)中ストック溶液も調製し、この20uLを配位子混合物に添加した。この混合物を50℃で7時間インキュベートした。この混合物の7時間でのESI−MS分析(図46)により、ZrDFOSqTaur錯体(図46)、[M]+m/z(計算値)=850.22の存在が示された。
Claims (15)
- 式(I):
の化合物またはその薬学的に許容される塩の放射性核種錯体。 - LがORである、請求項1に記載の放射性核種錯体。
- Rが、それぞれ任意選択により置換されているC1〜C10アルキル、C1〜C10ヘテロアルキル、C2〜C10アルケン、C2〜C10アルキンおよびアリールから選択される、請求項2に記載の放射性核種錯体。
- Rが、C1〜C10アルキル、好ましくはC1〜C6アルキル、より好ましくはメチルまたはエチル、より一層好ましくはエチルである、請求項3に記載の放射性核種錯体。
- 前記脱離基が、OCH2CH3、O−p−トルエンスルホナート、O−メタンスルホナート、O−トリフルオロメタンスルホナート、O−ベンゼンスルホナート、O−m−ニトロベンゼンスルホナート、シアナート、アジドおよびハロゲンから選択される、請求項1に記載の放射性核種錯体。
- 放射性核種が、ジルコニウム、ガリウム、ルテチウム、ホルミウム、スカンジウム、チタン、インジウムおよびニオブの放射性同位体から選択される、請求項1〜5のいずれか一項に記載の放射性核種錯体。
- 前記放射性核種が、ジルコニウムの放射性同位体(好ましくは89Zr)、ガリウムの放射性同位体(好ましくは68Ga)またはインジウムの放射性同位体(好ましくは111In)である、請求項6に記載の放射性核種錯体。
- 前記放射性核種がジルコニウムの放射性同位体(好ましくは89Zr)である、請求項7に記載の放射性核種錯体。
- 標的分子にさらにコンジュゲートされて、放射性核種で標識されたコンジュゲート体を形成する、請求項1〜8のいずれか一項に記載の放射性核種錯体。
- 前記標的分子が、抗体(例えば、ハーセプチン、リツキシマブおよびセツキシマブから選択される)などのポリペプチドである、請求項9に記載の放射性核種で標識されたコンジュゲート体。
- DFO−Ph−NCS、またはDFO−Ph−NCSと前記標的分子とのコンジュゲート体と比較した際に改善された親和性を有する、請求項1〜8のいずれか一項に記載の放射性核種で標識された錯体、または請求項9もしくは10に記載の放射性核種で標識されたコンジュゲート体。
- − 請求項9〜11のいずれか一項に記載の放射性核種で標識されたコンジュゲート体を患者に投与するステップと、
− 前記患者をイメージングするステップと
を含む、患者をイメージングする方法。 - 前記標的分子が、前記コンジュゲート体をin vivoでの所望の部位に標的させる役割を果たす、請求項12に記載の方法。
- 前記所望の部位が腫瘍である、請求項13に記載の方法。
- − 請求項9〜11のいずれか一項に記載の放射性核種で標識されたコンジュゲート体を細胞またはin vitro生検サンプルに投与するステップと、
− 前記細胞またはin vitro生検サンプルをイメージングするステップと
を含む、細胞またはin vitro生検サンプルをイメージングする方法。
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CN107250104A (zh) | 2017-10-13 |
EP3207027A1 (en) | 2017-08-23 |
JP6905121B2 (ja) | 2021-07-21 |
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CN110357967B (zh) | 2023-04-14 |
US10398660B2 (en) | 2019-09-03 |
EP3543226B1 (en) | 2024-03-06 |
CA2983459C (en) | 2023-11-07 |
US20200246286A1 (en) | 2020-08-06 |
AU2015333599B2 (en) | 2019-06-20 |
JP6689836B2 (ja) | 2020-04-28 |
EP3207027B1 (en) | 2019-06-19 |
US10653649B2 (en) | 2020-05-19 |
US20200009090A1 (en) | 2020-01-09 |
US20170326084A1 (en) | 2017-11-16 |
EP3207027A4 (en) | 2018-04-18 |
CA2983459A1 (en) | 2016-04-21 |
WO2016058056A1 (en) | 2016-04-21 |
EP3543226A1 (en) | 2019-09-25 |
NZ731966A (en) | 2019-11-29 |
CN107250104B (zh) | 2019-08-16 |
JP2020114860A (ja) | 2020-07-30 |
US11123316B2 (en) | 2021-09-21 |
CN110357967A (zh) | 2019-10-22 |
US20190099392A1 (en) | 2019-04-04 |
AU2015333599A1 (en) | 2017-06-08 |
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