JP5789821B2 - タンパク質、ペプチドおよび他の分子の改善されたf−18標識化のための方法および組成物 - Google Patents
タンパク質、ペプチドおよび他の分子の改善されたf−18標識化のための方法および組成物 Download PDFInfo
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Description
本出願は、2009年12月4日に提出された米国仮特許出願第61/266,773号;2010年2月8日に提出された同第61/302,280号;2010年3月22日に提出された同第61/316,125号;2010年5月24日に提出された同第61/347,486号;2010年9月10日に提出された同第61/381,720号および2010年9月30日に提出された同第61/388,268号に対する優先権を主張し、各々の優先権出願は、全体が、参照により本明細書に組み込まれる。
本出願は、EFS−Webを介してASCII形式で提出された、全体が参照により本明細書に組み込まれる配列表を含有する。2010年12月2日に作成された該ASCIIの複写は、IMM31W07.txtの名称を有し、サイズが16,889バイトである。
本発明は、例えば、PETまたはNMRインビボ画像化において使用するペプチドまたは他の分子を18Fまたは19Fによって標識化する方法に関する。好ましくは、18Fまたは19Fは、キレート部分を介してアルミニウムまたは別の金属に共役体[錯体]として付着され、タンパク質、ペプチドまたは他の分子と共有結合的に連結されてよい。本明細書に記載されている技術を用いることで、高い比活性度の18Fまたは19F標識化分子は、30分以下で調製され得、標識化分子のHPLC精製を必要とすることなく画像化技術における使用に好適である。標識化は、インビボでの直接使用に好適な生理食塩水媒体において起こり得る。代替の実施形態において、有機溶媒が添加されて、標識化の効率を改善することができる。標識化分子はインビボ条件下で安定であるが、キット製剤などのある一定の目的のために、アスコルビン酸、トレハロース、ソルビトールまたはマンニトールなどの安定化剤が添加されていてよい。他の代替の実施形態において、キレート部分は、18Fまたは19Fによる標識化の前に、アルミニウムと共に予め投入されていてよく、貯蔵のために凍結乾燥されていてよい。
18F標識化技術の比較
標的化可能な構築物
キレート部分
抗体
標的抗原
抗体を生じさせる方法
キメラ抗体
ヒト化抗体
ヒト抗体
公知の抗体
抗体フラグメント
抗体クローニングおよび産生のための一般的技術
二重特異的および多重特異的抗体
ドック・アンド・ロック(DNL)
前標的化
免疫共役体
クリックケミストリー
投与の方法
製剤および投与
ペプチドの投与
標識化分子を用いた画像化
キット
実施例
実施例1.ペプチドIMP272の18F標識化
実施例2.他の金属によるIMP27218F標識化
実施例3.血清安定性18F標識化ペプチドIMP449の産生および使用
IMP449
NOTA−ITCベンジル−D−Ala−D−Lys(HSG)−D−Tyr−D−Lys(HSG)−NH2(配列番号:4)
IMP449の18F標識化
高線量の18F標識化
実施例4.前標的化による18F画像化のためのDNL構築物の調製
DDD1:SHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA(配列番号:6)
DDD2:CGHIQIPPGLTELLQGYTVEVLRQQPPDLVEFAVEYFTRLREARA(配列番号:7)
AD1:QIEYLAKQIVDNAIQQA(配列番号:8)
AD2:CGQIEYLAKQIVDNAIQQAGC(配列番号:9)
CH1の調製
DDD1とCH1とのライゲーティング
AD1とCH1とのライゲーティング
pdHL2系ベクター中へのCH1−DDD1またはCH1−AD1のクローニング
h679−Fd−ADl−pdHL2の構築
C−DDD1−Fd−hMN−14−pdHL2の構築
C−DDD2−Fd−hMN−14−pdHL2
H679−Fd−AD2−pdHL2
実施例5.TF2DNL構築物の生成
実施例6.TF10DNL構築物の産生
実施例7.DNLに関する配列変異体
Ht31
DLIEEAASRIVDAVIEQVKAAGAY(配列番号:20)
RIAD
LEQYANQLADQIIKEATE(配列番号:21)
PV−38
FEELAWKIAKMIWSDVFQQC(配列番号:22)
結果
実施例10.18F標識化ペプチドを用いたインビボ画像化および18F[FDG]との比較
生体内分布およびマイクロPET画像化
結果
実施例11.Al−18Fを用いたIMP460の調製および標識化
IMP460の放射性標識化
実施例12.IMP461およびIMP462NOTA共役ペプチドの合成および標識化
ジ−t−ブチル−NOTAの合成
IMP461の合成
IMP0462の合成
IMP461およびIMP462の18F標識化
実施例13.IMP467の調製および18F標識化
IMP467C−NETA−スクシニル−D−Lys(HSG)−D−Tyr−D−Lys(HSG)−NH2(配列番号:29)
放射性標識化
放射性標識化されたペプチドの収率の比較
ペプチド濃度
アルミニウム濃度
Al18F IMP467放射性標識化の動力学
pHの影響
IMP467の高線量放射性標識化
ヒト血清安定性試験
Al18F IMP467の最適化された標識化
18Fの濃度および精製
実施例16.IMP470の合成および標識化
IMP470 L−NETA−スクシニル−D−Lys(HSG)−D−Tyr−D−Lys(HSG)−NH2(配列番号:30)
実施例17.アルミニウムによってプレインキュベートされたペプチドへの18Fの添加による標識化
実施例18.IMP468ボンベシンペプチドの合成および標識化
実施例19.18F標識化ボンベシンを用いた腫瘍の画像化
実施例20.ソマトスタチン類似体IMP466の合成および標識化
IMP466NOTA−D−Phe−Cys−Phe−D−T−Lys−Thr−Cys−Throl(配列番号:33)
イオン強度の影響
実施例21.18F−および68Ga標識化IMP466による神経内分泌腫瘍の画像化
方法
実施例22.前標的化を用いた68Gaおよび18F PET画像化の比較
方法
IMP288DOTA−D−Tyr−D−Lys(HSG)−D−Glu−D−Lys(HSG)−NH2(配列番号:34)
結果
結論
実施例23.葉酸NOTA共役体の合成
実施例29.ヒトにおける前標的化PET画像診断
実施例25.18F標識化による血管新生受容体の画像診断
実施例26.炭水化物標識化
実施例27.F−18標識化に及ぼす有機溶媒の影響
実施例30.19F標識化ペプチドの調製
実施例31.IMP479、IMP485およびIMP487の合成および標識化
4−(ブロモメチル)フェニル酢酸(Aldrich 310417)(0.5925g、2.59mmol)のCH3CN(無水)(50mL)の溶液を0℃でNO2AtBu(1.0087g、2.82mmol)のCH3CN溶液(50mL)に滴加した。4時間後、無水K2CO3(0.1008g、0.729mmol)を反応混合物に添加し、室温で一晩中撹拌させた。溶媒を蒸発させ、粗混合物を分取RP−HPLCによって精製して白色固体を生じた(0.7132g、54.5%)。
18F標識化
凍結乾燥されたペプチドの収率への充填剤の影響
標識化の経時変化
IMP485単独の生体内分布
TF2 DNL標的化分子によるIMP485の前標的化
実施例32.画像化のためのIMP485のキット製剤
試薬リスト
ペプチドキットの製剤
18Fの精製
放射性標識化
表21.充填剤の放射性標識化収率への影響
pHの放射性標識化への影響
IMP490の合成
IMP491(Al19F IMP490)の合成
IMP493の合成
NODA−MPAA−(PEG)3−Gln−Trp−Ala−Val−Gly−His−Leu−Met−NH2(配列番号:39)
IMP494(Al19F IMP493)の合成
実施例33.Al18FまたはAl19Fを用いた他の補欠分子族標識化方法
生理食塩水中の18Fによるキットの放射性標識化
実施例34.18F標識化のためのNOTAのマレイミド共役体
ビス−t−ブチル−NODA−MPAA NHSエステル:(tBu)2NODA−MPAA NHSエステルの合成
NODA−MPAEM:(MPAEM=メチルフェニルアセトアミドエチルマレイミド)
NODA-MPAEMの18F標識化
0.978mCi→92.5%のAl18F(NODA−MPAEM)
実施例34.hMN14F(ab’)2の調製および標識化
Claims (21)
- 分子を18Fまたは19Fによって標識する方法であって、
前記18Fまたは前記19Fと第IIIA族金属との錯体をキレート部分に結合させるステップを含み、
前記キレート部分が、NODA−MPAAまたはNODA−MPAEMであり、
前記キレート部分が前記分子に結合しているか、または前記キレート部分を前記ステップの後に前記分子に結合させる、方法。 - 前記分子が、抗体、モノクローナル抗体、二重特異的抗体、多重特異的抗体、抗体融合タンパク質および抗原結合抗体フラグメントからなる群から選択される標的化分子である、請求項1に記載の方法。
- 前記キレート部分が、前記分子に結合している、請求項1に記載の方法。
- 前記キレート部分を、前記ステップの後に前記分子に結合させるものであり、
前記キレート部分を前記分子に結合させるステップをさらに含む、請求項1に記載の方法。 - 前記第IIIA族金属が、アルミニウム、ガリウム、インジウム、およびタリウムからなる群から選択される、請求項1に記載の方法。
- 前記第IIIA族金属が、アルミニウムである、請求項1に記載の方法。
- 前記18Fまたは前記19Fで標識された分子が、前記方法の開始から30分未満で生成される、請求項1に記載の方法。
- 前記錯体を、水性媒体中で前記キレート部分に結合させる、請求項1に記載の方法。
- 有機溶媒を前記水性媒体に添加して、前記錯体を前記キレート部分に結合させる、請求項8に記載の方法。
- 前記錯体を、マイクロ波照射によって前記キレート部分に結合させる、請求項1に記載の方法。
- 前記錯体を、加熱によって前記キレート部分に結合させる、請求項1に記載の方法。
- 前記キレート部分を、クリックケミストリー反応によって前記分子に結合させる、請求項4に記載の方法。
- 前記キレート部分を、マレイミド−スルフヒドリル反応によって前記分子に結合させる、請求項4に記載の方法。
- 前記キレート部分が標的化可能な構築物に結合しており、
前記構築物の比放射能が、少なくとも115GBq/μmolである、請求項1又は2に記載の方法。 - 前記キレート部分が標的化可能な構築物に結合しており、
前記構築物が、放射性標識前に貯蔵のために凍結乾燥される、請求項1又は2に記載の方法。 - 前記構築物が、ソルビトール、マンニトールおよびトレハロースからなる群から選択される充填剤中で凍結乾燥される、請求項15に記載の方法。
- NODA−MPAAまたはNODA−MPAEMを含む組成物。
- 前記NODA−MPAAまたは前記NODA−MPAEMが、分子に結合している、請求項17に記載の組成物。
- 前記NODA−MPAAまたは前記NODA−MPAEMが、金属−18Fと錯体化されている、請求項17に記載の組成物。
- 前記NODA−MPAAまたは前記NODA−MPAEMが、A1−18Fと錯体化されている、請求項17に記載の組成物。
- 前記NODA−MPAAまたは前記NODA−MPAEMが、68Gaと錯体化されている、請求項17に記載の組成物。
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US30228010P | 2010-02-08 | 2010-02-08 | |
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US31612510P | 2010-03-22 | 2010-03-22 | |
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US38172010P | 2010-09-10 | 2010-09-10 | |
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US38826810P | 2010-09-30 | 2010-09-30 | |
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PCT/US2010/058724 WO2011068965A1 (en) | 2009-12-04 | 2010-12-02 | Methods and compositions for improved f-18 labeling of proteins, peptides and other molecules |
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US8444956B2 (en) | 2013-05-21 |
WO2011068965A1 (en) | 2011-06-09 |
IN2012DN03177A (ja) | 2015-09-25 |
CN102666567A (zh) | 2012-09-12 |
CA2782223A1 (en) | 2011-06-09 |
EP2507254A4 (en) | 2013-12-04 |
US20110110854A1 (en) | 2011-05-12 |
US8617518B2 (en) | 2013-12-31 |
AU2010326004A1 (en) | 2012-05-17 |
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