JP2012519176A - タンパク質標識方法及び組成物 - Google Patents
タンパク質標識方法及び組成物 Download PDFInfo
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Images
Classifications
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- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
- A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
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- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
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- A61K51/1027—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against receptors, cell-surface antigens or cell-surface determinants
- A61K51/103—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against receptors, cell-surface antigens or cell-surface determinants against receptors for growth factors or receptors for growth regulators
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
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- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
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Abstract
Description
米国特許法施行規則第37条1.53(b)に基づき出願されたこの非仮出願は、出典明示により全体が援用される2009年2月27日出願の米国仮出願第61/156165号の米国特許法第119条第(e)項の優先権を主張する。
本発明は一般にタンパク質に基をコンジュゲートし又は標識する方法に関する。本発明はまた新規な治療薬及び診断試験の研究及び臨床開発のための標識タンパク質、標識タンパク質を調製するために有用な中間体及び試薬にも関する。
本発明の一態様は、標識用試薬とタンパク質を反応させて標識されたタンパク質を形成することを含むタンパク質の標識方法を含む。標識用試薬には、
が含まれ、ここで、n及びmは独立して2から12の整数から選択される。
本発明のある実施態様を詳細に参照するが、その例を添付の構造及び式で例証する。本発明を列挙する実施態様に関連して説明するが、それらは本発明をその実施態様に限定することを意図するものではないことは理解されよう。それどころか、本発明は特許請求の範囲によって定まる本発明の範囲に含まれうるあらゆる代替例、変形例、及び均等物を包含することが意図される。当業者であれば、本発明の実施において使用されうるここに記載のものと同様な又は均等な多くの方法及び材料が分かるであろう。本発明は記載された方法及び材料に決して限定されるものではない。
他の記載がなければ、次の用語及び語句は次の意味を有するものである:
「タンパク質」は直鎖状に配置され、隣接するアミノ酸残基のカルボキシル及びアミノ基間のペプチド結合によって互いに接合されたアミノ酸から構成される有機化合物である。タンパク質は生物学的な巨大分子であり、酵素及び抗体を含む。多くのタンパク質は代謝、細胞シグナル伝達、免疫反応、細胞接着、細胞周期作用に非常に重要であり、又は筋肉及び細胞骨格におけるように、構造的な又は機械的な機能を有している。例示的なタンパク質の機能的クラスには、抗体、非抗体代替結合タンパク質(Binz 等(2005) Nature Biotechnology 23(10):1257-1268;Skerra, A. (2007) Current Opin. in Biotech. 18:295-304)、インターフェロン、リンホカイン、サイトカイン、ホルモン、又は増殖因子が含まれる。
本発明は、18Fをタンパク質に効率的に導入することができる様々な水溶性補欠分子族の迅速な調製のためのモジュラープラットホームを含む(Gill等(2009)Jour. Med. Chem. 52(19):5816-5825)。このプラットホームの有用性は、2工程のワンポット合成で迅速に製造される標識用試薬[18F]FPEGMA5とチオール特異的補欠分子族とによって実証される(図1)。加えて、水溶解度とその結果の水性条件下でのタンパク質との[18F]FPEGMAのコンジュゲーション効率を促進させるために、ポリエチレングリコール(PEG)ベースの「構築ブロック」を使用した。[18F]FPEGMA5は4D5チオFabでの補欠分子族として評価され、得られたコンジュゲート(18F−4D5チオFab)は、Hsp90阻害剤によって調節されるヒト腫瘍異種移植マウスモデルでのHER2発現レベルの造影剤としてインビボで確認された(Smith-Jones等(2006) J Nucl Med 47:793-6;Smith-Jones等(2004)Nat Biotechnol 22:701-6)。
(上式中、nは2から12の整数である)
を持つ18F−PEG−アルキン試薬と、銅触媒の存在下で反応し、標識されたタンパク質を形成しうる。
ペプチド標識法はよく知られている。Haugland, 2003, Molecular Probes Handbook of Fluorescent Probes and Research Chemicals, Molecular Probes, Inc.;Brinkley, 1992, Bioconjugate Chem. 3:2;Garman, (1997) Non-Radioactive Labelling: A Practical Approach, Academic Press, London; Means (1990) Bioconjugate Chem. 1:2;Glazer 等(1975) Chemical Modification of Proteins. Laboratory Techniques in Biochemistry and Molecular Biology (T. S. Work及びE. Work編) American Elsevier Publishing Co., New York;Lundblad, R. L.及びNoyes, C. M. (1984) Chemical Reagents for Protein Modification, Vols. I and II, CRC Press, New York;Pfleiderer, G. (1985) “Chemical Modification of Proteins”, Modern Methods in Protein Chemistry, H. Tschesche, Ed., Walter DeGryter, Berlin and New York;及びWong (1991) Chemistry of Protein Conjugation and Cross-linking, CRC Press, Boca Raton, Fla.);De Leon-Rodriguez 等(2004) Chem.Eur. J. 10:1149-1155;Lewis 等(2001) Bioconjugate Chem. 12:320-324;Li 等(2002) Bioconjugate Chem. 13:110-115;Mier 等(2005) Bioconjugate Chem. 16:240-237を参照のこと。
本発明の標識されたシステイン操作抗体は、例えば(i)MRI(磁気共鳴画像);(ii)マイクロCT(コンピュータ断層撮影);(iii)SPECT(単一光子放射型コンピュータ断層撮影法);(iv)PET(ポジトロン放出断層撮影) Chen等(2004) Bioconjugate Chem. 15:41-49;(v)バイオルミネセンス;(vi)蛍光;及び(vii)超音波のような生物医学的及び分子イメージングの様々な方法及び技術によって、イメージング生物マーカー及びプローブとして有用である。免疫シンチグラフィーは放射性物質で標識された抗体を動物又はヒト患者に投与し、抗体が局在化している身体の部位の写真を撮るイメージング方法である(米国特許第6528624号)。イメージングバイオマーカーは客観的に測定され、通常の生物学的過程、病原性過程又は治療的介入への薬理学的応答の指標として評価されうる。バイオマーカーは幾つかのタイプでありうる:タイプ0は疾患の天然の履歴マーカーであり、既知の疾患の指標、例えば関節リウマチにおける関節滑膜炎症のMRI評価と長期的に相関する;タイプIマーカーは、機序が臨床結果とは関係していない場合があるとしても、作用機序に従って介入の影響を捕らえる;タイプIIマーカーは、バイオマーカーの変化又はそれからのシグナルが、CTにより関節リウマチにおいて測定された骨びらんのような、標的応答を「確証する」臨床的恩恵を予測する代替エンドポイントとして機能する。よって、イメージングバイオマーカーは、(i)標的タンパク質の発現、(ii)治療薬の標的タンパク質への結合、つまり選択性、及び(iii)クリアランス及び半減期の薬物動態学的データについての薬物動力学(PD)的な治療上の情報を提供しうる。研究室ベースのバイオマーカーに対するインビボイメージングバイオマーカーの利点は、非侵襲的処置、数量化可能な、全身のアセスメント、反復投薬及びアセスメント、つまり複数時点、及び前臨床(小動物)から臨床(ヒト)結果への潜在的に伝達可能な効果を含む。幾つかの用途では、バイオイメージングは、前臨床研究における動物実験に取って代わり又はその数を最小にする。
本発明の薬学的組成物又は製剤は、本発明の標識されたタンパク質、及び一又は複数の薬学的に許容可能な担体、流動促進剤、希釈剤、又は賦形剤を含む。
この発明の範囲にまた入るものはここに記載される標識されたタンパク質のインビボでの代謝産物である。そのような産物は、例えば投与された化合物の酸化、還元、加水分解、アミド化、脱アミド化、エステル化、脱エステル化、酵素分解等々から生じうる。従って、本発明は、本発明の化合物を、その代謝産物を生じるのに十分な時間、哺乳動物に接触させることを含む方法によって産生される化合物を含む標識されたタンパク質の代謝産物を含む。代謝産物の構造は常套的な方法、例えばMS、LC/MS又はNMR分析によって決定されうる。一般に、代謝産物の分析は当業者によく知られた一般的な薬剤代謝研究と同じ方法でなされる。代謝産物は、それらがインビボで見出される等がない限り、本発明の化合物の治療用投薬の診断アッセイにおいて有用である。
本発明の他の実施態様では、疾患及び障害の診断に有用な標識されたタンパク質を含む製造品、又は「キット」が提供される。一実施態様では、キットは標識されたタンパク質を含む容器を含む。該キットは容器上に又は容器に付随してラベル又はパッケージ挿入物を更に含みうる。「パッケージ挿入物」なる用語は、診断製品の商業的パッケージに常套的に含まれる説明書であって、用法、用量、投与法、禁忌及び/又はこのような治療製品の使用に関する警告についての情報を含むものを指すために使用される。適切な容器には、例えば、ビン、バイアル、シリンジ、ブリスターパック等が含まれる。容器は、ガラス又はプラスチックなどの様々な材料から形成されうる。容器は、標識されたタンパク質又はその製剤を収容し、無菌のアクセスポートを有し得る(例えば、容器は皮下注射針で貫通可能なストッパーを有する静脈内溶液バッグ又はバイアルでありうる)。組成物中の少なくとも一種の活性剤は標識されたタンパク質である。一実施態様では、ラベル又はパッケージ挿入物は異常な細胞増殖に起因する疾患の診断に使用可能な標識されたタンパク質を含む。ラベル又はパッケージ挿入物はまた組成物が他の疾患を治療するのに使用できること示しうる。あるいは、又は加えて、製造品は、注射用静菌水(BWFI)、リン酸緩衝生理食塩水、リンゲル液及びデキストロース溶液等の薬学的に許容可能なバッファーを含む第2の容器を更に含んでいてもよい。それは、他のバッファー、希釈剤、フィルター、針、及びシリンジを含む商業的及び使用者の観点から望ましい他の材料を更に含みうる。キットには標識されたタンパク質の薬学的な製剤の投与のための指示書も更に含む。
水素化ナトリウムの鉱油中60%分散液(0.86g、21.4mmol)を少しずつ0℃の無水THF(40mL)中のヘキサエチレングリコール(5.5g、19.4mmol)の溶液に加えた。反応混合物を0℃で15分間攪拌した後、トルエン中80%(2.4mL、21.4mmol)の臭化プロパルギルを滴下して加えた。混合物を室温まで温め、3時間攪拌した。形成された臭化ナトリウムを濾過によって除き、溶媒を蒸発させた。粗生成物をメタノール/ジクロロメタン勾配0−100%を使用するSiO2カラムで精製し、3.4g(54%)の1を無色の油として得た。1H NMR(500MHz,CDCl3):δ2.45(t,J=2.4Hz,1H),2.74(bs,1H),3.61−3.71(m,24H),4.21(d,J=2.4Hz,2H);13CNMR(100.6MHz,CDCl3):δ58.4,61.7,69.1,70.3−70.6,72.5,74.5,79.7;MS ESI(m/z):[M+H]+C15H29O7に対する計算値,321.38;実測値321.4。
アゾジカルボン酸ジイソプロピル(730μL、3.43mmol)を無水THF(20mL)中の3,6,9,12,15,18-ヘキサオキサヘニコス-20-イン-1-オール1(1000mg、3.12mmol)、トリフェニルホスフィン(900mg、3.43mmol)及びマレイミド(456mg、4.70mmol)の氷冷溶液に窒素雰囲気下で滴下して加えた(図3)。生じた茶色の溶液を室温まで温め、室温で1時間攪拌した。溶媒を減圧下で蒸発させ、粗生成物をヘキサン/酢酸エチル勾配0−100%を使用するSiO2カラムで精製して650mgの黄色油を得、これを続いて半分取HPLC(システムE)で精製して、トリフェニルホスフィン酸化物を含まない2を無色の油として310mg(25%)得た。1H NMR(400MHz,CDCl3):δ2.43(t,J=2.36Hz,1H),3.60−3.72(m,24H),4.20(d,J=2.37Hz,2H),6.70(s,2H);13C NMR(100.6MHz,CDCl3):δ37.2,58.4,67.8,69.1,70.1,70.4−70.6,74.5,79.7,134.1,170.6;MS ESI(m/z):[M+H]+,C19H30NO8に対する計算値,400.19;実測値400.0
ピリジン(4mL)中の23-アジド-3,6,9,12,15,18,21-ヘプタオキサトリイコサン-1-オールの溶液(800mg、2.02mmol)をピリジン(10mL)中の塩化トルエンスルホニル(771mg、4.04mmol)及び4-ジメチルアミノピリジン(100mg)の溶液に室温で滴下して加えた。混合物を24時間、室温で攪拌した。溶媒を蒸発させ、粗生成物を、ヘキサン/酢酸エチル0−100%勾配と、続いて酢酸エチル/メタノール勾配0−100%を使用するの勾配でSiO2カラムで精製し、ついで半分取HPLC(システムE)で精製し、280mg(25%)の3を無色の油として得た。1H NMR(400MHz,CDCl3):δ2.45(s,3H),3.38(t,J=5.02Hz2H),3.58−3.70(m,28H),4.16(t,J=5.00Hz,2H),7.34(d,J=8.4Hz,2H),7.80(d,J=8.4Hz,2H);13C NMR(100.6MHz,CDCl3):δ21.6,50.7,68.7,69.2,70.0,70.5−70.8,128.0,129.7,133.1,144.7;MS ESI(m/z):[M+H]+C23H39N3O10Sに対する計算値549.24;実測値549.9。
23-アジド-3,6,9,12,15,18,21-ヘプタオキサトリイコサン-1-オール(500mg、1.26mmol)をDCM(2mL)に溶解させ、−10℃に冷却した。DAST(482μL、3.78mmol)を冷却溶液に徐々に加え、得られた混合物を−10℃で30分間攪拌した後、室温まで温め、更に20時間攪拌した。過剰のDASTをメタノール(5mL)でクエンチし、溶媒を続いて減圧下で蒸発させた。油性の残留物を水(3mL)に溶解し、NaHCO3を使用してpHを5に調節した。粗生成物を半分取HPLC(システムE)で精製し、122mg(24%)の4を黄色油として得た。1H NMR(500MHz,CDCl3):δ3.39(t,J=5.0Hz,2H),3.65−3.68(m,26H),3.75(dt,J=4.2Hz,29.6Hz,2H),4.56(dt,J=4.0Hz,47.5Hz,2H);13C NMR(125.7MHz,CDCl3):δ50.8,70.1,70.4,70.5,70.7−70.8,70.9,83.2(d,J=169Hz);19F NMR(470.6MHz,CDCl3):δ−225.9;MS ESI(m/z):[M+H]+C16H33FO7N3に対する計算値,398.2;実測値398.0。
アセトニトリル(0.1mL)に溶解したCu(MeCN)4PF6(7.5mg、0.02mmol)をアセトニトリル(0.2mL)中の1-(3,6,9,12,15,18-ヘキサオキサヘニコス-20-イン-1-イル)-2,5-ピロールジオン2(8.0mg、0.02mmol)、23-アジド-1-フルオロ-3,6,9,12,15,18,21-ヘプタオキサトリコサン4(8.0mg、0.02mmol)、2,6-ルチジン(2.5μL、0.02mmol)及びTBTA(2.0mg、0004mmol)の溶液に室温で加えた。生じた混合物を22時間室温で攪拌した後、水で4mLまで希釈し、形成された沈殿物を濾過により除去した。生成物を含む濾過物を半分取HPLC(システムE)で精製して、7.5mg(47%)の5(FPEGMA)を無色の油として得た。1H NMR(500MHz,CDCl3):δ3.58−3.80(m.50H),3.87(t,J=4.5Hz,2H),4.53(t,J=5.0Hz,2H),4.55(dt,J=47.3,4.2Hz,2H),4.68(s,2H),6.70(s,2H),7.73(s,1H);13C NMR(125.7MHz,CDCl3):δ37.2,50.3,64.7,67.9,69.5,69.7,70.2,70.6−70.7,70.9,83.2(d,J=169Hz),123.8,134.2,145.0,170.7;19FNMR(470.6MHz,CDCl3):δ−225.8;MS ESI(m/z):[M+H]+C35H62FO15N7に対する計算値,797.4;実測値797.4;HPLC(システムA)保持時間2.91分。
SPE樹脂床体積と共に増加し、長時間樹脂床上に該産物が残った場合に増加した。よって、[18F]5は小体積のPhenomenex Strata−X60mgカートリッジから速やかに溶出され、これが良好な回収率及び許容可能な不純物レベルをもたらした。
4D5−チオFabを、過去に記載された手順(Junutula, J.R. 等(2008) J Immunol Methods 332:41-52;米国特許出願第2007/0092940号)と同様にして調製した。システイン置換を、部位特異的変異誘発によってトラスツズマブ(4D5、ハーセプチン)抗体コンストラクトの軽鎖のVal110位に導入した。発現されて精製された4D5−チオMabを25mMトリス(pH8.0)中の1mg/mLまで希釈し、酵素対抗体比が1:1000(wt:wt)のLys−C(Wako)を使用して37℃で1時間酵素的に消化させた。5μMのプロテアーゼ阻害剤トシル−L−リジンクロロメチルケトン(TLCK)で消化を停止し、50mMの酢酸ナトリウムバッファー及び0−300mMのNaCl 10CV勾配を使用して5mLのHi−トラップSP FFカラム(GE Healthcare)で陽イオン交換クロマトグラフィーによって精製した。単離したチオFabをついで還元及び酸化手順によるコンジュゲーションのために調製し、Cys110に結合したジスルフィド付加物を除去した。先ず、タンパク質を25mのMMES,pH5.8、300mLのNaCl、及び5mMのEDTAを含むバッファー中の2mMのトリス(2−カルボキシエチル)ホスフィン(TECP)(Pierce)を加えることによって24時間かけて還元した。還元後、タンパク質を5mMのデヒドロアスコルビン酸(Sigma)を添加して酸化させ、S200カラム(GE Healthcare)、及び25mMのMES,pH5.8、300mMのNaCl、及び5mMのEDTAを含むバッファーを使用するゲル濾過によって精製した。単離したタンパク質をSDS−PAGE及び質量分析法によって分析し、タンパク質が適切に還元され、酸化されたことを確認した。
アジ化ナトリウム(0.47g、7.24mmol)をDMF(30mL)中のジエチレングリコールジトシレート(3g、7.24mmol)の溶液に加え、生じた混合物を110℃で5時間加熱した。反応混合物を冷却水(125mL)に注ぎ、生成物を酢酸エチル(3×100mL)で抽出し、収集した有機抽出物を水(3×100mL)、ブラインで洗浄し、MgSO4で乾燥させた。粗生成物をSiO2で溶離剤としてDCM/MeOH0−100%勾配で精製し、0.34g(16%)の7を無色の油として得た。1H NMR(400MHz,CDCl3):δ2.45(s,3H),3.16(t,J=4.8Hz,2H),3.60(t,J=4.8Hz,2H),3.70(t,J=4.8Hz,2H),4.17(t,J=4.8Hz,2H),7.35(d,J=8Hz,2H),7.81(d,J=8Hz,2H);13C NMR(100.6MHz,CDCl3):δ21.6,50.6,68.7,69.1,70.2,128.0,129.9,133.0,144.9;MS ESI(m/z):[M+H]+ C11H15N3O4Snに対する計算値,286.08;実測値286.1
アジ化ナトリウムとテトラエチレングリコールジトシレートを実施例7pに従って反応させ、0.7g(19%)の8を無色の油として得た。1H NMR(400MHz,CDCl3):δ2.44(s,3H),3.38(t,J=5.2Hz,2H),3.55−3.70(m,12H),4.16(t,J=5.2Hz,2H),7.34(d,J=8.4Hz,2H),7.78(d,J=8.4Hz,2H);13C NMR(100.6MHz,CDCl3):δ21.6,50.7,68.7,68.8,69.2,70.0,70.6−70.7,127.9,129.8,133.1,144.7MS ESI(m/z):[M+H]+C15H24O6N3Sに対する計算値,374.2;実測値374.2
DCM(5mL)中の20-アジド-3,6,9,12,15,18-ヘキサオキサイコサン-1-アミン(NH2-PEG6-N3(0.5g、1.43mmol)とトリエチルアミン(0.2mL、1.43mmol)の溶液をDCM(10mL)中の臭化ブロモアセチル(0.190mL、2.15mmol)の冷却(0℃)溶液に滴下して加えた。冷浴を取り除き、混合物を90分間攪拌した。溶液を氷水(10mL)に注ぎ、DCM(2×10mL)で抽出した。収集した有機抽出物をブラインで洗浄し(2×10mL)、MgSO4で乾燥させた。溶媒を蒸発させ、粗生成物をSiO2でのフラッシュクロマトグラフィーを使用し溶離剤としてDCM/MeOH上の0−100%の勾配で精製して、0.66g(98%)の9を黄色の油として得た。1H NMR(400MHz,CDCl3):δ3.39(t,J=4.8Hz,2H),3.47−3.51(m,2H),3.60(t,J=5.2Hz,2H),3.63−3.69(m,22H),3.88(s,1H),7.07(bs,1H),13C NMR(100.6MHz,CDCl3):δ29.1,40.0,50.6,69.4,70.0,70.4,70.6−70.7,165.8;MS ESI(m/z):[M+H]+C16H32BrO7N4,471.1に対する計算値,473.1;実測値471.0,473.0
DCM(5mL)中の20-アジド-3,6,9,12,15,18-ヘキサオキサイコサン-1-アミン(NH2-PEG7-N3,0.5g,1.43mmol)及びヨード酢酸N-サクシニミジル(0.4g,1.43mmol)の溶液を室温で2時間攪拌した。溶媒を蒸発させ、粗生成物を、0−100%のDCM/MeOH勾配を用いたSiO2でのフラッシュクロマトグラフィーで精製して、0.44g(60%)の9aを黄色油として得た;MS ESI(m/z):[M+H]+C16H32IO7N4に対する計算値519.34;実測値519.4.1H NMR(400MHz,CDCl3):δ3.39(t,J=5.2Hz,2H),3.44−3.48(m,2H),3.58(t,J=5.2Hz,2H),3.63−3.69(m,22H),3.74(s,2H),7.10(bs,1H).13C NMR(100.6MHz,CDCl3):δ26.0,40.9,51.3,70.0,70.6−71.3,168.5不明瞭
実施例3に従って3,6,9,12,15,18-ヘキサオキサヘニコス-20-イン-1-オール1と塩化トルエンスルホニルを反応させ、0.5g(47%)の10を無色の油として得た。1H NMR(400MHz,CDCl3):δ2.42(t,J=2.4Hz,1H),2.45(s,3H),3.58−3.70(m,22H),4.16(t,J=5.0Hz,2H),4.20(d,J=2.4Hz,2H),7.34(d,J=8.0Hz,2H),7.80(d,J=8Hz,2H);13C NMR(100.6MHz,CDCl3):δ21.6,58.4,68.7,69.1,70.4−70.7,74.5,79.5,128.0,129.8,133.1,144.7;MS ESI(m/z):[M+H]+C22H35O9Sに対する計算値,475.19;実測値475.2。
ジエチレングリコール(3.0g、28.1mmol)と臭化プロパルギルを実施例1に従って反応させ、1.2g(30%)の11を無色の油として得た。1H NMR(400MHz,CDCl3):δ2.38(bs,1H),2.46(t,J=2.4Hz,1H),3.62(t,J=4Hz,2H),3.71−3.75(m,6H),4.22(d,J=2.4Hz,2H);MS ESI(m/z):[M+H]+C7H13O3に対する計算値,145.08;実測値145.3。
実施例3に従って3,6,-ジオキサノン-8-イン-1-オール11(1.2g、8.3mmol)と塩化トルエンスルホニルを反応させ、1.7g(68%)の12を無色の油として得た。1H NMR(400MHz,CDCl3):δ2.44(t,J=2.4Hz,1H),2.45(s,3H),3.60−3.65(m.4H),3.70(t,J=4.8Hz,2H),4.15−4.18(m,4H),7.35(d,J=8.0Hz,2H),7.80(d,J=8Hz,2H);13C NMR(100.6MHz,CDCl3):δ21.6,58.4,68.7,69.0,69.2,70.6,74.6,79.5,128.0,129.8,133.1,144.8;MS ESI(m/z):[M+H]+C14H19O5Sに対する計算値,299.09;実測値299.1。
[18F]フッ化物を、0.6mLのアセトニトリル/水1:1(v/v)中の10μLの1.3MのTBAHCO3(重炭酸テトラ−n−ブチルアンモニウム)を使用してT&Rカートリッジから4mLのv−バイアル中に溶出させた。水をアルゴン流(600ccm)下で60W、120℃でマイクロ波加熱によって共沸的に除去した後、無水アセトニトリル(4×0.7mL)を加えた。アセトニトリル(0.6mL)に溶解させた3,6,9,12,15,18-ヘキサオキサヘニコス-20-イン-1-イルp-トルエンスルホネート(プロパルギル-PEG6-OTs)10(2mg、4.2μmol)を加え、混合物を隔膜シールした容器内で40W、120℃で3分間マイクロ波加熱し、[18F]1-フルオロ-3,6,9,12,15,18-ヘキサオキサヘニコス-20-イン:
を得た。
5倍過剰の1-(3,6,9,12,15,18-ヘキサオキサヘニコス-20-イン-1-イル)-2,5-ピロールジオン2(0.4mg、1μmol)を4D5チオFab(10mg、0.2μmol、5mg/mL、50mMのリン酸ナトリウムpH7.2)に加え、37℃で1時間インキュベートした。溶液を10%酢酸でpH4〜5に調節し、100mMの塩化ナトリウムと共に50mMのトリスバッファーpH8を用いてHiTrap SP FFカラム(GE Healthcare)で陽イオン交換クロマトグラフィーによって精製した。回収したプロパルギル修飾された4D5チオFab(100ug)のアリコートを乾燥[18F]23-アジド-1-フルオロ-3,6,9,12,15,18,21-ヘプタオキサトリコサン4に加え、続いて脱気したバッファー(250uLトリス(pH8))中の1.2mgのBPDS及び20uLのアセトニトリル中の0.26mgのCu(MeCN)4PF6を加えた。大気中の酸素をアルゴンでの反応系から除外した。しかしながら、反応は10分経過すると濃い茶色から無色へ変わり、これは反応が酸素によってクエンチされ、更に厳密な脱気条件が必要とされることを示している。
6〜8週齢のベージュヌードXIDマウスをHarlan Sprague Dawley(Livermore、CA)から取得した。細胞播種の3日前に、マウス(皮下、左側腹部)に0.36mgの60日の徐放性の17β−エストラジオールペレット(Innovative Reseach of America)を移植し、血清エストロゲンレベルを維持した。50%のフェノールレッド非含有マトリゲル中、5×106のBT474のサブクローンのBT474M1細胞(California Pacific Medical Centerから入手)をマウスの乳腺脂肪パッドに播種した。動物の世話及び処置は、国際実験動物管理公認協会(AAALAC)によって公認されたジェネンテック社のアニマルケア及び使用委員会によって承認されたプロトコルに従った。
DCM(5mL)中の卵黄リン脂質(0.5g)を500mLの丸底フラスコに移し、溶媒を蒸発させ、残留物を減圧下で16時間保存した。デキストロース(25mL)の5%(m/v)溶液を乾燥リン脂質に加え、混合物を室温で60分間超音波処理し、乳白色のエマルジョンを得た。17−AAG(25mg)をDMSO(1mL)に溶解し、そのアリコート(0.25mL)を卵黄リン脂質エマルジョン(4.8mL)と混合し、室温で15分間超音波処理した。生じたエマルジョンを、先に記載されたようにして(Smith-Jones等(2006) J Nucl Med 47:793-6;Smith-Jones等(2004) Nat Biotechnol 22:701-6)、24時間の期間にわたって3回の1mL用量(各々50mg/kg)を腹腔内注射で、調製から30分に投与した。17−AAGは17-N-アリルアミノ-17-デメトキシゲルダナマイシンであり、あるタイプの白血病又は固形腫瘍を持つ特定の若年患者の癌治療において研究されている物質である。17−AAGは、また[(3S,5S,6R,7S,8E,10R,11S,12E,14E)-21-(アリルアミノ)-6-ヒドロキシ-5,11-ジメトキシ-3,7,9,15-テトラメチル-16,20,22-トリオキソ-17-アザビシクロ[16.3.1]ドコサ-8,12,14,18,21-ペンタエン-10-イル]カルバメート(CAS登録番号75747-14-7)とも称される。
マウスを3%のセボフルランで麻酔し、等張液(50−100μL)中の0.3−0.4mCiの18F−チオ4D5Fabを尾静脈カテーテルを介した静脈注射により接種させた。動物を通院まで温めたブランケット上で回復させた後、ケージに戻した。意識が回復して2時間後に、動物を3%のセボフルランで麻酔し、頭部を先に腹臥位でスキャナーベッドに置いた。体温を直腸プローブによって測定し、温かい空気で維持した。動的な60分スキャンを取得した。全身の画像再構成を最大事後確率アルゴリズム(MAP)を使用して得、最大値投影(MIP)をASIProソフトウェア(CTI分子イメージング)を用いてつくり出した。MAP再構成画像を使用し、ASIProソフトウェア(CTI分子イメージング)を用いて各対象臓器における定量的な活性レベルを得た。
Claims (22)
- タンパク質が遊離システインチオールを含む請求項1記載のタンパク質の標識方法。
- タンパク質の遊離システインチオールが標識用試薬と反応する請求項1記載のタンパク質の標識方法。
- タンパク質が、モノクローナル抗体、二重特異性抗体、マウス抗体、キメラ抗体、ヒト抗体、及びヒト化抗体から選択される抗体である請求項1に記載の方法。
- 抗体がFab断片である請求項9に記載の方法。
- Fab断片が4D5チオFabである請求項10に記載の方法。
- 銅触媒がCu(MeCN)4PF6又はCuSO4である請求項1に記載の方法。
- 標識されたタンパク質が抗原に結合する請求項19に記載の方法。
- 動物が腫瘍異種移植マウスモデルである請求項19に記載の方法。
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JP2016520529A (ja) * | 2013-03-15 | 2016-07-14 | カポン、ダニエル・ジェイ. | 非ペプチジル結合を含むハイブリッド免疫グロブリン |
JP2017518975A (ja) * | 2014-05-10 | 2017-07-13 | ソレント・セラピューティクス・インコーポレイテッドSorrento Therapeutics, Inc. | 化学的に固定された二重特異性抗体 |
JP2019041588A (ja) * | 2017-08-29 | 2019-03-22 | 大陽日酸株式会社 | 標識タンパク質の製造方法、標識ペプチドの製造方法、及びキット |
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CN102333548B (zh) | 2013-01-30 |
US8435488B2 (en) | 2013-05-07 |
JP5713923B2 (ja) | 2015-05-07 |
CA2752884A1 (en) | 2010-09-02 |
EP2400992A1 (en) | 2012-01-04 |
WO2010099273A1 (en) | 2010-09-02 |
US20100221176A1 (en) | 2010-09-02 |
ES2547712T3 (es) | 2015-10-08 |
EP2400992B1 (en) | 2015-07-22 |
SG173812A1 (en) | 2011-09-29 |
CN102333548A (zh) | 2012-01-25 |
US20130216475A1 (en) | 2013-08-22 |
US8865122B2 (en) | 2014-10-21 |
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