JP6856725B2 - 細胞内ターゲッティングのための硫酸化デンドリマーを有する治療複合体 - Google Patents
細胞内ターゲッティングのための硫酸化デンドリマーを有する治療複合体 Download PDFInfo
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- JP6856725B2 JP6856725B2 JP2019183222A JP2019183222A JP6856725B2 JP 6856725 B2 JP6856725 B2 JP 6856725B2 JP 2019183222 A JP2019183222 A JP 2019183222A JP 2019183222 A JP2019183222 A JP 2019183222A JP 6856725 B2 JP6856725 B2 JP 6856725B2
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Description
式:E−[G−L−D(OSO3 -M+)n]m
[式中、
Eは、治療又は診断エフェクター分子であり、
D(OSO3 -M+)nは、n個の硫酸基OSO3 -M+を担持するデンドリマーDであり、ここで前記硫酸基の数であるnは6〜96から選択され、
Mは、アニオン性硫酸基に対するカチオン性無機又は有機対イオンであり、
Lは、D及びE間のリンカー又はスペーサーであり、
Gは、LとEとの間に結合を形成する結合官能基であり、そして
mは、1〜20の整数である]で表される、複合体。
1.式:E−[G−L−D(OSO3 -M+)n]m
[式中、
Eは、治療又は診断エフェクター分子であり、
D(OSO3 -M+)nは、n個の硫酸基OSO3 -M+を担持するデンドリマーDであり、ここで前記硫酸基の数であるnは6〜96から選択され、
Mは、アニオン性硫酸基に対するカチオン性無機又は有機対イオンであり、
Lは、D及びE間のリンカー又はスペーサーであり、
Gは、LとEとの間に結合を形成する結合官能基であり、そして
mは、1〜20の整数である]で表される、複合体。
科学的には、複合体は、複数の化合物の連結により形成される化合物を言及する。本発明の記載及び請求項において使用される場合、用語「複合体(conjugate)」とは、式E−[G−L−D(OSO3 -M+)n]m、特にエフェクター分子E、結合官能基G、リンカーL、デンドリマーD、及びn個の硫酸基(OSO3 -M+)(ここで、Mは、カチオン性無機又は有機対イオンである)の要素を有する化合物が連結した群を意味し、ここでmは1〜20の整数である。
デンドリマーを、NaH/アリルブロミドによる交互アリル化及びジヒドロキシル化の4反応工程下で、公開された方法(Zieringer et al., Chem. Phys. Chem. 2010, 1 1, 2617 及びWyszogrodska et al, Eur. J. Org. Chem. 2008, 53)により、24個のヒドロキシ基を用いて、グリセロールモノマー(1,2−置換パターン)から成るデンドロンから構築する。生成物は、10−アジドデシル−グリセロール(OH24)(分子量1873g/mol)であり、これを次の工程で硫酸化する。
100mg(0.053mmol)の10−アジドデシルデンドロン(OH24)を、0.5mlの無水DMFに溶解し、そして60℃に加熱する。攪拌下で、SO3−ピリジン複合体(245mg、1.54mmol)を添加し、続いて60℃で5時間、及び室温で18時間、攪拌する。その反応混合物を、水により急冷し、1mMのNaOHを用いてpH9−10に調節し、濾過し、そして水による限外濾過(MWCO 1000)に供する。生成物10−アジドデシルデンドロン(OSO3 -Na+)24(150mg、65%)を、凍結乾燥の後、得る。元素分析は、完全な硫酸化を示した。N 0.863、C 21.70、S 17.83、 H 3.042、分子量 4322g/mol。
24個の硫酸基及びさらなる反応性リンカーを有するポリグリセロールデンドリマーシステムの合成を、アジド、プロパルギル、シクロオクチニル、ピリジニルジスルフィド、チオアセチル又はマレイミド基を含む、異なった二官能性PEG−COOH NHSエステルを用いることにより達成する。化合物d01との反応を、実施例2aに従って実施する(収率70−85%)。表2は、生成物d03〜d09を要約する。
他方では、アミノ基を、イソチオシアネート基に直接、転換することができる。10mg(2.33μmol)の化合物d01を、0.5mlのDMFに溶解し、そしてジ(2−ピリジル)−チオノカーボネート(1.1mg、4.66μmol)を添加し、続いて、40℃で6時間、振盪する。生成物d10を、実施例2aに記載のようにして、単離する。転換を、FTIR(2100Cm-1)(MW4338g/mol)によりモニターする。
水/DMF(1:1)の混合物1ml中、100mg(0.023mmol)のアジドデンドリマー(実施例1d)の溶液に、CuSO4・5H2O(5.7mg、0.023mmol)、アスコルビン酸(0.035mmol)及び(0.058mmol)プロパルギル−PEG4−COOtブチルエステル(Broadpharm Ltd., US)を添加し、そしてその混合物を80℃で18時間、攪拌する。凍結乾燥後に得られる残渣を、ジクロロメタン(5ml)、トリフルオロ酢酸(3ml)及び水(0.1ml)の混合物に懸濁し、40℃で5時間、攪拌し、遊離カルボン酸基を得る。蒸発の後、残渣を、メタノールに懸濁し、そしてジエチルエーテル下で沈殿し、ジクロロメタンにより洗浄し、そして遠心分離により単離する。残渣を、NaCl及び蒸留水に対して透析し(標準的セルロース、MWCC 1kDa)、凍結乾燥の後、80mgのカルボキシデンドリマー(MW4582g/mol)を得る。
実施例4a:アジドウンデシルリンカーによる、ポリグリセロールデンドロン[G3.0]−OH(Wyszogrodzka M. et al., Chemistry 2008, 14, 9202)に基づくポリグリセロールデンドリマーの修飾。
24個の硫酸基及びさらに、反応性リンカーを有するポリグリセロールデンドリマーの合成を、アジド、プロパルギル、シクロオクチニル、ピリジニルジスルフィド、チオアセチル又はマレイミド基を含む異なった二官能性PEG−COOH NHSエステルを用いることにより達成する。化合物d01との反応を、実施例2a/4cに従って行う(収率65−86%)。表3は、達成可能な生成物d13〜d17を要約する。
2mlのDMF中、11−アジドウンデカンカルボン酸(0.11g、0.5mmol)及びDIPEA(0.16g、1.2mmol)の溶液に、HBTU(0.2g、0.56mmol)を添加し、そしてその混合物を1時間、攪拌し、続いてアミノメチル−トリス(プロピオン酸)−トリス(トリグリセロールアミド)(0.3g、0.33mmol;実施例5a)を添加する。その混合物を、室温で48時間、攪拌し、蒸発乾燥し、そして水/メタノールを用いて、RP C−18クロマトグラフィー(Licroprep)により精製し;粘性油状物として、0.26g(71%)を得る。
24個の硫酸基及びさらなる反応性リンカーを有するポリグリセロール/アミドデンドリマー系の合成を、アジド、フロパルギル、シクロオクチニル、ピリジニルジスルフィド、チオセチル又はマレイミド基を含む異なった二官能性PEG−COOH NHSエステルを用いることにより達成する。化合物d01との反応を、実施例2a/4cに従って実施する(収率65−86%)。表4は、達成可能な生成物d19〜d22を要約する。別の選択肢は、遊離カルボン酸(生成物d22)を導入するために、既知方法により、無水物、例えばジグリコール酸無水物によるアミノ基の誘導体化、又はイソチオシアネート基(生成物d23;また実施例2iも参照のこと)へのアミノ基の転換である。
実勢例8a−c:シアニン色素によるアミノデンドリマー化合物d01、d12及びd18の複合体化。
実施例10a:24個の硫酸基及びアミノへキシルリンカーを有するポリグリセロールデンドリマー系(化合物d27)の合成。
化合物d27は、アミノへキシル基を有するd01と類似し、そして出発材料として1,6−ジブロモヘキサンを用いて、実施例1a−cに従って合成され;d27の分子量は、4240g/molである。
実施例11a:マレイミド基を有するデンドリマー系(d02、d03、dl3、dl4、dl9、d20)を用いての一般的複合体化方法。
1mlの50mMのリン酸緩衝液pH7.4/10mMのEDTA中、2mgのタンパク質の溶液と、10モル当量の2−イミノチオランとを、60分間、反応せしめる。この混合物に、14モル当量のマレイミド−官能化デンドリマー(例えば、d02、d03、dl3、dl4、dl9、d20)を添加し、続いて18時間インキュベートする。この混合物を、NAP 10カラム又はSlide−A−Lyzer 透析カセット (標準的セルロース、MWCO 10 kDa)を用いて、TRIS−緩衝生理食塩水(TBS:pH7.4)への精製に供する。
1mlの50mMのリン酸緩衝液pH7.4/10mMのEDTA中、2mgのタンパク質の溶液と、10モル当量の2−イミノチオランとを、60分間、反応せしめる。この混合物に、10mol当量のマレイミド−官能化デンドリマー(例えば、d04、d05、d15、d21)を添加し、続いて3時間インキュベートする。この混合物を、NAP 10カラム又はSlide−A−Lyzer 透析カセット (標準的セルロース、MWCO 10 kDa)を用いて、TRIS−緩衝生理食塩水(TBS:pH7.4)への精製に供する。
1mlのPBS(pH7.4)中、2mgのタンパク質の溶液と、10mol当量のイソチオシアネート又はNHSエステルデンドリマー(例えば、d10、d11、d23)とを、24時間、反応せしめる。この混合物を、NAP 10カラム又はSlide−A−Lyzer 透析カセット(標準的セルロース、MWCO 10 kDa)を用いて、TRIS−緩衝生理食塩水(TBS:pH7.4)への精製に供する。
実施例12a:マレイミド基を有するデンドリマー系(d02、d13、d19)と酵素L−アスパラギナーゼとの複合体化。
L−アスパラギナーゼは、各モノマー単位におけるジスルフィド架橋で修飾され得る、34kDaの分子量の4単位のホモテトラマーである(Balan et al., Bioconjugate Chem 2007, 18, 61)。L−アスパラギナーゼ(10mg、0.29μmolのモノマー;L−アスパラギナーゼ5000E、Medac、Germany)を、2mlの50mMのリン酸緩衝液pH8/10mMのEDTAに溶解する。ジチオトレイトール(DTT:80mg)を添加し、そしてその溶液を1時間、振盪する。過剰のDTTを、SEC(Sephadex G50; リン酸緩衝液pH8 / 10 mM のEDTA)を通して除去する。得られる溶液(UVにより測定される場合、4ml中、約8mg)に、約0.2mlの水中、2.3μmol(8モル当量)のマレイミドデンドリマー(例えば、d02、d13、d19)の溶液を添加し、続いて、軽く振盪しながら、24時間インキュベートする。精製を、限外濾過(Centriprep(登録商標)フラスコ、標準的セルロース、MWCO 20,000)により達成する。
合成を、実施例11aに記載のようにして達成し、TBS(pH7.4)中、溶液としてDNアーゼ−d02を得る。
1mlのPBS(pH7.4)中、2mg(65nmol)のDNアーゼ(牛膵臓由来のデオキシリボヌクレアーゼI、31Da)の溶液に、0.2mlのPBS中、5mol当量のイソチオシアネートデンドリマーd10(1.4mg)を添加し、続いて室温で18時間、反応せしめる。精製を、Float−A−Lyzer透析カセット(セルロースエステル、MWCO 10kDa)でTBS(pH7.4)中で行う。
実施例13a:モノメチルアウリスタチンEを有するデンドリマー複合体の合成。
ペプチド配列P1−P17(C末端アミドとして)を、一般的な固相ペプチド合成により合成した。それらのペプチドは、チオール基へのマレイミドデンドリマーの結合のためのN−末端システインを担持する。デンドリマー(d02、d03、dl3、d14、d19)への複合体化を実施した。例として、デンドリマーd02を用いる手順を記載する:1mgのペプチドを、200μlのDMFに溶解し、そしてさらに、50mMのリン酸緩衝液(500μlまでの)により希釈する。この溶液に、5mol当量のTCEP(水中、原液)を添加し、続いて、200−300μlの水に溶解された0.9モル当量のデンドリマーを添加する。その混合物を、25℃で18時間、軽く振盪する。精製を、HPLC(水/アセトニトリル)又はSEC(Sephadex LH−20、水/DMF)、又は両者の組み合わせにより実施し、表6に列挙される複合体を得る。
実施例14a:スタウロスポリンを有するデンドリマー複合体の合成。
ヒト癌細胞系A2780及びQGP−1を、RPMI培地において培養し、そして10%ウシ胎児血清(FCS)、2%グルタミン及びペニシリン/ストレプトマイシンを添加する。すべての細胞を、1×105個の細胞/mlで、培地に播種し、5%CO2下で37℃で培養し、そして週、2度、1:5に分割する。上皮ヒト癌細胞系A549、MCF7、HaCaT及びHepG2を、10%胎児FCS、2%グルタミン及びペニシリン/ストレプトマイシンを含む、DMEM培地(PAN Biotech)において培養した。細胞を、1×105個の細胞/mlで、培地中に播種する(5%CO2下で37℃、週2度、1:10に分割する)。細胞顕微鏡のために、細胞を、ガラスカバースリップ(Sigma)上の24−ウェル培養プレートに、2×105個の細胞/mlで播種し、37℃で24時間、培養し、次に、48個の硫酸基を有する、10-6MのICC−d01、ICC−d12、ICC−d18又はそれぞれの誘導体、又はタンパク質(実施例12及び13)又は10-6Mのグリセロール−ICC(対照)を有するデンドリマー複合体を含む培地において、37℃で24時間まで、培養する。その後、細胞を冷アセトンにより固定し、すすぎ、そして核対比染色のために、4,6−ジアミジノ−2−フェニルインドール(DAPI、Abcam)により被覆する。画像取得を、Leica DMRB顕微鏡(Leica)を用いて実施する。画像を、すべての画像に対して同じ露光時間で、デジタルカメラ(スポット32、Diagnostic Instruments)により撮影する。図8Aは、細胞質ゾル領域における細胞内分布の例を示す(ICC−d01、実施例8)。硫酸化デンドリマーにより介在される細胞取り込みを定量化するために、ICC−d01(実施例8)を用いて、10-6MのICC−d01と共に、107個のSKBR3腫瘍細胞を24時間インキュベートする。この量及び時間は、プールし、そしてDMSOによる細胞溶解の後、上清液を測定するのに十分である。図8Bは、得られる吸収スペクトル(ICC 消衰係数(559nm)150,000M-1cm-1)を示し、10-17mol/細胞が得られ、これは、細胞当たり約5Mio分子に相当する。
細胞毒性測定のために、2×105個の細胞を、上昇する濃度の試験物質を含む培地1mlと共にインキュベートした。72時間の処理の後、アポトーシス工程のパラメーターとしての細胞数、生存率及び細胞直径を、細胞カウンター及び分析装置システム(CASY(登録商標), Scharfe Systems)により分析した。さらに、薬物細胞毒性を、細胞の代謝活性についての試験としてMTTアッセイ(3−(4,5−ジメチルチアゾール−2−イル)−2,5−ジフェニルテトラゾリウムブロミド)を用いて、インビトロで評価した。ウェル当たり1×104個の細胞を、上昇する濃度の試験物質を含む培地100μlを含む96−ウェルプレート上に播種した。10μlのMTT(PBS中、5mg/ml、Sigmaから入手された)を、各ウェルに添加し、そしてプレートを、4時間、24時間、48時間又は72時間までインキュベートした。得られるホルマザン生成物を、酸イソプロパノールと共に溶解し、そして570nmの波長での吸光度(Ex570)を、マイクロプレート分光光度計 (Anthos htll, Microsystems)上で読み取った。いくつかの実験において、試験物質を有する培地を、48時間後、除き、細胞を計数し、そして試験物質を含まない新培地を用いて、同一の細胞数を、新しいプレートに播種した。MTTアッセイを、72時間のさらなるインキュベーションの後、実施した。
細胞培養測定を、実施例16に記載のようにして行った。表9は、異なったペプチド−デンドリマー複合体についての結果を示す。
FACSにより測定された細胞取り込みに対する研究を、実施例13に記載のようにして実施した。化合物Asp−d13を、QGP−1腫瘍細胞において、10-7Mの濃度で、3及び6時間インキュベートする。インキュベーションを、次の2種の基質の1つの存在下で実施する:(1)0.1mMのゲニステイン、すなわちエンドサイトーシス取り込みのためのインヒビター(Rejman et al.. Mol. Ther. 2005, 1 2, 468-474)、又は(2)50mMのリファマイシン、すなわち有機アニオントランスポータータンパク質を介しての取り込みのインヒビター(OATP; Bi et al, Drug Metab Dispos. 2012. 40, 1085-92)。その結果は、インヒビターを含まないAsp−d13に関するFACSシグナル(100%として定義される)は、リファマイシンの存在下で37−40%まで低下し、ところが有意な低下はゲニステインの存在下で測定され得られない(80−85%)ことを示し、データについては表10を参照のこと。ポリグリセロールスルフェート(12000Daの平均分子量;国際公開第2001/095311号に従って使用される)に結合されるL−アスパラギナーゼについては、エンドサイトーシスがゲニステインによる阻害のために同定され得る。
この実施例においては、サポリン複合体Sap−d02(実施例11)を、匹敵する分子量(6000 g/molでの平均値; Groger et al, Bioconjugatc Chem 2013, 24, 1507に従って合成される)を有するポリマー性の非特定の性質のポリグリセロールスルフェートを用いて類似複合体と比較する。このポリマーを、実施例2aに記載のようにしてリンカーマレイミド−PEG(4)−COOH NHSエステルにより官能化し、そしてさらに、RPクロマトグラフィーにより補正する。サポリンへの結合を、実施例11に記載のようにして達成する。比較細胞毒性測定を、実施例16に従って実施し、4つの異なる細胞系におけるMTT試験からのIC50値を得る(表11を参照のこと)。
実施例20a:
デンドリマーは、タンパク質及び抗体治療薬、並びに合成ペプチドにより、それらのポリアミノ酸がシステイン標識を提供される場合、複合体化され得、それにより、マレイミド、ピリジニルジスルフィド又は当業者に知られている他のチオール−選択性基(例えば、ブロモアセチル、ビニルスルホン)を担持するデンドリマーとのシステインへの化学選択的複合体化を可能にする。
N末端システイン又はシステインサロゲートを有するタンパク質を、ネイティブ化学連結(NCL)方法によりチオエステル部分を使用する他の高分子と融合することができる(Wong CT et al, Mol Biosyst. 2013, 9, 826-33)。驚くべきことには、硫酸化デンドリマーを、チオエステルとして合成することができ、そしてN末端システインを有するタンパク質へのNCL型複合体化を可能にする。
実施例21a:カルバルデヒド基を有する硫酸化デンドリマーd31の合成。
この工程は、50mMのリン酸緩衝液(pH7.0)中、2.5mg/mlのタンパク質溶液により実施される。一般的手順:1mgのタンパク質(0.4ml)及び3モル当量のデンドリマーd31の溶液を、水中、シアノ水素ホウ素ナトリウム(NaBH3CN)の原液により処理し、混合物中、1mMの最終濃度のNaBH3CNを得、これを20℃で48時間、軽く振盪する。精製を、TBS(pH7.4)中でのSlide-A-Lyzer透析カセット(セルロースエステル、MWCO 20kDa)において達成する。デンドリマー複合体化を、ゲル電気泳動により決定し、複合体へのタンパク質の50−70%の転換率を得る(デンドリマー:タンパク質の比は未知である)。使用されるタンパク質は、オボアルブミン、サポリン、ジフテリア毒素及び非特異的IgGであった。精製を、SEC HPLCにより行う。デンドリマー:タンパク質の比の分析を、ゲル電気泳動により実施する。
Claims (10)
- 式:E−[G−L−D(OSO3 −M+)n]mで表される、複合体
[式中、
Eは、治療又は診断エフェクター分子であり、
D(OSO3 −M+)nは、n個の硫酸基OSO3 −M+を担持するデンドリマーDであり、ここで前記硫酸基の数であるnは6〜96から選択され、
Mは、アニオン性硫酸基に対するカチオン性無機又は有機対イオンであり、
Lは、D及びE間のリンカー又はスペーサーであり、
Gは、LとEとの間に結合を形成する結合官能基であり、そして
mは、1〜20の整数であり、そして
前記複合体の各デンドリマーDは、同じ分子量を有し、そして
前記硫酸基の数nが各デンドリマーDについて同じであり、
ここでリンカー単位Lは、ある位置でデンドリマーDの焦点に共有結合され、それにより、この焦点から、デンドリマーは成長し、そのデンドリマー構造に達し、そして
デンドリマーD(OSO3 -M+)nは、M+がナトリウムイオンであるとする計算により、nと分子量との間で次の関係を有する:
ここで、前記エフェクター分子は、p19INK4D、GSK−3、myc、p16INK4A、p53、KRas、NRas、Hras、p27KIP1、GSK3 β、HER4、Src、PTEN、Bcl−2、Bcl−xL、mcl−1、Ataxin−1、カテニン、IRAK1、IRAK2、IRAK4、VEGFR1、ZAP70、Aurora A、Aurora B、及びAurora Cからなる群より選択される標的に結合するポリペプチドである、複合体。 - 式:E−[G−L−D(OSO3 −M+)n]mで表される、複合体
[式中、
Eは、治療又は診断エフェクター分子であり、
D(OSO3 −M+)nは、n個の硫酸基OSO3 −M+を担持するデンドリマーDであり、ここで前記硫酸基の数であるnは6〜96から選択され、
Mは、アニオン性硫酸基に対するカチオン性無機又は有機対イオンであり、
Lは、D及びE間のリンカー又はスペーサーであり、
Gは、LとEとの間に結合を形成する結合官能基であり、そして
mは、1〜20の整数であり、そして
前記複合体の各デンドリマーDは、同じ分子量を有し、そして
前記硫酸基の数nが各デンドリマーDについて同じであり、
ここでリンカー単位Lは、ある位置でデンドリマーDの焦点に共有結合され、それにより、この焦点から、デンドリマーは成長し、そのデンドリマー構造に達し、そして
デンドリマーD(OSO3 -M+)nは、M+がナトリウムイオンであるとする計算により、nと分子量との間で次の関係を有する:
ここで、前記エフェクター分子は、myc、Bcl−2、Bcl−xL、mcl−1、カテニン、及びp53からなる群より選択される標的に結合するポリペプチドである、複合体。 - 式:E−[G−L−D(OSO3 −M+)n]mで表される、複合体
[式中、
Eは、治療又は診断エフェクター分子であり、
D(OSO3 −M+)nは、n個の硫酸基OSO3 −M+を担持するデンドリマーDであり、ここで前記硫酸基の数であるnは6〜96から選択され、
Mは、アニオン性硫酸基に対するカチオン性無機又は有機対イオンであり、
Lは、D及びE間のリンカー又はスペーサーであり、
Gは、LとEとの間に結合を形成する結合官能基であり、そして
mは、1〜20の整数であり、そして
前記複合体の各デンドリマーDは、同じ分子量を有し、そして
前記硫酸基の数nが各デンドリマーDについて同じであり、
ここでリンカー単位Lは、ある位置でデンドリマーDの焦点に共有結合され、それにより、この焦点から、デンドリマーは成長し、そのデンドリマー構造に達し、そして
デンドリマーD(OSO3 -M+)nは、M+がナトリウムイオンであるとする計算により、nと分子量との間で次の関係を有する:
ここで、前記エフェクター分子は、BIM、BID、NOXA、PUMAからなる群より選択されるアポトーシス増感タンパク質に由来するα−ヘリックスペプチドである、複合体。 - 式:E−[G−L−D(OSO3 −M+)n]mで表される、複合体
[式中、
Eは、治療又は診断エフェクター分子であり、
D(OSO3 −M+)nは、n個の硫酸基OSO3 −M+を担持するデンドリマーDであり、ここで前記硫酸基の数であるnは6〜96から選択され、
Mは、アニオン性硫酸基に対するカチオン性無機又は有機対イオンであり、
Lは、D及びE間のリンカー又はスペーサーであり、
Gは、LとEとの間に結合を形成する結合官能基であり、そして
mは、1〜20の整数であり、そして
前記複合体の各デンドリマーDは、同じ分子量を有し、そして
前記硫酸基の数nが各デンドリマーDについて同じであり、
ここでリンカー単位Lは、ある位置でデンドリマーDの焦点に共有結合され、それにより、この焦点から、デンドリマーは成長し、そのデンドリマー構造に達し、そして
デンドリマーD(OSO3 -M+)nは、M+がナトリウムイオンであるとする計算により、nと分子量との間で次の関係を有する:
ここで、前記エフェクター分子は、
CGMRPEIWIAQELRRIGDEFNA
CGDMRPEIYI(Aib)QELRRIGD(Aib)Y
CGLSQEQLEHRERSLQTLRDIQRMLF
CGLSKEQLEHRERSLQTLRDIERLL
CGEEQWAREIGAQLRRMADDLNAQYER
CGEDIIRNIARHAAQVGASADRSI
CPKVVILKKATAYILSVQAEEQKL
からなる群より選択されるペプチドである、複合体。 - 式:E−[G−L−D(OSO3 −M+)n]mで表される、複合体
[式中、
Eは、治療又は診断エフェクター分子であり、
D(OSO3 −M+)nは、n個の硫酸基OSO3 −M+を担持するデンドリマーDであり、ここで前記硫酸基の数であるnは6〜96から選択され、
Mは、アニオン性硫酸基に対するカチオン性無機又は有機対イオンであり、
Lは、D及びE間のリンカー又はスペーサーであり、
Gは、LとEとの間に結合を形成する結合官能基であり、そして
mは、1〜20の整数であり、そして
前記複合体の各デンドリマーDは、同じ分子量を有し、そして
前記硫酸基の数nが各デンドリマーDについて同じであり、
ここでリンカー単位Lは、ある位置でデンドリマーDの焦点に共有結合され、それにより、この焦点から、デンドリマーは成長し、そのデンドリマー構造に達し、そして
デンドリマーD(OSO3 -M+)nは、M+がナトリウムイオンであるとする計算により、nと分子量との間で次の関係を有する:
ここで、前記エフェクター分子は、ジフテリア毒素、受容体結合活性を欠いているジフテリア毒素、シュードモナス外毒素A、受容体結合ドメインIaを欠いている切断形のシュードモナス外毒素、リシン毒素、サポリン、ジアンチン、ゲロニン、トリコサンチン、ヤマゴボウ抗ウィルスタンパク質(PAP)、ブーゲニン、炭疽防御抗原、αトキシン、アブリン、アポトーシス誘導ポリペプチドからなる群より選択される毒素ポリペプチドである、複合体。 - 式:E−[G−L−D(OSO3 −M+)n]mで表される、複合体
[式中、
Eは、治療又は診断エフェクター分子であり、
D(OSO3 −M+)nは、n個の硫酸基OSO3 −M+を担持するデンドリマーDであり、ここで前記硫酸基の数であるnは6〜96から選択され、
Mは、アニオン性硫酸基に対するカチオン性無機又は有機対イオンであり、
Lは、D及びE間のリンカー又はスペーサーであり、
Gは、LとEとの間に結合を形成する結合官能基であり、そして
mは、1〜20の整数であり、そして
前記複合体の各デンドリマーDは、同じ分子量を有し、そして
前記硫酸基の数nが各デンドリマーDについて同じであり、
ここでリンカー単位Lは、ある位置でデンドリマーDの焦点に共有結合され、それにより、この焦点から、デンドリマーは成長し、そのデンドリマー構造に達し、そして
デンドリマーD(OSO3 -M+)nは、M+がナトリウムイオンであるとする計算により、nと分子量との間で次の関係を有する:
ここで、前記エフェクター分子は、デオキシリボヌクレアーゼI(DNアーゼI)、デオキシリボヌクレアーゼII(DNアーゼII)、α−チューブリンを標的とするポリペプチド、β−チューブリンを標的とするポリペプチド、ダイニンを標的とするポリペプチド、キネシンを標的とする結合ポリペプチド、NEDD1を標的とするポリペプチド、トランスフォーミング酸性コイルド−コイルタンパク質TACCを標的とするポリペプチド、結腸肝腫瘍過剰発現遺伝子chTOGを標的とするポリペプチドからなる群より選択される毒素ポリペプチドである、複合体。 - 式:E−[G−L−D(OSO3 −M+)n]mで表される、複合体
[式中、
Eは、治療又は診断エフェクター分子であり、
D(OSO3 −M+)nは、n個の硫酸基OSO3 −M+を担持するデンドリマーDであり、ここで前記硫酸基の数であるnは6〜96から選択され、
Mは、アニオン性硫酸基に対するカチオン性無機又は有機対イオンであり、
Lは、D及びE間のリンカー又はスペーサーであり、
Gは、LとEとの間に結合を形成する結合官能基であり、そして
mは、1〜20の整数であり、そして
前記複合体の各デンドリマーDは、同じ分子量を有し、そして
前記硫酸基の数nが各デンドリマーDについて同じであり、
ここでリンカー単位Lは、ある位置でデンドリマーDの焦点に共有結合され、それにより、この焦点から、デンドリマーは成長し、そのデンドリマー構造に達し、そして
デンドリマーD(OSO3 -M+)nは、M+がナトリウムイオンであるとする計算により、nと分子量との間で次の関係を有する:
ここで、前記エフェクター分子はベバシズマブ又はIgGである、複合体。 - 式:E−[G−L−D(OSO3 −M+)n]mで表される、複合体
[式中、
Eは、治療又は診断エフェクター分子であり、
D(OSO3 −M+)nは、n個の硫酸基OSO3 −M+を担持するデンドリマーDであり、ここで前記硫酸基の数であるnは6〜96から選択され、
Mは、アニオン性硫酸基に対するカチオン性無機又は有機対イオンであり、
Lは、D及びE間のリンカー又はスペーサーであり、
Gは、LとEとの間に結合を形成する結合官能基であり、そして
mは、1〜20の整数であり、そして
前記複合体の各デンドリマーDは、同じ分子量を有し、そして
前記硫酸基の数nが各デンドリマーDについて同じであり、
ここでリンカー単位Lは、ある位置でデンドリマーDの焦点に共有結合され、それにより、この焦点から、デンドリマーは成長し、そのデンドリマー構造に達し、そして
デンドリマーD(OSO3 -M+)nは、M+がナトリウムイオンであるとする計算により、nと分子量との間で次の関係を有する:
ここで、前記エフェクター分子は、野生型p53、野生型p21、アポトーシス誘導因子1(AIF1)、ASK1、アポトーシス誘導タンパク質(AIP)、カスパーゼ−2、カスパーゼ−3、カスパーゼ−6、カスパーゼ−7、カスパーゼ−8、カスパーゼ−9、カスパーゼ−10、Bax、セリンプロテアーゼ、Smac、シトクロムc、Apaf−1、アポプチンから選択されたタンパク質である、複合体。 - (i)癌、炎症、自己免疫疾患、代謝性疾患及び線維症を包含する群より選択される疾患の治療における、又は(ii)抗増殖性、増殖促進性、抗アポトーシス性、アポトーシス促進性、抗線維性、線維化促進性、抗脂質生成性、抗糖尿病性、免疫刺激性及び抗加齢性の治療を包含する群より選択される治療における使用のための、請求項1〜8のいずれか1項に記載の複合体。
- 請求項1〜9のいずれか1項に記載の複合体を含む医薬組成物。
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