JP6416832B2 - 多機能性の双性イオン重合体コンジュゲート - Google Patents
多機能性の双性イオン重合体コンジュゲート Download PDFInfo
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- JP6416832B2 JP6416832B2 JP2016159104A JP2016159104A JP6416832B2 JP 6416832 B2 JP6416832 B2 JP 6416832B2 JP 2016159104 A JP2016159104 A JP 2016159104A JP 2016159104 A JP2016159104 A JP 2016159104A JP 6416832 B2 JP6416832 B2 JP 6416832B2
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Description
本発明は、ホスホリルコリンなどの双性イオンと、及び少なくとも1種の機能性剤(本明細書中に定義した)とを有するランダム共重合体を提供する。高い生体適合性の分子としてのホスホリルコリンなどの双性イオンは基本的な生体適合性をドライブする。それは、温度又は他のストレス下でタンパク質を保護することによって、シャペロンタイプの機能も有している。それは、可逆的な細胞取込み(reversible cellular uptake)などの他の機能を可能にすることもできる。機能性剤は、生体活性剤、例えば、薬剤、治療タンパク質又は標的化剤など、並びに検出剤、イメージング剤、標識化剤又は診断剤であることができる。ランダム共重合体は、1種又は2種以上の適切な機能性剤を選択することによって、様々な症状及び疾患状態の治療に有効である。複数の生体活性剤をランダム共重合体に連結することができ、このようにして単一の疾病の症状又はメカニズムだけでなく、むしろ全疾病(whole disease)の治療を可能にする。さらに、非開裂性(non-cleavable)リンカーを介して安定に生体活性剤を連結させ、又は種々の予め定められたトリガーがプロドラッグ又はダブルプロドラッグリンカー及び連結基ストラテジーを用いることによってそれぞれの生体活性剤を放出するように様々な開裂性リンカーを介して生体活性剤を連結させることができる。さらに、本発明のランダム共重合体は、適当な標的化剤及びイメージング剤の結合(attachment)によって診断及びイメージングの目的に対して有効である。本発明のランダム共重合体は治療剤及び診断剤の双方を単一の重合体中に含んでいることによって、疾病を治療し並びに検出及び診断をする治療診断剤(theranostic agent)を提供することができる。
本発明の目的のために、下記の用語を、以下に説明する定義に従って用いる。
ノフェン−1−イル、2−アミノフェン−1−イル、4−フェニル−フェン−1−イル、4−(イミダゾール−1−イル)フェン−イル、4−(イミダゾール−1−イルメチル)−フェン−1−イル、4−(モルホリン−1−イル)−フェン−1−イル、4−(モルホリン−1−イルメチル)−フェン−1−イル、4−(2−メトキシエチルアミノメチル)−フェン−1−イル及び4−(ピロリジン−1−イルメチル)−フェン−1−イル、4−(チオフェニル)−フェン−1−イル、4−(3−チオフェニル)−フェン−1−イル、4−(4−メチルピペラジン−1−イル)−フェン−1−イル、及び4−(ピペリジニル)−フェニル及び4−(ピリジニル)フェニルであり、複素環式環は場合により置換されている。
はもとのスルフヒドリルが保有している基の残部へのチオールの硫黄原子の結合点を表す]を有する−S−マレイミド基を形成する。
本発明は、双性イオン基、例えば、ホスホリルコリンなど、及び少なくとも1の機能性剤を有するランダム共重合体を提供する。幾つかの実施形態において、本発明のランダム共重合体は、ホスホリルコリンを有する第一の単量体、機能性剤又は連結基を有する少なくとも1の第二の単量体、及び機能性剤又は連結基を有する開始剤成分を有しており、ここで前記機能性剤は第二の単量体に又はリンカーを介して開始剤成分に連結されていることができる。
が共単量体M2上に存在している場合、開始剤I2を用いた重合が、開始剤I−I’を用いた重合の後に一般に生じる。幾つかの実施形態において、I−I’及びI2を介した重合は同時であることができる。さらに、開始剤I2は、開裂性又は非開裂性リンカーL2を介して共単量体M2に連結されていることができる。
本発明のランダム共重合体は任意の適当な開始剤を用いて重合される。本発明に有用な開始剤は次式:I−(I’)m[式中、下付き文字mは1〜20の整数である]によって表わされることができる。開始剤フラグメントIは重合を開始する任意の基であることができる。ラジカルスカベンジャーI’は生長する重合体鎖を可逆的に停止する任意の基であることができる。ラジカルスカベンジャーI’は、重合後に重合体の末端が官能化されることを可能にする、ハロゲン、例えば、臭素であることができる。さらに、開始剤フラグメントIは場合により、様々な官能基を含んでいることができるR1基で官能化されてランダム共重合体の官能性を調整することができる。
種C)を形成する。重合過程中、ラジカルスカベンジャーI’のラジカルは、生長性重合体ラジカルと可逆的に反応して重合体の生長を一時的に停止させる。単量体とラジカルスカベンジャーI’との間の結合も不安定であり、当該結合は開裂しそして生長性重合体ラジカルがさらなる単量体と反応することを可能にして重合体を成長させることができる。重合過程の最終的結果は、開始剤フラグメントIが重合体鎖の一端に位置しそしてラジカルスカベンジャーI’が当該重合体鎖の反対側に位置することである。
(F)r−Sp1−C−Sp2−I’
[上記式中、開始剤フラグメントIはF−Sp1−C−Sp2に対応する]を有する。各F基は、本発明の機能性剤又は連結基との反応のための官能基である。下付き文字rは1〜10である。Sp1基及びSp2基はスペーサーであり共有結合を形成する任意の適当な基、例えば、C1−6アルキル基、アリール基又はヘテロアリール基であることができる。C基は、1又は2以上のスペーサーSp2(同じであるか又は異なっていることができる)及び1又は2以上のラジカルスカベンジャーI’に連結するための1又は複数の点を提供し、かつ1又は2以上のスペーサーSp1(同じであるか又は異なっていることができる)及び1又は2以上の官能基F(同じであるか又は異なっていることができる)に連結するための1又は複数の点を提供する任意のコアであることができる。コアCは任意の適当な構造、例えば、分枝状構造、ヘテロ原子を含む架橋構造、例えば、シルセスキオキサンなど、及び複数のペンダント官能基を有する直鎖の短い重合体など、であることができる。さらに、コアCは、限定的でなく、エステル基、アミド基、エーテル基、及びケトン基を含む、共有結合を形成するための任意の適当な基によって1又は2以上のSp1及びSp2スペーサーに結合されていることができる。ラジカルスカベンジャーI’はラジカル移動可能な(radically transferable)原子又は基、例えば、限定的でなく、ハロゲン原子、Cl原子、Br原子、I原子、OR10基、SR11基、SeR11基、OC(=O)R11基、OP(=O)R11基、OP(=O)(OR11)2基、O−(R11)2基、S−C(=S)N(R11)2基、CN基、NC基、SCN基、CNS基、OCN基、CNO基、N3基、OH基、O基、C1−C6−アルコキシ基、(SO4)基、PO4基、HPO4基、H2PO4基、トリフレート基、ヘキサフルオロホスフェート基、メタンスルホネート基、アリールスルホネート基、ハロゲン化カルボン酸基など、である。R10は、炭素原子1〜20個のアルキル基又は各水素原子がハリド基で置換されていることができる炭素原子1〜20個のアルキル基、炭素原子2〜20個のアルケニル基、炭素原子2〜10個のアルキニル基、フェニル基、ハロゲン原子1〜5個又は炭素原子1〜4個を有するアルキル基で置換されたフェニル基、アルアルキル基、アリール基、アリール置換されたアルキル基(アリール基はフェニル基又は置換されたフェニル基でありそしてアルキル基は炭素原子1〜6個である)であり、そしてR11はアリール基又は直鎖若しくは分枝鎖のC1−C20アルキル基であるか又はN(R11)2基が存在する場合には、2つのR11基は結合されて5員、6員又は7員の複素環式環を形成することができる。スペーサーSp1は官能基F及びコアCと共有結合しているが、スペーサーSp2はコアC及びラジカルスカベンジャーI’と共有結合している。
本発明のランダム共重合体を製造するのに有用な単量体はラジカル重合可能な任意の単量体を含む。一般には、かかる単量体はビニル基を有する。適当な単量体として、限定的でなく、アクリレート、メタクリレート、アクリルアミド、メタクリルアミド、スチレン、ビニル−ピリジン及びビニル−ピロリドン単量体を挙げることができる。双性イオン成分ZWを含む単量体M1として、限定的でなく、以下:
本発明の双性イオンは、陰電荷及び陽電荷の双方を有する任意の化合物を含む。陰電荷を有しかつ本発明の双性イオンに用いるのに適した基として、限定的でなく、ホスフェート、スルフェート、他のオキソアニオン等を挙げることができる。陽電荷を有しかつ本発明の双性イオンに用いるのに適した基として、限定的でなく、アンモニウムイオンを挙げることができる。幾つかの実施形態において、双性イオンはホスホリルコリンであることができる。
本発明のランダム共重合体は任意の適当なリンカーLを含んでいることができる。リンカーは機能性剤の開始剤I及び単量体M2への結合を提供する。リンカーは開裂性又は非開裂性の、ホモ二官能性又はヘテロ二官能性であることができる。他のリンカーはヘテロ二官能性でかつ開裂性、又はホモ二官能性でかつ開裂性であることができる。
Press, 2d ed., 2008(その全体が本明細書中に組み込まれる)に記載されたもの、及びAngew. Chem. Int. Ed. 2009, 48, 6974-6998 (Bertozzi, C.R. and Sletten, E.M)(そ
の全体が本明細書中に組み込まれる)に記載されたものを挙げることができる。
本発明のリンカー及び機能性剤は開始剤フラグメントI又は単量体M2上の連結基と反応して結合を形成することができる。本発明の連結基LGは、別の官能基への結合を形成し、それによって2つの基を一緒に連結することができる任意の適当な官能基であることができる。例えば、本発明に有用な連結基LGとして、とりわけ、クリックケミストリー、マレイミドケミストリー、及びNHS−エステルに用いられるものを挙げることができる。クリックケミストリーに関与する連結基として、限定的でなく、ヒュスゲン環化付加法によってトリアゾール環を形成するアジ化物及びアルキンを挙げることができる(例えば、その全体が本明細書中に組み込まれる、米国特許第7,375,234号参照)。マレイミドケミストリーは、安定な結合を形成する、マレイミドオレフィンと求核試薬、例えば、−OH、−SH又は−NH2など、との反応を包含する。他の連結基として、Bioconjugate Techniques, Greg T. Hermanson, Academic Press, 2d ed., 2008(その全体が本明細書中に組み込まれる)に記載されているものを挙げることができる。
本発明のランダム共重合体に有用な機能性剤として、特定のリガンド、受容体、複合体、オルガネラ、細胞、組織、上皮シート、若しくは器官を標的化することができ、又は特定の症状又は疾患状態を治療することができる、任意の生物学的剤又は合成化合物を挙げることができる。とりわけ興味深いのは、特定の疾病に共通のメカニズムを一緒に標的にする生物学的剤の組み合わせである。例えば、疾病においてアップレギュレートされるタンパク質に結合する生体薬剤学的剤(biopharmaceutical agent)である第一の生体活性
剤(安定に結合される);細胞外マトリックス組織成分、例えば、ヘパリン硫酸(heparin sulfate)など、に結合するペプチドである第二の生体活性剤(安定に結合される);
経時的に放出して局所的な細胞内作用、例えば、抗増殖作用など、を発揮する小分子薬剤である第三の生体活性剤(不安定に結合される)。幾つかの実施形態において、生体活性剤は、薬剤、治療タンパク質、小分子、ペプチド、ペプトイド、オリゴヌクレオチド(アプタマー、siRNA、microRNA)、ナノ粒子、炭水化物、脂質、糖脂質、リン脂質又は標的化剤である。単量体の比は、予め定められた化学量論に基づいて(例えば、生物学的親和性に適合させるように;生物学的化学量論に適合させるように;「ギアリング(gearing)」効果を与えるように)選択される。本発明のランダム共重合体に有効な他の機能性剤として、限定的でなく、放射性ラベル、フルオロフォア及び色素を挙げることができる。
1つのとりわけ有用な実施形態において、機能性剤は治療タンパク質である。多数の治療タンパク質、例えば、限定的でなく、エリスロポイエチン、顆粒球コロニー刺激因子(G−CSF)、G−CSF、インターフェロンα、インターフェロンβ、ヒト成長ホルモン、及びイミグルセラーゼ(imiglucerase)など、が本願明細書を通じて開示される。
ルコシダーゼ、N−アセチルガラクトサミン−6−スルフェートスルファターゼ、コラーゲン、シクロスポリン、αデフェンシン、βデフェンシン、デスモプレシン、エキセンディン−4、サイトカイン、サイトカイン受容体、顆粒球コロニー刺激因子(G−CSF)、トロンボポイエチン(TPO)、α−1プロテイナーゼインヒビター、エルカトニン、顆粒球マクロファージコロニー刺激因子(GM−CSF)、フィブリノーゲン、フィルグラスチム、成長ホルモンヒト成長ホルモン(hGH)、ソマトロピン、成長ホルモン放出ホルモン(GHRH)、GRO−β、GRO−β抗体、骨形態形成タンパク質(bone morphogenic protein)、例えば、骨形態形成タンパク質−2、骨形態形成タンパク質−6、副甲状腺ホルモン、副甲状腺ホルモン関連ペプチド、OP−1;酸性線維芽細胞成長因子、塩基性線維芽細胞成長因子、線維芽細胞成長因子21、CD−40リガンド、ヘパリン、ヒト血清アルブミン、低分子量ヘパリン(LMWH)、インターフェロンα、インターフェロンβ、インターフェロンγ、インターフェロンω、インターフェロンτ、コンセンサスインターフェロン、ヒトリシルオキシダーゼ様2(LOXL2);インターロイキン及びインターロイキン受容体、例えば、インターロイキン−1受容体、インターロイキン−2、インターロイキン−2融合タンパク質、インターロイキン−1受容体アンタゴニスト、インターロイキン−3、インターロイキン−4、インターロイキン−4受容体、インターロイキン−6、インターロイキン−8、インターロイキン−12、インターロイキン−17、インターロイキン−21、インターロイキン−23、p40、インターロイキン−13受容体、インターロイキン−17受容体;ラクトフェリン及びラクトフェリンフラグメント、黄体形成ホルモン放出ホルモン(LHRH)、インスリン、プロ−インスリン、インスリン類似体、レプチン、グレリン、アミリン、C−ペプチド、ソマトスタチン、オクトレオチドを含むソマトスタチン類似体、バソプレシン、卵胞刺激ホルモン(FSH)、イミグルセラーゼ、インフルエンザワクチン、インスリン様成長因子(IGF)、インスリントロピン、マクロファージコロニー刺激因子(M−CSF)、プラスミノーゲン活性化剤、例えば、アルテプラーゼ、ウロキナーゼ、レテプラーゼ、ストレプトキナーゼ、パミテプラーゼ、ラノテプラーゼ、及びテネテプラーゼ(teneteplase);神経成長因子(NGF)、オステオプロテゲリン、血小板由来成長因子、組織成長因子、形質転換成長因子−1、血管内皮成長因子、白血病抑制因子、ケラチノサイト成長因子(KGF)、グリア成長因子(GGF)、T細胞受容体、CD分子/抗原、腫瘍壊死因子(TNF)(例えば、TNF−α及びTNF−β)、TNF受容体(例えば、TNF−α受容体及びTNF−β受容体)、CTLA4、CTLA4受容体、単球化学誘引物質タンパク質−1、内皮成長因子、副甲状腺ホルモン(PTH)、グルカゴン様ペプチド、ソマトトロピン、チモシンα1、ラスブリカーゼ、チモシンα1IIb/IIIaインヒビター、チモシンβ10、チモシンβ9、チモシンβ4、α−1抗トリプシン、ホスホジエステラーゼ(PDE)化合物、VLA−4(最晩期抗原−4)、VLA−4インヒビター、ビスホスポネート(bisphosponate)、呼吸器系合胞体ウイルス抗体、嚢胞性線維症膜貫通調節(CFTR)遺伝子、デオキシリボヌクレアーゼ(Dnase)、殺菌性/透過性増大タンパク質(BPI)、及び抗−CMV抗体を挙げることができる。典型的なモノクロナール抗体として、エタネルセプト(IgG1のFc部分に結合したヒトの75kDのTNF受容体の細胞外リガンド結合部分から成る二量体融合タンパク質)、アブシキシマブ(abciximab)、アダリムマブ(adalimumab)、アフェリモマブ(afelimomab)、アレムツズマブ(alemtuzumab)、Bリンパ球に対する抗体、アトリズマブ(atlizumab)、バシリキシマブ(basiliximab)、ベバシズマブ(bevacizumab)、ビシロマブ(biciromab)、ベルチリムマブ(bertilimumab)、CDP−484、CDP−571、CDP−791、CDP−860、CDP−870、セツキシマブ(cetuximab)、クレノリキシマブ(clenoliximab)、ダクリズマブ(daclizumab)、エクリズマブ(eculizumab)、エドレコロマブ(edrecolomab)、エファリズマブ(efalizumab)、エプラツズマブ(epratuzumab)、フォントリズマブ(fontolizumab)、ガビリモマブ(gavilimomab)、ゲムツズマブオゾガマイシン(gemtuzumab ozogamicin)、イブリツモマブチウキセタン(ibritumomab tiuxetan)、インフリキシマブ(infliximab)、イノリモマブ(inolimomab)、ケリキシマブ(keliximab)、ラベツズマブ(labetuzumab)、レルデリムマブ(lerdelimumab)、オリズマブ(olizumab)、放射標識されたlym−1、メテリムマブ(metelimumab)、メポリズ
マブ(mepolizumab)、ミツモマブ(mitumomab)、ムロモナド(muromonad)−CD3、ネバクマブ(nebacumab)、ナタリズマブ(natalizumab)、オヅリモマブ(odulimomab)、オマリズマブ(omalizumab)、オレゴボマブ(oregovomab)、パリビズマブ(palivizumab)、ペムツモマブ(pemtumomab)、ペキセリズマブ(pexelizumab)、rhuMAb−VEGF、リツキシマブ(rituximab)、サツモマブペンデチド(satumomab pendetide)、セビルマブ(sevirumab)、シプリズマブ(siplizumab)、トシツモマブ(tositumomab)、I131トシツモマブ、トラスツズマブ(trastuzumab)、ツビルマブ(tuvirumab)、ビシリズマブ(visilizumab)、及びそれらのフラグメント及びミメティックを挙げることができる。機能性剤は、これらの特異的に同定された多糖、タンパク質又はペプチド生体活性剤に結合する剤も含む。
化抗CD52 IgG1抗体であるキャンパス1H/LDP−03(Leukosite社);ヒト化抗CD33 IgG抗体であるスマート(Smart)M195(Protein Design Lab/Kanebo社);キメラ抗CD2O IgG抗体であるRITUXANTM(IDEC Pharm/Genentech社、Roche/Zettyaku社);ヒト化抗CD22 IgG抗体であるLYMPHOCIDETM(Immunomedics社);ヒト化抗ICAM3抗体であるICM3(ICOS Pharm社);霊長類抗CD80抗体であるIDEC−114(IDEC Pharm/Mitsubishi社);放射標識されたマウス抗CD20抗体であるZEVALINTM(IDEC/Schering AG社);ヒト化抗CD40L抗体であるIDEC−131(IDEC/Eisai社);霊長類化抗CD4抗体であるIDEC−151(IDEC社);霊長類化抗CD23抗体であるIDEC−152(IDEC/Seikagaku社);ヒト化抗CD3 IgGであるスマート(SMART)抗CD3(Protein Design Lab社);ヒト化抗補体因子5(CS)抗体である5G1.1(Alexion Pharm社);ヒト化抗TNF−α抗体であるD2E7(CATIBASF社);ヒト化抗TNF−α FabフラグメントであるCDP870(Celltech社);霊長類化抗CD4 IgG1抗体であるIDEC−151(IDEC Pharm/SmithKline Beecham社);ヒト抗CD4 IgG抗体であるMDX−CD4(Medarex/Eisai/Genmab社);ヒト化抗TNF−α IgG4抗体であるCDP571(Celltech社);ヒト化抗α4β7抗体であるLDP−02(LeukoSite/Genentech社);ヒト化抗CD4 IgG抗体であるオルソクローン(OrthoClone)OKT4A(Ortho Biotech社);ヒト化抗CD40L IgG抗体であるANTOVATM(Biogen社);ヒト化抗VLA−4 IgG抗体であるANTEGRENTM(Elan社);ヒト抗TGF−β2抗体であるCAT−152(Cambridge Ab Tech社);モノクローナル抗EGF受容体(EGFr)抗体であるセツキシマブ(BMS);抗VEGFヒトモノクローナル抗体であるベバシズマブ(Genentech社);自己免疫疾患を治療するために用いられるキメラ(マウス及びヒト)モノクローナル抗体であるインフリキシマブ(Centocore社、JJ);化学療法に用いられるモノクローナル抗体であるゲムツヅマブオゾガマイシン(Wyeth社);及び黄斑変性を治療するために用いられるキメラ(マウス及びヒト)モノクローナル抗体であるラニビズマブ(Ranibizumab)(Genentech社)を挙げることができる。
本明細書中に開示されたように生体活性剤として用いられるタンパク質及びペプチドは、インビトロ合成による製造及び生物学的系における製造を含む任意の有効な方法によって製造されることができる。当該技術分野で周知のインビトロ合成法の典型的な例として、固相合成(「SPPS」)及び固相フラグメント縮合(「SPFC」)を挙げることができる。タンパク質の製造に用いられる生物学的系も当該技術分野で周知である。細菌(例えば、大腸菌及びバチルス種(Bacillus sp.))及び酵母(例えば、サッカロミセス・セレビシエ(Saccharomyces cerevisiae)及びピキア・パストリス(Pichia pastoris))が異種タンパク質の製造に広く用いられている。さらに、本明細書に開示されたように用いられる生体活性剤の製造のための異種遺伝子発現は、動物細胞系、例えば、哺乳動物細胞系(例えば、CHO細胞)など、を用いて達成されることができる。1つのとりわけ有用な実施形態において、生体活性剤はトランスジェニック又はクローン化動物、例えば、ウシ、ヒツジ、ヤギ及び鳥類(例えば、ニワトリ、ウズラ、アヒル及びシチメンチョウ)において産生され、そのそれぞれが当該技術分野で理解されている。例えば、参照によりその全体が本明細書中に組み込まれる、2004年8月24日に発行された米国特許第6,781,030号を参照されたい。
別の実施形態において、生体活性剤は、特異的に同定された薬剤又は治療剤から選択されることもでき、その例として、限定的でなく、以下を挙げることができる:タクリン、メマンチン、リバスチグミン、ガランタミン、ドネペジル、レベチラセタム、レパグリニド、アトルバスタチン、アレファセプト、タダラフィル、バルデナフィル、シルデナフィル、ホスアンプレナビル、オセルタミビル、バラシクロビル及びバルガンシクロビル、アバレリックス、アデホビル、アルフゾシン、アロセトロン、アミホスチン、アミオダロン、アミノカプロン酸、アミノ馬尿酸ナトリウム、アミノグルテチミド、アミノレブリン酸、アミノサリチル酸、アムロジピン、アムサクリン、アナグレリド、アナストロゾール、アプレピタント、アリピプラゾール、アスパラギナーゼ、アタザナビル、アトモキセチン、アントラサイクリン、ベキサロテン、ビカルタミド、ブレオマイシン、ボルテゾミブ、ブセレリン、ブスルファン、カベルゴリン、カペシタビン、カルボプラチン、カルムスチン、クロラムブシン(chlorambucin)、シラスタチンナトリウム、シスプラチン、クラドリビン、クロドロネート、シクロホスファミド、シプロテロン、シタラビン、カンプトテシン、13−シスレチノイン酸、すべてのトランスレチノイン酸;ダカルバジン、ダクチノマイシン、ダプトマイシン、ダウノルビシン、デフェロキサミン、デキサメタゾン、ジクロフェナク、ジエチルスチルベストロール、ドセタキセル、ドキソルビシン、デュタステリド、エレトリプタン、エムトリシタビン、エンフビルチド、エプレレノン、エピルビシン、エストラムスチン、エチニルエストラジオール、エトポシド、エキセメスタン、エゼチミブ、フェンタニル、フェキソフェナジン、フルダラビン、フルドロコルチゾン、フルオロウラシル、フルオキシメステロン、フルタルニド(flutarnide)、フルチカゾン、フォンダパリナックス、フルベストラント、γ−ヒドロキシブチレート、ゲフィチニブ、ゲムシタビン、エピネフリン、L−ドーパ、ヒドロキシウレア、イコデキストリン、イダルビシン、イホスファミド、イマチニブ、イリノテカン、イトラコナゾール、ゴセレリン、ラロニダーゼ、ランソプラゾール、レトロゾール、ロイコボリン、レバミゾール、リシノプリル、ロボチロキシンナトリウム(lovothyroxine sodium)、ロムスチン、メクロレタミン、メドロキシプロゲステロン、メゲストロール、メルファラン、メマンチン、メルカプトプリン、メキノール、酒石酸水素メタラミノール、メトトレキサート、メトクロプラミド、メキシレチン、ミグルスタット、マイトマイシン、ミトタン、ミトキサントロン、モダフィニル、ナロキソン、ナプロキセン、ネビラピン、ニコチン、ニルタミド、ニタゾキサニド、ニチシノン、ノルエチンドロン、オクトレオチド、オキサリプラチン、パロノセトロン、パミドロネート、ペメトレキセド、ペルゴリド、ペントスタチン、ピルカマイシン(pilcamycin)、ポルフィマー、プレドニゾン、プロカルバジン、プロクロルペラジン、オンダンセトロン、パロノセトロン、オキサリプラチン、ラルチトレキセド、ロスバスタチン、シロリムス、ストレプトゾシン、ピメクロリムス、セルタコナゾール、タクロリムス、タモキシフェン、テガセロッド、テモゾロミド、テニポシド、テストステロン、テトラヒドロカンナビノール、サリドマイド、チオグアニン、チオテパ、チオトロピウム、トピラメート、トポテカン、トレプロスチニル、トレチノイン、バルデコキシブ、セレコキシブ、ロフェコキシブ、バルルビシン、ビンブラスチン、ビンクリスチン、ビンデシン、ビノレルビン、ボリコナゾール、ドラセトロン、グラニセトロン、ホルモテロール、フルチカゾン、ロイプロリド、ミダゾラム、アルプラゾラム、アンホテリシンB、ポドフィロトキシン、ヌクレオシド抗ウイルス薬、アロイルヒドラゾン、スマトリプタン、エレトリプタン;マクロライド系薬剤、例えば、エリスロマイシン、オレアンドマイシン、トロレアンドマイシン、ロキシスロマイシン、クラリスロマイシン、ダベルシン(davercin)、アジスロマイシン、フルリスロマイシン、ジリスロマイシン、ジョサマイシン、スピロマイシン、ミデカマイシン、ロラタジン、デスロラタジン、ロイコマイシン、ミオカマイシン、ロキタマイシン、アンダジスロマイシン(andazithromycin)、及びスウィノ
リド(swinolide)A;フルオロキノロン、例えば、シプロフロキサシン、オフロキサシ
ン、レボフロキサシン、トロバフロキサシン、アラトロフロキサシン(alatrofloxacin)、モキシフロキシシン(moxifloxicin)、ノルフロキサシン、エノキサシン、ガチフロキサシン、ゲミフロキサシン、グレパフロキサシン、ロメフロキサシン、スパルフロキサシン、テマフロキサシン、ペフロキサシン、アミフロキサシン、フレロキサシン、トスフロキサシン、プルリフロキサシン、イルロキサシン(irloxacin)、パズフロキサシン、クリナフロキサシン、及びシタフロキサシン;アミノグリコシド、例えば、ゲンタマイシン、ネチルマイシン、パラメシン、トブラマイシン、アミカシン、カナマイシン、ネオマイシン、及びストレプトマイシン、バンコマイシン、テイコプラニン、ラムポラニン(rampolanin)、ミデプラニン(mideplanin)、コリスチン、ダプトマイシン、グラミシジン、コリスチメタート;ポリミキシン、例えば、ポリミキシンB、カプレオマイシン、バシトラシン、ペネム;ペニクリナーゼ感受性(penicllinase-sensitive)薬剤を含むペニシリン、例えば、ペニシリンG、ペニシリンV;ペニシリナーゼ耐性薬剤、例えば、メチシリン、オキサシリン、クロキサシリン、ジクロキサシリン、フロキサシリン、ナフシリン;グラム陰性微生物活性剤、例えば、アンピシリン、アモキシシリン、及びヘタシリン、シリン(cillin)、及びガランピシリン(galampicillin);抗緑膿菌性(antipseudomonal)ペニシリン、例えば、カルベニシリン、チカルシリン、アズロシリン、メズロシリン、及びピペラシリン;セファロスポリン、例えば、セフポドキシム、セフプロジル、セフトブテン(ceftbuten)、セフチゾキシム、セフトリアキソン、セファロチン、セファピリン、セファレキシン、セフラドリン(cephradrine)、セフォキシチン、セファマンドール、セファゾリン、セファロリジン、セファクロル、セファドロキシル、セファログリシン、セフロキシム、セフォラニド、セフォタキシム、セファトリジン、セファセトリル、セフェピム、セフィキシム、セフォニシド、セフォペラゾン、セフォテタン、セフメタゾール、セフタジジム、ロラカルベフ、及びモキサラクタム、モノバクタム、例えば、アズトレオナム;及びカルバペネム、例えば、イミペネム、メロペネム、及びエルタペネム、ペンタミジンイセチオネート、硫酸アルブテロール、リドカイン、硫酸メタプロテレノール、ベクロメタゾンジプレピオネート(beclomethasone diprepionate)、トリアムシノロンアセトアミド(triamcinolone acetamide)、ブデソニドアセトニド(budesonide acetonide)、サルメテロール、臭化イプラトロピウム、フルニソリド、クロモリンナトリウム、及び酒石酸エルゴタミン;タキサン、例えば、パクリタキセル;SN−38、及びチルホスチン。生体活性剤は、別の実施形態において、アミノ馬尿酸ナトリウム、アンホテリシンB、ドキソルビシン、アミノカプロン酸、アミノレブリン酸、アミノサリチル酸(arninosalicylic acid)、酒石酸水素メタラミノール、パミドロネート二ナトリウム、ダウノルビシン、レボチロキシンナトリウム、リシノプリル、シラスタチンナトリウム、メキシレチン、セファレキシン、デフェロキサミン、及びアミホスチンからなる群から選択されることもできる。
本発明のランダム共重合体に有用な診断剤として、イメージング剤及び検出剤、例えば、放射性ラベル、フルオロフォア、色素及び造影剤などを挙げることができる。
機能性剤はナノ粒子を含んでいることもできる。本発明に有用なナノ粒子は1〜1000nm範囲の大きさを有する粒子を含む。ナノ粒子はビーズ、金属粒子であることができるか又は一部の場合にミセルであることができそして一部の他の場合にリポソームであることができる。他のナノ粒子として、カーボンナノチューブ、量子ドット及びコロイド金を挙げることができる。ナノ粒子に診断剤及び/又は治療剤を詰める(pack)ことができる。
[上記式中、下付き文字x及びy1は、重合体部分のMnが約95,000g/モルとなるものであり;A1は抗体であり;そしてL−CPTは下記式:
本発明のランダム共重合体は当該技術分野で公知の任意の手段によって製造されることができる。幾つかの実施形態において、本発明は、本発明のランダム共重合体の製造方法であって、フリーラジカル重合によってランダム共重合体を製造するのに充分な条件下に、第一の単量体と第二の単量体との混合物を開始剤I’と接触させ、ここで前記第一の単量体がホスホリルコリンを含み、そして第二の単量体及び開始剤がそれぞれ独立して少なくとも1の機能性剤又は機能性剤に連結するための連結基を含んでいる工程を含む方法を提供する。
本発明のランダム共重合体の製造に有用な開始剤として、原子移動ラジカル重合(ATRP)による重合に適した任意の開始剤、例えば、上記したものなど、を挙げることができる。他の有用な開始剤として、ニトロキシド媒介ラジカル重合(NMP)、又は可逆的付加−開裂−停止(reversible addition-fragmentation-termination)(RAFT又はMADIX)重合用のものを挙げることができる。フリーラジカル重合法を制御するさらに他の技術を用いることができ、例えば、イニファーター、縮退的移動法又はテロメリゼーション法を用いることができる。さらに、本発明に有用な開始剤として、少なくとも1の分枝点を有するもの、例えば、上記したものなど、を挙げることができる。
ATRP又は基ラジカル移動重合(group radical transfer polymerization)に用いられる触媒として、Cu1+、Cu2+、Fe2+、Fe3+、Ru2+、Ru3+、Cr2+、Cr3+、Mo2+、Mo3+、W2+、W3+、Mn2+、Mn2+、Mn4+、Rh3+、Rh4+、Re2+、Re3+、Co1+、Co2+、Co3+、V2+、V3+、Zn1+、Zn2+、Ni2+、Ni3+、Au1+、Au2+、Ag1+及びAg2+の適当な塩を挙げることができる。適当な塩として、限定的でなく、以下:ハロゲン、C1−C6−アルコシキ、硫酸塩、リン酸塩、トリフラート、ヘキサフルオロリン酸塩、メタンスルホン酸塩、アリールスルホン酸塩を挙げることができる。幾つかの実施形態において、触媒は上記した金属イオンの塩素塩、臭素塩である。他の実施形態において、触媒はCuBr、CuCl又はRuCl2である。
幾つかの実施形態において、好ましくは、本発明の「リビング」又は制御されたラジカル重合法を実施し、3〜約2000の範囲の重合度を、そして他の実施形態において約5〜約500を達成する。他の実施形態における重合度は範囲10〜100にあり、又は代わりに約10〜約50の範囲にある。基又は原子移動ラジカル重合法における重合度は、開始剤と単量体との初期比に直接関連する。従って、幾つかの実施形態において、開始剤と単量体との初期比は、1:(3〜約2,000)又は約1:(5〜500)、又は約1:(10〜100)、又は約1:(10〜50)の範囲にある。
幾つかの実施形態において、ハロゲン又は他のラジカルスカベンジャーI’を別の官能基で置換することが望ましいことがある。脂肪族ハロゲンの変換は様々な反応を用いることができる。幾つかの実施形態において、脂肪族ハロゲンの変換は、アルキル基、アルコキシ基、シクロアルキル基、アリール基、ヘテロアリール基又はヒドロキシ基を生成する反応を含んでいることができる。ハロゲン原子はアルケン(二重結合)を生じる脱離反応を起こしやすいこともある。ハロゲン化末端を改変する他の方法は、その全体が参照により本明細書中に組み込まれる、Matyjaszewski et al. Prog. Polym. Sci. 2001, 26, 337に記載されている。
本発明のランダム共重合体への機能性剤の結合は、行われる反応に適用可能な化学的条件及び試薬を用いて行われることができる。典型的な方法は、Bioconjugate Techniques, Greg T. Hermanson, Academic Press, 2d ed., 2008(その全体が本明細書中に組み込まれる)に記載されている。他のバイオコンジュゲーション法は、それぞれ全体が参照により本明細書中に組み込まれる、Bertozzi et al. Angewandte Chemie 2009, 48, 6974、及びGauthier et al. Chem. Commun. 2008, 2591に記載されている。
本発明は、本発明の化合物1種又は2種以上及び薬剤学的に許容することのできる賦形剤1種又は2種以上を含む医薬組成物を含みかつそれを提供する。本発明の化合物は、薬剤学的に許容することのできる塩、プロドラッグ、代謝物、それらの類似体又は誘導体として本発明の医薬組成物中に存在することができる。「薬剤学的に許容することのできる賦形剤」又は「薬剤学的に許容することのできる担体」とは、本明細書中で用いる場合、医薬品投与と適合性のある、任意かつすべての溶媒、分散媒、被覆剤、抗菌剤及び抗真菌剤、等張性剤及び吸収遅延剤などを含むことを意図する。
本発明のランダム共重合体は任意の疾患状態又は症状を治療するのに有効である。適切な標的化剤、薬剤及び治療タンパク質を双性イオン、例えば、ホスホリルコリンなど、と一緒に組み合わせることによる、本発明のランダム共重合体を用いて、いずれか1つの疾患状態又は症状によって与えられるメカニズムの防備に対処することができる。例えば、疾患状態又は症状は急性又は慢性であることができる。
・治療遺伝子、MRI分析用のガドリニウム造影剤を封入し、かつ特異的な疾病部位を標的とする抗体で機能化された、合成の生分解性重合体をベースとするナノ粒子。
・小さい又は大きい薬剤分子を封入し、PET分析用の18フッ素で標識され、かつ特異的な疾病部位を標的とする抗体で機能化されたリポソーム。
・siRNA分子、MRI分析用の酸化鉄造影剤を含み、かつ標的化された細胞送達及び細胞内送達それぞれのための細胞結合リガンド及び細胞透過性ペプチドで改変されたポリプレックス。
・送達のセンシング及び光学イメージング用の薬剤分子がインターカレートされかつ特異的疾病を標的とするRNAアプタマーで機能化された蛍光量子ドット。
・遺伝子治療用のアンチセンスオリゴヌクレオチド、MRI分析用のガドリニウム造影剤、光学イメージング用のフルオロフォアを含み、かつ特異的疾病を標的とするように表面改変された無機又は有機のナノ粒子。
・pHに応じて放出される薬剤分子、MRIイメージング用の酸化鉄造影剤、光学イメージング用のCdTe量子ドットを有し、かつ特異的疾病を標的とする抗体で機能化されたpH感受性高分子ナノコンポジット。
・薬剤及びSPECTイメージング用の111Inなどの放射性トレーサーを含みかつ疾病特異的な膜抗体で機能化されたナノ粒子−DNAアプタマーコンジュゲート。
・治療遺伝子(生体活性1)、MRI分析用のガドリニウム造影剤(機能的1)、及び特異的な疾病部位を標的とする小タンパク質(例えば、抗体フラグメントなど)を含むホスホリルコリン重合体をベースとする構築物。
・PET分析用18フッ素、かつ特異的な疾病部位を標的とする小タンパク質(例えば、抗体フラグメントなど)で機能化されたイメージング剤。
・siRNA分子1種又は2種以上、MRI分析用の酸化鉄造影剤を含み、かつ標的化された細胞送達及び細胞内送達それぞれのための細胞結合リガンド及び細胞透過性ペプチドで改変されたホスホリルコリン重合体。
・送達のセンシング及び光学イメージング用の薬剤分子(機能性剤)がインターカレートされかつ特異的疾病を標的とするRNAアプタマー又は小タンパク質(例えば、抗体フラグメント又はスカフォールド誘導タンパク質)で機能化された蛍光量子ドット(機能性剤)を含むホスホリルコリン重合体。
・遺伝子治療用のアンチセンスオリゴヌクレオチド、MRI分析用のガドリニウム造影剤、光学イメージング用のフルオロフォア、及び特異的疾病を標的化するためのさらなる機能性剤、例えば、腫瘍に対する葉酸塩又は細胞外マトリックスを標的化するための静電相互作用に対するコリンなど、を含むホスホリルコリン含有重合体。
・pHに応じて放出される薬剤分子、MRIイメージング用の酸化鉄造影剤、光学イメージング用のCdTe量子ドットを有し、かつ特異的疾病を標的としそれを治療する抗体又は他のタンパク質又はアプタマーで機能化されたpH感受性ホスホリルコリン重合体。
・薬剤及びSPECTイメージング用の111Inなどの放射性トレーサーを含みかつ疾病特異的な膜抗体でさらに機能化されたアプタマー機能性剤コンジュゲートを有するホスホリルコリン重合体。
実施例1:N−(2−ヒドロキシエチル)−エキソ−3,6−エポキシ−1,2,3,6−テトラヒドロフタリミドの調製
1HNMR(400MHz,CDCl3):δ=2.90(s,2H,CH),3.71(m,2H,OCH2),3.77(t,J=5.0Hz,NCH2),5.29(t,J=1.0Hz,2H,OCH),6.53(t,J=1.0Hz,2H,CH=CH)。
1HNMR(400MHz,CDCl3):δ=1.20(s,3H,CH3CC=O),1.43(s,3H,CH3),1.46(s,3H,CH3),3.70(d,J=12.4Hz,2H,OCH2),4.17(d,J=12.4Hz,2H,OCH2)。
1HNMR(400MHz,CDCl3):δ=1.89(s,6H,CH3),2.87(s,2H,CH),3.82(t,J=5.4Hz,2H,NCH2),4.33(t,J=5.4Hz,2H,OCH2),5.27(t,J=1.0Hz,2H,OCH),6.51(t,J=1.0Hz,2H,CHvinyl)。
保護されたマレイミドイソプロピリデン酸
1HNMR(400MHz,CDCl3):δ=1.19(s,3H,CH3CC=OO),1.37(s,3H,CH3),1.41(s,3H,CH3),1.55(s,6H,(CH3)2C),2.86(s,2H,C=OCHCHC=O),3.58(d,J=12Hz,CH2O),3.78(t,J=5.4Hz,CH2CH2O),4.14(d,J=12H,CH2O),4.30(t,J=5.4Hz,CH2CH2O),5.27(t,2H,CHOCH),6.51(s,2H,CH=CH)。
1HNMR(400MHz,CDCl3):δ=1.32(s,3H,CH 3CC=O),1.91[s,12H,(CH3)2CBr],2.90(s,2H,CHC=O),3.78(t,2H,NCH2CH 2O),4.28(t,2H,NCH 2CH2O),4.31(app q,4H,CH2OC=O),5.30(s,2H,CHOCH)
,6.52(s,2H,CH=CH)。
1HNMR(400MHz,CDCl3):δ=2.90(s,2H,CH),3.49(m,2H,OCH2),3.59(m,4H,OCH2),3.65(m,2H,NCH2),5.15(t,J=0.8Hz,2H,OCH),6.55(t,J=0.8Hz,2H,CH=CH)。
1HNMR(400MHz,CD3OD):δ=1.33(s,3H,CCH3),1.90(s,12H,(CH 3)2CBr),4.30(d,J=5.4Hz,2H,NCH2),4.39(d,J=5.4Hz,2H,OCH2)。
1HNMR(400MHz,CD3OD):δ=1.34(s,3H,CH3),1.90(s,6H,CH3),2.94(s,2H,CH),3.64(m,6H,OCH2),4.22(t,J=5.4Hz,2H,NCH2),4.35(app q,4H
,OCH2),5.15(t,J=1.0Hz,2H,OCH),6.54(t,J=1.0Hz,2H,CH=CH)。
NMR(CD3OD):δ6.546(t,2H,CH=CH,J=0.8Hz),5.158(t,2H,CH−O,J=0.8Hz),4.180(m,2H,CH2−CH 2−O−C=O,J=4.9Hz),3.63(m,10H,N−CH2 and N−CH2−CH 2 and CH 2−CH2−O−C=O and CH2−OH),2.936(s,2H,CH−CH),1.147(s,3H,CH3)。
NMR(CD3OD):δ6.55(t,2H,CH=CH,J=0.8Hz),5.17(t,2H,CH−O,J=0.8Hz),3.34(m,12H,CCH2),4.23(m,2H,CH2−CH 2−O−C=O,J=4.7Hz),3.68(m,2H,N−CH2,J=4.7Hz),3.64(appq,4H,N−CH2−CH 2andCH 2−CH2−O−C=O),2.95(s,2H,CH−CH),1.907(s,24H,Br−C−CH3),1.34(s,6H,CH3),1.308(s,3H,CH3)。
NMR(CDCl3):δ6.19(s,2H,CH=CH),4.37(app q,4H,CCH2O,J=10.9,29.7Hz),4.23(t,2H,CH2CH 2O,J=6.3Hz),4.15(t,2H,CH2CH 2O,J=6.3Hz),3.62(t,2H,NCH2,J=7.4Hz),3.22(s,2H,CHC=O),2.48(t,2H,CH2C=O,J=7.4Hz),2.00(m,2H,CH2CH 2CH2,J=6.3Hz),1.92(s,12H,Br−C(CH3)2),1.78(s,6H,CH3),1.35(s,3H,CH3)。
1HNMR(400MHz,CDCl3):δ=1.20(t,6H,CH 3CH2O),1.34(s,3H,CH 3CC=O),1.92[s,12H,(CH3)2CBr],1.98(app q,2H,CHCH 2CH2),3.50(m,2H,OCH
2CH3),3.66(m,2H,OCH 2CH3),4.24(t,2H,CH2CH 2OC=O),4.37(app q,4H,CH2OC=OCBr),4.60(t,
1H,O−CH−O)。
1HNMR(400MHz,CD3OD):δ=1.34(s,3H,CH3),1.77(m,2H,CH2CH 2CH2),1.90(s,12H,CH3),2.15(q,J=7.2Hz,2H,CHCH 2CH2),4.16(t,J=6.4Hz,2H,OCH2),4.36(app q,4H,CCH2O),5.02(m,2H,CH
2=CH),5.82(m,1H,CH2=CH)。
1HNMR(400MHz,CDCl3):δ=1.36(s,3H,CH3),1.92(s,12H,CH3),3.90(app q,J=5.4Hz,2H,NCH 2
CH2O),4.05(dd,1H,J=2.4,6.8Hz,=CH),4.19(dd,J=2.4,14.4Hz,1H,=CH),4.39(m,2H,NCH2CH 2O),4.40(app q,4H,OCH2),6.45(dd,1H,J=6.8,
14.4Hz,=CHO)。
1HNMR(400MHz,CDCl3):δ=4.8(br s,1H,NH),4
.37(app q,4H,CH2OC=OCBr),4.22(t,2H,CH2CH
2OC=O),3.20(app q,2H,NHCH2),1.92[s,12H,(
CH3)2CBr],1.85(t,2H,CH2CH 2CH2),1.43(s,9H,(CH3)3O),1.35(s,CH 3CC=O)。
NMR(CDCl3):δ6.70(t,1H,NH,J=5.4Hz),4.33(app q,4H,CH2O,J=16.3,11.4Hz),3.51(q,2H,N
CH2,J=6.0Hz),2.46(t,2H,CH2CO,J=6.0Hz),1.93(s,12H,Br−C(CH3)2),1.45(s,9H,C(CH3)3),1.33(s,3H,CH3)。
1HNMR(400MHz,CDCl3):δ=1.13(s,6H,CH3),1.25(s,3H,CH3),2.96(s,2H,CHC=ON),3.57−3.65(m,8H,CH2OH),3.64(t,J=2.8Hz,2H,CH2CH 2OC=O),4.22(app q,4H,C(CH3)CH 2OC=Ol),4.22(t,J=2.8Hz,CH 2CH2OC=O),5.21(t,J=0.8Hz,CHOCH),6.55(t,J=0.8Hz,CH=CH)。
1HNMR(400MHz,CDCl3):δ=1.26(s,3H,CH 3CC=O),1.34(s,6H,CH 3CC=O),1.90(s,24H,(CH3)2CBr),2.95(s,2H,CH),3.78(t,J=5Hz,2H,NCH2),4.25(m,6H,OCH2C(4H) and CH 2CH2N(2H)),4.35(app q,8H,OCH2),5.23(tJ=1Hz,2H,CHOCH),6.5
5(t,J=1Hz,2H,CH=CH)。
NMR(CD3OD):δ4.38(app q,4H,CCH2,J=11.2,30.2Hz),4.20(t,2H,CH 2OH,J=5.0Hz),3.75(t,2H,CH 2CH2OH,J=5.0Hz),1.90(s,12H,Br−CCH3),1.36(s,3H,CH3)。
NMR(CDCl3):δ4.38(app q,4H,CCH2O,J=11.2H
z),4.31(t,2H,CH2CH 2O,J=6.3Hz),3.71(q,2H,CH2OH,J=5.9Hz),1.92(s,12H,Br−C(CH3)2),1.9(m,2H,CH2CH 2CH2),1.35(s,3H,CH3)。
NMR(CDCl3):δ4.38(app q,4H,CCH2O,J=31.8,
11.2Hz),4.31(t,2H,CH2CH 2OC=O,J=5.0Hz),3.6−3.73(m,14H,CH2O),2.46(t,1H,OH,J=6.3Hz),1.92(s,12H,Br−C(CH3)2),1.35(s,3H,CH3)。
NMR(CDCl3):δ4.47(m,2H,CH2O(C=O)O),4.37(app q,4H,CCH2O,J=11.2,31.6Hz),4.30(m,2H,
CH2CH 2O(C=O)C),3.79(m,2H,CH 2CH2O(C=O)C),3.71(t,2H,CH 2CH2O(C=O)O,J=5.0Hz),3.67(s,4H,CH2O),3.65(s,4H,CH2O),2.84(s,4H,CH2C=O),1.92(s,12H,Br−C(CH3)2),1.35(s,3H,CH3)。
NMR(CDCl3):δ4.38(app q,4H,CCH2O),4.32(m,1H,OCH),4.19(m,2H,CHCH 2OC=O),4.07(d of d,1H,OCH 2CH,J=6.7,8.6Hz),3.76(d of d,1H,OCH 2CH,J=5.7,8.6Hz),1.92(s,12H,Br−C(CH3)2),1.43(s,3H,(CH3)2CO),1.36(s,3H,CH3),1.35(s,3H,(CH3)2CO)。
NMR(CDCl3+D2O):δ4.40(app qof d,4H,CCH2O,J=2.8,11.5,30.2Hz),4.24(app q of d,2H,CHC
H 2OC=O,J=4.5,6.6,11.5Hz),3.96(m,1H,CH),3.66(app q of d,2H,HOCH 2CH,J=3.8,5.6,11.5,
37.9Hz),1.92(s,12H,Br−C(CH3)2),1.37(s,3H,CH3)。
NMR(CDCl3):δ4.39(app q of d,4H,CCH2O,J=4.1,11.1,3.0,37.6Hz),4.31(t,2H,OCH2CH 2OC=O,J=4.7Hz),3.87(m,1H,CH−OH),3.54−3.77(m,2H,CH 2−OH),3.72(m,2H,OCH 2CH),3.58(app t,
2H,OCH 2CH2OC=O),2.68(d,1H,CH−OH,J=5.1Hz),2.15(app t,1H,CH2−OH,J=6.1Hz),1.92(s,12
H,Br−C(CH3)2),1.36(s,3H,CH3)。
NMR(CDCl3):δ5.87−5.97(m,1H,CH2CH=CH2),5.28(dq,1H,H−CH=CH),5.18(dq,1H,H−CH=CH),4.37(app q,CH 2OC=O),4.30(dd,2H,CH2CH 2OC=O),4.02(d,2H,CH2=CHCH 2),3.60−3.72(m,14H,CH2CH 2OCH2),1.92(s,12H,Br−C(CH3)2),1.35(s,3H,CH3)。
NMR(CDCl3):δ4.38(app q,4H,CCH2OC=O),4.30(t,2H,CH2CH 2OC=O,J=5.0Hz),3.85(p,1H,CHOH,J=5Hz),3.71(t,2H,OCH 2CHOH,J=4.8Hz),3.72−3.55(m,16H,OCH 2CH 2O and CH 2OH),3.12(s,1H,CHOH),2.37(s,1H,CH2OH),1.92(s,12H,Br−C(CH3)2),1.35(s,3H,CH3)。
1HNMR(400MHz,CDCl3):δ=1.23(s,3H,C=OCCH3),1.39(s,3H,CH3),1.43(s,3H,CH3),3.66(m,4H),4.02(dd,2H,CH2=CHCH 2),4.20(d,2H),4.31(t,2H,C=OOCH 2),5.18(dd,1H,=CH),5.28(dd,1H,=CH),5.89(m,=CHCH 2)。
1HNMR(400MHz,CDCl3):δ=5.84−5.94(ddt,1H,H2C=CHCH2),5.28(dq,1H,HHC=CHCH2),5.22(dq,1H,HHC=CHCH2),4.36(app t,2H,OCH 2CH2),4.
02(dt,2H,H2C=CHCH 2),3.86(dd,2H,CH2OH),3.74(dd,2H,CH2OH),3.68(app t,2H,OCH2CH 2),2
.90(br d,2H,OH),1.11(s,CH3)。
NMR(CDCl3):δ5.89(m,1H,CH2CH=CH2),5.28(d
of q,1H,H−CH=CH,J=17.2,1.7Hz),5.20(d of q,1H,H−CH=CH,J=10.5,1.5Hz),4.38(app q,4H,
CH2OC=O),4.31(t,2H,OCH2,J=4.7Hz),4.01(d
of t,2H,OCH2,J=5.6,1.5Hz),3.65(t,2H,OCH2
,J=4.7Hz),1.91(s,12H,Br−C(CH3)2),1.35(s,3H,CH3)。
NMR(CDCl3):δ5.88(m,1H,CH2CH=CH2),5.28(d
of q,1H,H−CH=CH,J=17.4,1.6Hz),5.20(d of q,1H,H−CH=CH,J=10.3,1.3Hz),4.24−4.44(m,14H,CH2OC=O),4.01(d,2H,CH2=CHCH 2,J=5.6),3.65(t,2H,CH2CH 2OCH2,J=4.7Hz),1.91(s,24H,Br−C(CH3)2),1.33(s,6H,CH3),1.30(s,3H,CH3)。
NMR(CDCl3):δ4.28−4.41(m,14H,CCH2OC=O),3.86(m,1H,CH2CHOHCH2),3.69−3.75(m,3H),3.56−3.65(m,3H),2.78(dd,1H,OH),2.23(app t,1
H,OH),1.92(s,24H,CH3CBr),1.34(s,6H,CH3),1.31(s,3H,CH3)。
NMR(CDCl3):δ4.39(app q,4H,CCH2O,J=11.1,
33.8Hz),4.31(t,2H,OCH2CH 2OC=O,J=5Hz),3.72(t,2H,CH2N3,J=5Hz),3.67(t,2H,CH 2CH2N3,J=5Hz),3.38(t,2H,OCH 2CH2OC=O,J=5Hz),1.92(s,12H,Br−C(CH3)2),1.36(s,3H,CH3)。
1HNMR(400MHz,CDCl3):δ=2.08(s,12H,CH3),7.29(t,1H,J=2.4Hz,ArH),7.61(d,J=2.4Hz,2H,ArH),10.0(s,1H,CHO)。
NMR(DMSO−d6):δ7.70−7.82(m,6H,PhH),7.26−7.51(m,9H,PhH),3.69−3.75(m,3H),3.56−3.65(m,3H),2.78(dd,1H,OH),2.23(app t,1H,OH),1.92(s,24H,CH3CBr),1.34(s,6H,CH3),1.31(s,3H,CH3)。
NMR(DMSO−d6):δ7.75(m,6H,CCH),7.44(m,6H,CCHCH),7.30(m,3H,CCHCHCH),5.86(m,1H,CH2=CH),5.70(s,1H,NCH(equatorial)),5.250(s,2H,NCH(axial)),5.23(d of q,1H,CH 2=CH),5.11(d of q,1H,CH 2=CH),3.93(d of t,2H,CH−CH 2−O),3.55−3.25(m,16H,OCH 2CH 2O),3.26(m,2H,NCH2),3.19(d,2H,NCH2),2.88(s,2H,NCH2),2.719(s,2H,CCH2O)。
NMR(DMSO−d6):δ8.004(t,3H,NH),5.87(m,1H,CH),5.23(d of q,1H,CH 2=CH),5.12(d of q,1H,CH 2=CH),3.93(d of t,2H,CH 2−CH),3.6−3.45(m,16H,OCH 2CH 2O),3.289(s,2H,CCH2O),3.12(d,6H,CCH2N),1.907(s,18H,CH3)。
NMR(CDCl3):δ7.91(t,3H,NH),3.88(m,1H,HOCH2CHOHCH2),3.55−3.72(complex m,21H),3.35(s,1H,OCH 2C(CH2)3),3.19(d,6H,J=6.4Hz,CH2NH),1.99(s,18H,CH3)。
NMR(CDCl3):δ7.76(t,3H,NH,J=6.3Hz),3.68(m,4H,OCH 2CH 2O),3.63(m,2H,N3CH2CH 2O),3.40(t,2H,N3CH2,J=5.0Hz),3.37(s,2H,CCH2O),3.19(d,6H,CCH2N,J=6.8Hz),1.99(s,18H,CH3)。
NMR(CDCl3):δ7.78(t,3H,NH,J=6.5Hz),5.91(m,1H,CH),5.27(d of q,1H,CH 2=CH,J=17.4,1.6Hz),5.18(d of q,1H,CH 2=CH,J=10.4,1.4Hz),4.38(app q,12H,CH2OC=O),4.01(d of t,2H,CH−CH 2,J=5.7,1.4Hz),3.61(two m,16H,OCH 2CH 2O
),3.30(s,2H,CCH2O),3.14(d,6H,CH2N,J=6.1Hz),1.92(d,36H,BrC(CH3)2,J=1.2Hz),1.38(s,9H,CH3)。
NMR(CDCl3):δ7.78(t,3H,NH,J=6.0Hz),4.39(app q,12H,CH2OC=O),3.86(broad s,1H,OH−CH),3.62(m,20H,OCH 2CH 2O and OHCHCH 2Oand OH−CH 2),3.27(s,2H,CCH2O),3.13(s,6H,NCH2),2.40(s,2H,OH),1.92(s,36H,BrC(CH3)2),1.38(s,9H,CH3)。
t−ブチル9−ヒドロキシ−4,7−ジオキサノナノエートメタンスルホネートの調製
NMR(CDCl3):δ4.38(m,2H),3.76(m,2H),3.70(t,2H,J=6.4Hz,C=OCH 2),3.61−3.66(m,4H),3.08(s,3H,OSO2CH3),2.49(t,2H,J=6.4Hz,C=OCH2CH 2),1.45(s,9H,CH3)。
NMR(CDCl3):δ3.73(t,2H,J=6.4Hz,C=OCH 2),3.63−3.69(m,6H),3.39(app t,2H,CH 2N3),2.51(t,2H,J=6.4Hz,C=OCH2CH 2),1.45(s,9H,CH3)。
NMR(CDCl3):δ3.79(t,2H,J=6.4Hz,C=OCH 2),3.68(app t,2H),3.67(s,4H),3.39(app t,2H,CH 2N3),2.66(t,2H,J=6.4Hz,C=OCH2CH 2)。
NMR(CDCl3):δ3.87(t,2H,J=6.4Hz,C=OCH 2),3.68(app t,2H),3.67(s,4H),3.39(app t,2H,CH 2N3),2.91(t,2H,J=6.4Hz,C=OCH2CH 2),2.84(br s,4H,CH2CH2)。
2−(2−アジドエトキシ)エタノールの合成
1HNMR(400MHz,CDCl3):δ=2.05(t,J=6.4Hz,1H,OH),3.42(t,J=5Hz,2H),3.63(dd,J=4.4,5.6Hz),3.71(dd,J=4.4,4.8Hz,2H),3.77(dt,J=4.4,6Hz,2H)。
1HNMR(400MHz,CDCl3):δ=1.97(quintet,J=7.2Hz,2H),2.45(t,J=7.2Hz,4H),3.39(t,J=4.8Hz,2H),3.66−3.72(m,4H),4.26(app t,J=4.6Hz
,2H)。
1HNMR(400MHz,CDCl3):δ=0.98(t,J=7.6H),1.98(quintet,J=7.2Hz,2H),2.13−2.32(complexm,2H),2.45(t,J=7.6Hz,2H),2.51−2.65(complex m,2H),3.35(t,J=5Hz,2H),3.63−3.68(m,4H),4.21−4.25(m,2H),5.30(br s,2H),5.41(d,J=17.2Hz,1H),5.68(d,J=17.2Hz,1H),7.21(s,1H),7.68(t,J=6.8Hz,1H),7.84(app t,J=8.4Hz,1H),7.95(d,J=8Hz,1H),8.23(d,J=8Hz,1H),8.40(s,1H)。
カンプトテシングラフト化共重合体のサンプルを、Trisバッファー(pH8.0)中の約10mg/mLで調製した。ウサギ肝臓からの肝臓エステラーゼ(Sigma−Aldrich・E0887−IKU,Lot#061K74451)をサンプルに加え、サンプルを37℃で65時間までインキュベートした。
重合
重合
4−アーム保護マレイミド官能化PC−重合体の調製
重合
重合
実施例39からの開始剤を使用した。重合反応混合物を−78℃にて充分に脱ガスし、反応を室温で64時間進行させた。反応物を空気に露出させて急冷した。メタノール1mL中に溶解したテトラブチルアンモニウムフルオライド100mgの溶液を反応混合物に添加した。粗反応混合物をシリカゲルに通し、濃縮し、ジエチルエーテル中に注意深く沈殿させた。固体をろ過によって単離し、ジエチルエーテルで数回洗浄した。重合体を40℃のオーブン内で1晩乾燥した。光散乱分析によれば、Mnは71,000g/molであり、Mpは64000g/molであり、そしてPDiは1.15であった。乾燥重合体の1HNMR分光分析によれば、TMS基は観察されなかった。
アルカリホスファターゼ(Sigma・Aldrich)を25mM−Hepes(pH7)(コンジュゲーションバッファー)にバッファー交換し、5〜8mg/mLに濃縮した。実施例60からのヘキサグルタミン酸含有アルデヒド官能化PC共重合体の3〜5xモル過剰下でコンジュゲーション反応を実施し、40mMシアノホウ化水素ナトリウムの存在下で最終タンパク質濃度1mg/mL以下のタンパク質とした。全ての反応を、クリンプでシールしたガラスビン中で室温にて1晩実施した。重合体からのジオール形をネガティブコントロールとして用いた。各反応物40μLを、Superdex200カラム(10/300mm)上で、1xPBS(pH7.4)中で1mL/分にて分画した。画分1mLを集め、アルカリホスファターゼ活性を以下のように試験した。SEC画分5μLを20mMTris(pH7.5)x5で希釈し、PNPP基質100μLを加え、サンプルを37℃で20分間インキュベートした。Molecular・DevicesからのSpectraMax−Plus384プレートリーダーを用いて、OD405nmを測定した。予想通り、ジオール官能化重合体を使用した場合には、コンジュゲーションは観察されなかった。しかしながら、アルデヒド官能化重合体の場合には、8〜10分の保持時間(これは、フリーの重合体及びより高い分子量種に相当する)、及び12〜13分の範囲(フリーアルカリホスファターゼに相当する)において、アルカリホスファターゼ活性が測定された。
ヒトFabの調製は、全ヒトIgG(Innovative・Research)のペプシン消化によってFab2を得、続いて、TCEPによる還元によってFabを得た。IgGのペプシン消化は、0.1M酢酸ナトリウム(pH4.5)中で4℃にて1晩実施して、90%を超える消化効率を得た。Fab2分画を、MacroCap・SPカラムを備えたカチオン交換クロマトグラフィーを用いて更に精製した。純粋なFab2分画を、100−200mM−NaClでpH5にて溶出し、一方で、フリーペプシン及びその他の全ての不純物を非結合分画に溶出した。続いて、純粋なFab2を、TCEPの2xモル比で37℃にて30分間還元し、ゲルろ過クロマトグラフィーを用いて、非還元Fab2及びフリーのTCEPからFabを精製した。続いて、Fab分画をプールし、コンジュゲーションバッファーにバッファー交換した。下記のコンジュゲーション実験は、実施例48からのカンプトテシン含有マレイミド官能化PC共重合体(84kDa)の13xモル過剰へのFab1mgのコンジュゲーション用である。コンジュゲーション反応は、2mMEDTAにより、10mM酢酸ナトリウム(pH5)中で実施した。最終のFab濃度は、コンジュゲーションバッファー中に溶解した重合体13xモル過剰及び還元剤としてのTCEP3xモル過剰の存在下で2.7mg/mLであった。重合体を100〜300mg/mLの濃度で、コンジュゲーションバッファー中に溶解し、TCEP及びFabを加えた。反応混合物を穏やかに混合し、暗所で室温にて1晩、コンジュゲーションを実施した。
コンジュゲーション反応条件、精製、分析及び結論は、以下の点を除いて、実施例62と本質的に同じであった。
本実施例では、全ヒトIgG(Innovative・Research)を、最初に、トラウト試薬(Traut’s reagent)により、1xPBS(pH7.4)中で、3倍モル過剰比で修飾した。反応用材料には、1xPBS(pH7.4)中の3mg/mLトラウト試薬及び10mg/mLのIgGが含まれており、反応容量は300μLであり、反応は、室温で暗所にて混合しながら、1時間実施した。反応完了後に、反応混合物に対し、10mLのBioGel・P30脱塩カラムを用い、2mM−EDTAにより、10mM酢酸ナトリウム(pH5)にバッファー交換を行なった。pH5では、EDTAの存在下で、スルホヒドリル基の酸化によるジスルフィド結合の形成が防止された。前記カラムを、OD280nm検出器、導電率計、及びフラクションコレクターを備えたAKTA・Prime・Plusと接続させた。タンパク質フラクションを集め、4.45mg/mLに濃縮した。サンプルは、こうして、重合体へのコンジュゲーションが準備された状態になった。SDS−PAGE分析は、これらの条件下でトラウト試薬によるIgGの修飾が、タンパク質凝集をもたらさなかったことを示した。
第1中間体
NMR(CDCl3):δ6.41(dd,1H,J=1.6,17.2Hz,ビニルCH),6.18(dd,1H,J=10.6,17.2Hz,ビニルCH),5.90(dd,1H,J=1.6,10.4Hz,ビニルCH),4.35(m,2H),4.27(m,2H),4.11(m,2H),3.63(m,2H),3.22(s,9H,N(CH3)3)。
NMR(CDCl3):δ6.18(t,1H,CCH2,J=1.2Hz),5.62(p,1H,CCH2,J=1.6Hz),4.76(s,2H,CH2),1.97(d of d,3H,CCH3,J=1.0,1.6Hz),0.187(s,9H,Si(CH3)3)。
NMR(CDCl3):δ6.25(s,1H,CH),4.08(app d of
d,2H,NCH2,J=2.6,5.3),3.72(s,2H,ICH2),2.28(t,1H,NH,J=2.6Hz)。
NMR(CDCl3):δ2.89(d of d,2H,CH 2C=O,J=7.9,6.4Hz),2.85(s,4H,O=CCH 2CH 2C=O),2.62(app
d of d of d,2H,CHCCH 2,J=8.6,6.9,2.7Hz),2.06(t,1H,CH,J=2.7Hz)。
NMR(CDCl3):δ6.77(s,2H,CHC=O),4.30(d,2H,NCH2,J=2.4Hz),2.22(t,1H,CCH,J=2.5Hz)。
NMR(CDCl3):δ9.81(t,1H,CH=O,J=2.6Hz),2.61(t of d,2H,CH 2CH=O,J=7.1,1.2Hz),2.28(t o
f d,2H,CCH2,J=7.1,2.6Hz),1.99(t,1H,CCH,J
=2.6Hz),1.86(p,2H,CCH2CH 2,J=7.0Hz)。
組換えヒトエリスロポエチン(R&D Systems)を25mM−Hepes(pH7:コンジュゲートバッファー)にバッファー交換し、5mg/mLに濃縮した。実施例60からのヘキサグルタミン酸含有アルデヒド官能化PC共重合体の3〜5Xモル過剰量で、40mMシアノホウ化水素ナトリウムの存在下で、最終タンパク質〜1mg/mLで、タンパク質へのコンジュゲート反応を実施した。全ての反応は、クリンプ密封ガラスビン内で、1晩室温で実施された。重合体のジオール型をネガティブコントロールとして用いた。反応物40μLごとに、1xPBS(pH7.4)中の1mL/minでのSuperdex200カラム(10/300mm)でフラクション化した。1mLのフラクションを収集し、OD220nm及びOD280nmで分析した。予想通り、ジオール官能化重合体を用いた場合には、コンジュゲートは観察されなかった。しかしながら、アルデヒド官能化重合体の場合には、OD280nm:OD220nm比が、8〜10分の保持時間(ここで、フリーの重合体及びより高い分子量種が溶出する)におけるフリー重合体単独の場合よりも非常に高いので、エリスロポエチン−重合体コンジュゲートの存在が観察された。フリーのエリスロポエチンは、14−15分で溶出された。
9−(メタクリロイルオキシ)−4,7−ジオキサノナノン酸,t−ブチルエステルの調製
NMR(CDCl3):δ6.13(br m,1H,C=CHH),5.57(br app t,1H,J=1.6Hz,C=CHH),4.29(app t,2H,J=4.8Hz,C=OOCH 2),3.70−3.76(m,4H),3.61−3.67(m,4H),2.50(t,2H,J=6.4Hz,C=OCH 2),1.95(app
t,3H,CH2=CCH 3),1.45(s,9H,C(CH3)3)。
NMR(CDCl3):δ6.14(br m,1H,C=CHH),5.58(br app t,1H,J=1.6Hz,C=CHH),4.31(app t,2H,J=4.8Hz,C=OOCH 2),3.73−3.80(overlapping tm,4
H,J=6Hz),3.66(m,4H),2.65(t,2H,J=6Hz,C=OCH 2),1.95(app t,3H,CH2=CCH 3)。
NMR(1H,CD3OD):δ6.10(h,1H,CH2,J=0.9Hz),5.61(p,1H,CH2,J=1.6Hz),4.27(m,2H,CH2OC=O),3.87(t,2H,CH 2CH2C=O,J=6.0Hz),3.75(m,2H,CH 2CH2OC=O),3.67(s,4H,OCH 2CH 2O),2.98(t,2H,CH2C=O,J=6.0Hz),1.92(d of d,3H,CH3,J=1.6,0.9Hz).NMR(19F,CD3OD):δ−140.92(m,2F,SCCF),155.00(m,2F,OCCF)。
(2−ブロモエチル)メタクリレートの調製
NMR(CDCl3):δ6.18(app p,1H,J=1.1Hz,C=CHH
),5.62(p,1H,C=CHH,J=1.6Hz),4.46(t,2H,J=6.0Hz,CH2OC=O),3.56(t,2H,CH2Br,J=6.0Hz),1.97(dd,3H,J=1.4,1.1Hz,CH3C=C)。
NMR(CD3OD):δ6.11(h,1H,CH2,J=0.9Hz),5.62(p,1H,CH2,J=1.6Hz),4.47(t,2H,OCH2,J=6.9Hz),3.31(t,2H,SCH2,J=6.9Hz),1.93(d of d,3H,CH3,J=1.5,1.0Hz)。
Claims (19)
- 第一の単量体と第二の単量体とを含むランダム共重合体であって、
前記第一の単量体がホスホリルコリンを含み、前記第二の単量体が第一の機能性剤に連結されており、前記第一の単量体及び前記第二の単量体が、前記重合体全体にわたってランダムに分布されており、前記ランダム共重合体が、分枝状開始剤フラグメントから重合される複数のアームを有しており、前記第一の単量体及び前記第二の単量体が、それぞれ独立して、アクリレート、メタクリレート、アクリルアミド、メタクリルアミド、スチレン、ビニル−ピリジン、及びビニル−ピロリドンからなる群から選択されており、そして、前記第一の機能性剤が、独立して、生体活性剤、標的化剤、検出剤、イメージング剤、標識化剤、及び診断剤からなる群から選択される、前記ランダム共重合体。 - 前記開始剤フラグメントが第二の機能性剤に連結されており、その第二の機能性剤が、独立して、生体活性剤、標的化剤、検出剤、イメージング剤、標識化剤、及び診断剤からなる群から選択される、請求項1に記載のランダム共重合体。
- 前記第一の機能性剤が前記第二の機能性剤と異なる、請求項2に記載のランダム共重合体。
- 前記開始剤フラグメントが、アルカン、シクロアルカン、アルキルカルボン酸、アルキルカルボン酸のエステル、シクロアルキルカルボン酸、シクロアルキルカルボン酸のエステル、エーテル、環式アルキルエーテル、アルキルアリール基、アルキルアミド、アルキル−アリールカルボン酸、及びアルキル−アリールカルボン酸のエステルから選択される、請求項1に記載のランダム共重合体。
- 前記第一の単量体が、2−(メタクリロイルオキシ)エチル(2−(トリメチルアンモニオ)エチル)ホスフェートを含む、請求項1に記載のランダム共重合体。
- 前記重合体が、2、3、4、5、6、7、8、又は9の重合体アームを有する、請求項1に記載のランダム共重合体。
- 約100〜約1,000の第一の単量体、及び約100〜約1,000の第二の単量体を含む、請求項1に記載のランダム共重合体。
- 約10〜約5,000の第一の単量体、及び約10〜約5,000の第二の単量体を含む、請求項1に記載のランダム共重合体。
- 前記第二の単量体が、前記第一の単量体に対して、100:1、50:1、40:1、30:1、20:1、10:1、9:1、8:1、7:1、6:1、5:1、4:1、3:1、2:1、1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8、1:9、1:10、1:20、1:30、1:40、1:50、又は1:100の比で存在する、請求項8に記載のランダム共重合体。
- 光散乱法によって決定される約1,000〜約1,500,000ダルトンの重量平均分子量を有する、請求項8に記載のランダム共重合体。
- ゲル透過クロマトグラフィーによって決定される約1.5未満の多分散性を有する、請求項10に記載のランダム共重合体。
- 前記第二の単量体が、開裂性リンカーを介して、前記第一の機能性剤に連結する、請求項1に記載のランダム共重合体。
- 前記開裂性リンカーが、加水分解性リンカー、酵素的開裂性リンカー、pH感受性リンカー、ジスルフィドリンカー、及び光不安定性リンカーからなる群から選択される、請求項12に記載のランダム共重合体。
- 前記第二の単量体が、非開裂性リンカーを介して、前記第一の機能性剤に連結する、請求項1に記載のランダム共重合体。
- 前記第二の単量体が、トリアゾール環を含むリンカーを介して、前記第一の機能性剤に連結する、請求項1に記載のランダム共重合体。
- 前記第一の機能性剤が生体活性剤である、請求項1に記載のランダム共重合体。
- 前記生体活性剤が治療タンパク質である、請求項16に記載のランダム共重合体。
- 前記生体活性剤が抗体又は抗体フラグメントである、請求項16に記載のランダム共重合体。
- 前記生体活性剤が薬剤である、請求項16に記載のランダム共重合体。
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EP4041312A4 (en) | 2019-10-10 | 2023-12-20 | Kodiak Sciences Inc. | METHOD FOR TREATING AN EYE DISORDER |
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US10363290B2 (en) | 2014-10-17 | 2019-07-30 | Kodiak Sciences Inc. | Butyrylcholinesterase zwitterionic polymer conjugates |
US11071771B2 (en) | 2014-10-17 | 2021-07-27 | Kodiak Sciences Inc. | Butyrylcholinesterase zwitterionic polymer conjugates |
US12071476B2 (en) | 2018-03-02 | 2024-08-27 | Kodiak Sciences Inc. | IL-6 antibodies and fusion constructs and conjugates thereof |
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