JP5948627B2 - 線維芽細胞成長因子(fgf)のリモデリングと糖質ペグ化 - Google Patents
線維芽細胞成長因子(fgf)のリモデリングと糖質ペグ化 Download PDFInfo
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Description
本出願は2004年10月29日に出願の米国仮特許出願60/623,342に関連し、全体を多目的のために本出願に関して参考として組み入れる。
復を含む多重生物活性を有する(例えばベイアード、エイ等(Baird, A. et.al.)、キャンサーセル(Cancer Cells)、3巻、239−243頁(1991)及びバーゲス、ダブリュエッチ等(Burgess, W.H., et al.)、アニュアルレビュオブバイオケミストリー(Annu. Rev. Biochem.)、58巻、575−606頁(1989)参照)。
この式による分岐ポリマー種は実質的に水溶性ポリマーである。X3'はイオン化可能基(例えばOH、COOH、H2PO4、HSO3、NH2及びその塩など)又は他反応性官能基、例えば以下の基を含む成分である。Cは炭素原子である。X5、R16及びR17は非反応性基(例えば、水素原子、非置換アルキル又は非置換ヘテロアルキル)とポリマーアーム(例えばPEG)から独立に選ぶ。X2及びX4は好ましくは生理的条件下では実質的に非反応性で、同一又は異なっても良い結合断片である。代表的リンカーとしては芳香族成分もエステル成分も含まれれない。代わりにこれら結合は生理関連条件下で分解するように設計した一つ以上の成分、例えばエステル、ジスルフィドなどが挙げられる。X2及びX4によりポリマーアームR16とR17を炭素原子と連結する。X3'がリンカー−糖又はリンカー−糖カセットのような補足反応性を持つ反応性官能基と反応する場合、X3'は結合断片成分X3に変換する。
R1はポリマー型修飾基であり、Lは一つの結合及び一つの連結基から選ぶ。指数wは1―6、好ましくは1―3、より好ましくは1―2から選んだ整数を表す。代表的連結基としては置換アルキル又は非置換アルキル、置換ヘテロアルキル又は非置換ヘテロアルキル成分及びシアル酸が挙げられる。リンカーの代表的成分はアシル成分である。他の代表的連結基はアミノ酸残基(例えば、システイン、セリン、リシン及び短鎖オリゴペプチド、例えば、Lys―Lys、Lys―Lys―Lys、Cys―Lys、Ser―Lys等)である。
PEG、ポリエチレングリコール;PPG、ポリプロピレングリコール;Ara、アラビノシル
;Fru、フルクトシル;Fuc、フコシル;Gal、ガラクトシル;GalNAc、N―アセチルガラクトサミニル;Glc、グルコシル;GlcNAc、N―アセチルグルコサミニル;Man、マンノシル;ManAc、マンノサミニルアセテート;Xyl、キシロシル;NeuAc、シアリル又はN―アセチルノイラミニル;Sia、シアリル又はN―アセチルノイラミニル及びそれら誘導体と類似体。
別に定義しない限りここに用いた全技術科学用語は、通常本発明が属する技術の通常技量者が一般に理解するのと同じ意味を有する。通常ここで用いた細胞培養、分子遺伝学、有機化学及び核酸化学とハイブリダイゼーションでの命名法と実験室手順は、技術的によく知られ通常的に使用されるものである。核酸とペプチド合成に標準的技法が用いられる。その技法と手順は技術的に在来法と本文書を通じて提供される種々の一般文献(サムブロック等(Sambrook, et al.)、モレキュラークローニング:ラボラトリーマニュアル(Molecular Cloning: A Laboratory Manual)、2版(1989年)、コールドスプリングハーバーラボラトリープレス(Cold Spring Harbor Laboratory Press)、コールドスプリングハーバー(Cold Spring Harbor)ニューヨーク(N.Y.)を通常参照し、ここに文献として取り入れる)により実施する。通常ここで用いた以下に記載の分析化学と有機化学での命名法と実験手順は技術的によく知られ通常的に使用されるものである。化学合成と化学分析に標準法やそれらの修正法が用いられる。
アラニン(A)、グリシン(G);
アスパラギン酸(D)、グルタミン酸(E);
アスパラギン(N)、グルタミン(Q);
アルギニン(R)、リシン(K);
イソロイシン(I)、ロイシン(L)、メチオニン(M)、バリン(V);
フェニルアラニン(F)、チロシン(Y)、トリプトファン(W);
セリン(S)、スレオニン(T)及び
システイン(C)、メチオニン(M)
(例えば、クレイトン(Creighton)、プロテイン(Proteins)(1984年)参照)。
2−ブタジエニル、2,4−ペンタジエニル、3−(1,4―ペンタジエニル)、エチニル、1−プロピニルと3−プロピニル、3−ブチニル及び高級同族体と異性体が挙げられる。“アルキル”という用語は別に記述しない限り、“ヘテロアルキル”のような以下により詳しく定義するアルキル誘導体を含むことを意味する。炭化水素基は限定したアルキル基は“ホモアルキル”と称する。
アリール基(又は複数環)を意味し、該窒素原子と硫黄原子は酸化されていても良く、且つ一つ又は複数の該窒素原子は4級化されていても良い。ヘテロアリール基はヘテロ原子により該分子残部と結合できる。アリール基とヘテロアリール基の非制限例としては、フェニル、1−ナフチル、2−ナフチル、4−ビフェニル、1−ピロリル、2−ピロリル、3−ピロリル、3−ピラゾリル、2−イミダゾリル、4−イミダゾリル、ピラジニル、2−オキサゾリル、4−オキサゾリル、2−フェニル―4―オキサゾリル、5−オキサゾリル、3−イソオキサゾリル、4−イソオキサゾリル、5−イソオキサゾリル、2−チアゾリル、4−チアゾリル、5−チアゾリル、2−フリル、3−フリル、2−チエニル、3−チエニル、2−ピリジル、3−ピリジル、4−ピリジル、2−ピリミジル、4−ピリミジル、5−ベンゾチアゾリル、プリニル、2―ベンゾイミダゾリル、5−インドリル、1−イソキノリル、5−イソキノリル、2−キノオキサリニル、5−キノオキサリニル、3−キノリル、テトラゾリル、ベンゾ[b]フラニル、ベンゾ[b]チエニル、2,3−ジヒドロベンゾ[1,4]ダイオキシン―6―イル、ベンゾ[1,3]ダイオキソール―5―イル及び6−キノリルが挙げられる。上記の各アリールとヘテロアリール環系に対する置換基は以下に記載の容認置換基群から選ぶ。
FGF―9は脳と子宮内膜で分泌蛋白質として発現する線維芽細胞成長因子である。208アミノ酸ヘパリン結合タンパク質は、野生型状態で非グリコシル化されていると考えられる。FGF―9は運動ニューロンと前立腺で見られるように、グリア細胞発達とFGF受容体を発現する他細胞増殖活性化で、自己分泌/パラ分泌成長因子として重要な役割を果たす。
FGF―18はFGFファミリの他構成員である。これは肝増殖と腸増殖刺激に関与し、骨軟骨分化の必須制御因子である。FGF―9のようにこのものは又野生型状態で非グリコシル化されていると考えられる。この207アミノ酸タンパク質は又筋線維芽細胞増殖分化を刺激して出生後の肺発達に関与する。FGF―18はカルシニュリンにより誘導されてノギン発現を阻止する能力があり、有効な神経保護剤として働く。
FGF―20は脳(例えば小脳と黒質緻密部)で分泌蛋白質として発現し、見掛け分子量が23キロダルトン単量体として大腸菌で発現する新規線維芽細胞成長因子である。この211アミノ酸ヘパリン結合タンパク質は、野生型状態で非グリコシル化されていると考えられる。その生物活性としては、神経発生、神経保護、中枢神経系(CNS)再生、抗炎症作用(例えば、腸抗炎症剤)及び創傷治癒が挙げられ、パーキンソン病やアルツハイマー症のような疾患治療用の有効薬剤となりうる。FGF―20は例えば化学療法及び放射線療法、核テロ/放射性物質テロ、放射線事故などで生ずる胃腸部や体の他部分での放射線毒性に対して、又は予防薬か緩和薬として用い得る。幾つかの研究でFGF―20は又穏和な紅斑から重症の有痛潰瘍形成範囲の症状を示す病気である口腔粘膜炎防止治療への有効性が示された。
本発明は野生型ペプチドには見られない一つ以上のO−連結かN−連結グルコシル化部位を含むFGF変異体を提供する。該変異体は野生型ペプチドでは通常はグルコシル化されないか、殆どグリコシル化されない一つ以上の部位で酵素的グリコシル化する基質である。従って該変異体ではグリコシル残基又はグリコシル連結基の位置を操作して、選択の所望物性を有するペプチドが得られる。グリコシル残基又はグリコシル連結基の位置と数以外に、該発明の変異体と方法を用いて変化できる他物性としては、薬物動態力学、薬力学、タンパク質分解耐性、免疫原性、細網内皮系による認識、組織分配及び類似体が挙げられる。
(FGFコード配列の獲得)
一般的組み換え技術
野生型FGFコード配列のクローン化とサブクローニング
FGF配列への変異導入
宿主生物での好ましいコドン使用用核酸の修飾
変異FGFの発現と精製
発現系
形質移入法
宿主細胞中の変異FGF発現の検出
組み換え産生変異FGFの精製
細菌からの組み換え産生変異FGFの精製
精製のための一般的タンパク質分離法
溶解度分画
サイズ分画濾過
カラムクロマトグラフィ
変異FGF発現検出用イムノアッセイ
変異FGFに対する抗体の産生
変異FGF発現検出用イムノアッセイ
変異FGFによるグリコシル化と複合糖質化
酵素法によるグリコシル化と複合糖質化
ペプチド複合物
ぺプチドバックボーンのアミノ酸残基と直接結合したグリコシル連結基を含むことができる。更に他の典型的実施形態ではペプチド複合物はFGFペプチドと該ペプチドのアミノ酸残基に直接連結した修飾基を含むことができる。本実施形態では該ペプチド複合物はグリコシル基を含まない。これら実施形態にいずれでも該FGFペプチドはグリコシル化されてもされなくても良い。本発明は又FGF上でのグリカン構造修飾法も含み、FGFと修飾基間の複合物を提供する。
ここでa、b、c、d及びsはゼロではない正の整数を表し、tはゼロか正の整数のいずれかである。“薬剤”は治療薬、生物活性薬剤、検出可能標識、水溶性成分(例えばPEG、m−PEG、PPG及びm−PPG)又は類似体である。“薬剤”はペプチド、例えば酵素、抗体、抗原などでも良い。リンカーは下記の広範囲の連結基のいずれかである。代わりにリンカーは単結合又は“ゼロ次リンカー”でも良い。
修飾糖
該発明成分の形成に有用な他糖成分としては限定されないが、フコース及びシアル酸、更にはグルコサミン、ガラクトサミン、マンノサミン、シアル酸の5アミン類似物及び類似体が挙げられる。該糖成分は天然に見出される構造でも良く、又該修飾基を複合化する部位を提供するように修飾しても良い。例えば一実施形態では該修飾糖は9―水酸基成分がアミンで置換されたシアル酸誘導体を提供する。該アミンは選択修飾基の活性化類似物で容易に誘導化される。
ここでR11―R14はH, OH, C(O)CH3, NH及び NHC(O)CH3から独立に選んだ構成員である。 R10は他のグリコシル残基(―O―グリコシル)又は第VII因子及び/又は活性化第VII因子ペプチド(―NH―(第VII因子及び/又は活性化第VII因子)のアミノ酸とのリンクである。R14はOR1、NHR1又は NH―L―R1である。R1とNH―L―R1は上記した。
グリコシル連結基
ここでJはグリコシル成分、Lは結合又はリンカー、R1は修飾基、例えばポリマー型修飾基である。代表的結合はグリコシル成分のアミノ成分と修飾基の相補的反応性基間で形成されるものである。例えばR1がカルボン酸成分を含む場合、この成分は活性化されグリコシル残基のアミノ成分と結合してNHC(O)R1構造を有する結合を与える。Jは好ましくはピラノース構造やフラノース構造を切断する条件、例えば酸化条件、例えば過ヨウ素酸ナトリウムに暴露しても分解していない“無傷な”グリコシル成分である。
―NH{C(O)(CH2)aNH}s{C(O)(CH2)b(OCH2CH2)cO(CH2)dNH}tR1で、ここで指数sとtは独立にゼロか1である。指数a、b及びdは独立に0から20の整数であり、cは1から2500の整数である。他の類似リンカーは―NH成分が他の基、例えば―S、―O又は―CH2で置換された種に基づく。技術の熟知者には指標sとtに対応する一つ以上の括弧内成分が、置換又は非置換アルキル成分又はヘテロアルキル成分で置換できることが分かる。
NHC(O)(CH2)aNHC(O)(CH2)b(OCH2CH2)cO(CH2)dNHR1、NHC(O)(CH2)b(OCH2CH2)cO(CH2)dNHR1、NHC(O)O(CH2)b(OCH2CH2)cO(CH2)dNHR1、NH(CH2)aNHC(O)(CH2)b(OCH2CH2)cO(CH2)dNHR1、NHC(O)(CH2)aNHR1、NH(CH2)aNHR1及びNHR1。これらの式で指標a、b及びdは整数0から20、好ましくは1から5から独立に選ぶ。指標cは1から約2500の整数である。
式IでR2は水素原子、CH2OR7、 COOR7 又はOR7であり、R7は水素原子、置換又は非置換アルキル又は置換又は非置換ヘテロアルキルである。COOR7がカルボン酸かカルボキシレートの場合には、両形は単一構造COO―またはCOOHの意味で表される。式Iと式IIで記号R3、R4、R5、R6及びR6'は独立に水素原子、置換又は非置換アルキル、OR8、NHC(O)R9を表す。指数dはゼロか1である。R8及びR9は水素原子、置換又は非置換アルキル又は置換又は非置換ヘテロアルキル、シアル酸又はポリシアル酸から独立に選ぶ。R3、R4、R5、R6及びR6'の少なくとも一つは修飾基を含む。この修飾基はポリマー型修飾成分、例えばPEGを一結合か一連結基を通して連結する。典型的実施形態ではR6及びR6'はこれらが付着した炭素原子と一緒にしたシアル酸のピルビル酸の側鎖成分である。更なる典型的実施形態では該ピルビル酸側鎖は該ポリマー型修飾基で機能化する。他の典型的実施形態ではR6及びR6'はこれらが付着した炭素原子と一緒にシアル酸の側鎖成分であり、該ポリマー型修飾基はR5の成分である。
ここで置換基は上記の通りである。グリコシル連結基としては制限無しでブドウ糖、グルコサミン、N−アセチルグルコサミン、ガラクトース、ガラクトサミン、N−アセチルガラクトサミン、マンノース、マンノサミン、N−アセチルマンノサミン及び類似体が挙げられる。
ここでDは水酸基及びR1−L−NH−から選んだ構成員である。Gは水素原子、R1−L−及び−C(O)(C1−C6)アルキルから選んだ構成員である。R1は直鎖又は分岐鎖ポリエチレングリコール残基からなる成分である。Lはリンカー、例えば結合(“ゼロ次”)、置換又は非置換アルキル又は置換及び非置換ヘテロアルキルである。典型的実施形態ではDが水酸基の場合、GはR1−L−であり、Gが−C(O)(C1−C6)アルキルの場合、DはR1−L−NH−である。
ここで指数tはゼロか1である。
ここで指数tはゼロか1である。
ここで指数pは1から10の整数を表し、aはゼロか1である。
このテーマによる典型種はSia−Sia結合を形成する酵素、例えばCST−II、ST8Sia−II、ST8Sia−III及びST8Sia−IVを用いてSia−L−R1をグリカンの末端シアル酸に複合化して産生する。
ここでR15は該シリアル連結基であり、指数pは1から10で選ぶ整数である。
ここでbは0乃至1の整数である。指数sは1から10の整数を表す。指数fは1から2500の整数を表す。
修飾基
修飾基のリンカー
R1はポリマー成分でありLは結合と連結基から選ぶ。指数wは1乃至6、好ましくは1乃至3、より好ましくは1乃至2から選ぶ整数である。典型的連結基としては置換又は非置換アルキル、置換又は非置換ヘテロアルキル成分及びシアル酸が挙げられる。リンカーの典型的成分はアシル成分である。
ここでsは0乃至20の整数であり、R1は線形ポリマー型修飾成分である。
ここでR1とLは上に検討したものであり、w’は2乃至6、好ましくは2乃至4、より好ましくは2乃至3の整数である。
水溶性ポリマー
ここでR2は水素原子、置換又は非置換アルキル、置換又は非置換アリール、置換又は非置換ヘテロアリール、置換又は非置換ヘテロシクロアルキル、置換又は非置換ヘテロアルキル、例えば、アセタール、OHC―、 H2N−CH2CH2−、 HS−CH2CH2− 、−(CH2)qC(Y1)Z2、―糖―ヌクレオチド又はタンパク質である。指数“n”は1乃至2500の整数を表す。指数m、o及びqは0乃至20の整数を独立に表す。記号Zは水酸基、アミノ基、ハロゲン原子、S−R3、活性エステルのアルコール部分、−(CH2)pC(Y2)V、−(CH2)pU(CH2)sC(Y2)v、糖―ヌクレオチド、タンパク質及び離脱基、例えばイミダゾール、p−ニトロフェニル、HOBT、テトラゾール、ハロゲン化物を表す。記号X,Y1、Y2、W,Uは独立に酸素原子、硫黄原子、N−R4を表す。記号Vは水酸基、アミノ基、ハロゲン原子、S−R5、活性エステルのアルコール部分、活性化アミドのアミン部分、糖―ヌクレオチド及びタンパク質を表す。指数p、s及びvは整数0乃至20から独立に選んだ構成員である。記号R3 、R4及びR5は水素原子、置換又は非置換アルキル、置換又は非置換ヘテロアルキル、置換又は非置換アリール、置換又は非置換ヘテロシクロアルキル、置換又は非置換複素アリールを独立に表す。
技術者にはジリシン構造での遊離アミンが又アミド又はウレタン結合によりPEG成分とペグ化できることが分かる。
ここで指数e、f及びf‘は1乃至2500の整数から独立に選ばれ、指数q、q’及びq”は1乃至20の整数から独立に選ばれる。
該発明の本実施形態による分岐PEG含有ペプチド複合物形成に用いる他の典型的前駆体は以下の式を有する。
ここで指数mとnは0乃至5000から独立に選んだ整数である。A1、A2、A3、A4、A5、A6、A7、A8、A9、A10及びA11は水素原子、置換又は非置換アルキル、置換又は非置換ヘテロアルキル、置換又は非置換シクロアルキル、置換又は非置換ヘテロシクロアルキル、置換又は非置換アリール、置換又は非置換ヘテロアリール、−NA12A13, −OA12 及び−SiA12A13から独立に選んだ構成員である。A12及びA13は置換又は非置換アルキル、置換又は非置換ヘテロアルキル、置換又は非置換シクロアルキル、置換又は非置換ヘテロシクロアルキル、置換又は非置換アリール、置換又は非置換ヘテロアリールから独立に選んだ構成員である。
この実施形態では典型的リンカーは天然アミノ酸又は非天然アミノ酸、アミノ酸類似体、アミノ酸擬態者又はこれら一種以上で形成の小ペプチドから誘導される。例えば、該発明化合物で見出されるある分岐ポリマーは下式を有する。
ここでXbは第二の結合断片でありXaに示した基から独立に選び且つLと同じであり,
L1は結合、置換又は非置換アルキル、置換又は非置換ヘテロアルキルである。
ここで種々の記号で表される官能基のアイデンティティは上で検討したものと同じである。Laは上でLとL1に関して検討した結合又はリンカー、例えば置換又は非置換アルキル、置換又は非置換ヘテロアルキル成分である。典型的実施形態ではLaは示したようなポリマー型修飾成分で機能化したシアル酸側鎖成分である。典型的La成分としては一つ以上の水酸基又はアミノ基含有の置換又は非置換アルキル鎖が挙げられる。
種々の記号で表される官能基のアイデンティティは上で検討したものと同じである。熟知者には分かるように式VIIと式VIIIのリンカーアームはここに示した他修飾糖に同様に適応できる。典型的実施形態では式VIIと式VIII種はここに示したグルカン構造に付着したR15成分である。
ここで官能基のアイデンティティは上に検討したものである。Laの典型種は−(CH2)jC(O)NH(CH2)hC(O)NH−であり、指数hとjは0乃至10から独立に選んだ整数である。更なる典型種は−C(O)NH−である。指数mとnは0乃至5000から独立に選んだ整数である。A1、A2、A3、A4、A5、A6、A7、A8、A9、A10及びA11は水素原子、置換又は非置換アルキル、置換又は非置換ヘテロアルキル、置換又は非置換シクロアルキル、置換又は非置換ヘテロシクロアルキル、置換又は非置換アリール、置換又は非置換ヘテロアリール、−NA12A13, −OA12 及びSiA12A13から独立に選んだ構成員である。A12及びA13は置換又は非置換アルキル、置換又は非置換ヘテロアルキル、置換又は非置換シクロアルキル、置換又は非置換ヘテロシクロアルキル、置換又は非置換アリール、置換又は非置換ヘテロアリールから独立に選んだ構成員である。
10キロダルトン、15キロダルトン、20キロダルトン、25キロダルトン、30キロダルトン、35キロダルトン、40キロダルトン及び45キロダルトンのPEGが使用される。
上記の各構造でリンカー断片−NH(CH2)n−はあってもなくても良い。
とトリリシンペプチド(Lys−Lys―Lys)、例えば
を基にした構造を有する。
上の各図で指数e、f、f‘及びf“は1乃至2500から独立に選んだ整数である。指数q、q’及びq”は1乃至20から独立に選んだ整数である。
以下から選んだ構成員式を有する。
ここでQは水素原子及び置換又は非置換C1−C6アルキルから選んだ構成員である。指数e及びfは1乃至2500から独立に選んだ整数であり、指数qは0乃至20から選んだ整数である。
以下から選んだ構成員式を有する。
ここでQは水素原子及び置換又は非置換C1−C6アルキルである。指数e、f及びf‘は1乃至2500から独立に選んだ整数であり、指数qとq’は1乃至20から独立に選んだ整数である。
ここで指数m及びnは0乃至5000から独立に選んだ整数である。A1、A2、A3、A4、A5、A6、A7、A8、A9、A10及びA11は水素原子、置換又は非置換アルキル、置換又は非置換ヘテロアルキル、置換又は非置換シクロアルキル、置換又は非置換ヘテロシクロアルキル、置換又は非置換アリール、置換又は非置換ヘテロアリール、−NA12A13, −OA12 及びSiA12A13から独立に選んだ構成員である。A12及びA13は置換又は非置換アルキル、置換又は非置換ヘテロアルキル、置換又は非置換シクロアルキル、置換又は非置換ヘテロシクロアルキル、置換又は非置換アリール、置換又は非置換ヘテロアリールから独立に選んだ構成員である。
典型的実施形態ではA1とA2はそれぞれメトキシ基または水素原子である。
指数a、b及びdは0乃至20の整数である。指数cは1乃至2500の整数である。上に示した構造はR15の成分でも良い。
上に示した構造はR15の成分でも良い。
ここでX4は結合又は酸素原子である。上記の各構造でアルキルアミンリンカー−(CH2)aNH−はあってもなくても良い。上に示した構造はR15/R15'の成分でも良い。
ここで指数qとeは上に検討したものである。
ここで指数tは0乃至1の整数である。指数sは1乃至10の整数を表し、指数fは1乃至2500の整数を表す。
非水溶性ポリマー
生体分子
方法
例えば、ステマー(Stemmer)、プロシーディングオブナショナルアカデミーオブサイエンスユウエスエイ(Proc. Natl. Acad. Sci. USA)、91巻、10747−10751頁(1994年);ステマー(Stemmer)、ネーチャー(Nature)、370巻、389−391頁(1994年)及び米国特許5,605,793、米国特許5,837,458、米国特許5,830,721及び米国特許5,811,238参照。
スキーム3
ここでSAはシアル酸、ポリマーはPEG、mPEG,ポリシアル酸、水溶性ポリマー又は非水溶性ポリマーである。該方法はFGF―20とFGF―21を参照して例示するが、技術者には他FGFペプチド、例えばFGF―9及びFGF―18にも同様に適応できることが分かる。
修飾糖類の産生
(a)限定はされないが、N−ヒドロキシスクシニミドエステル、N−ヒドロキシベンゾトリアゾールエステル、酸ハロゲン化物、アシルイミダゾール、チオエステル、p−ニトロフェニルエステル、アルキルエステル、アルケニルエステル、アルキニルエステル及び芳香族エステルを含むカルボキシル基と種々のその誘導体、
(b)例えばエステル、エーテル、アルデヒドなどに変換できる水酸基、
(c)ハロゲン化物で、例えばアミン、カルボン酸アニオン、チオールアニオン、カルバニオン又はアルコキシドイオンのような求核基で後に置換でき、その結果該ハロゲン原子の官能基に新しい基が共有結合付着するハロアルキル基、
(d)例えばマレイミド基のようにディールス―アルダー反応に加われられるジエノフィル、
(e)例えばイミン、ヒドラゾン、セミカルバゾン又はオキシムのようなカルボニル誘導体形成によるか、又はグリニャール付加又はアルキルリチウム付加のような機構により後続誘導体化が可能なようなアルデヒド基又はケトン基、
(f)アミンとの後続反応で、例えばスルホアミドを形成するハロゲン化スルホニル基、
(g)例えばジスルフィドへの変換やハロゲン化アシルとの反応が可能なチオール基、
(h)例えばアシル化、アルキル化又は酸化が可能なアミン基又はスルホヒドリル基、
(i)例えば付加環化、アシル化、マイケル付加などが起こるアルケン及び
(j)例えばアミン及びヒドロキシル化合物と反応できるエポキシド
が挙げられる。
が挙げられ、ここでLはシアル酸成分とPEG成分を連結する置換又は非置換アルキルリンカー成分又は置換又は非置換ヘテロアルキルリンカー成分であり、“n”は1以上であり、且つ
において、指数“s”は0乃至20の整数を表し且つ“n”は1以上である。
スキーム4
表1
ここでRは修飾基、例えば線型又は分岐PEGを又は−Lx−Rxを表し、Lxは結合(ゼロ次)、置換又は非置換アルキル又は置換又は非置換ヘテロアルキルから選んだリンカーであり、Rxは修飾基である。
ここでXは好ましくは−O−, −N(H)−, −S, CH2−及びN(R)2から選んだ連結基であり、各RはR1−R5から独立に選んだ構成員である。記号Y、Z、A及びBはそれぞれXのアイデンティティで上で示した基から選ぶ基を表す。X,Y、Z、A及びBはそれぞれ独立選択され、それ故同じでも異なっても良い。記号R1 、R2 、R3 、R4及びR5は水素原子、水溶性ポリマー、治療成分、生体分子又は他成分を表す。代わりにこれら記号は水溶性ポリマー、治療成分、生体分子又は他成分と結合したリンカーを表す。
架橋基
切断可能リンカー基
修飾糖のペプチドとの複合化
スキーム5
スキーム6
表2
X=酸素原子、NH、硫黄原子、CH2, N−(R1−5)2
Y=X,Z=X;A=X;B=X
Q=H2、酸素原子、硫黄原子、NH、N−R
R,R1−4=水素原子、リンカー−M、M
M=興味の配位子
興味の配位子=アシルPEG、アシルPPG、アルキルPEG、アシルアルキルPEG、アシルアルキルPEG、カルバモイルPEG、カルバモイルPPG、PEG、PPGアシルアリールPEG、アシルアリールPPG、アリールPEG、アリールPPG、マンノース6リン酸、ヘパリン、ヘパラン、SLex、マンノース、FGF、VFGF、タンパク質、コンドロイチン、ケラタン、デルマタン、アルブミン、インテグリン、ペプチドなど。
スキーム7
酵素種
アシル転移
タンパク質分解酵素
リパーゼ
するためにリパーゼPSを用いる(ロー等(Lo, et al.)、バイオオーガニックメディシナルケミストリーレター(Bioorg. Med. Chem. Lett.)、9巻、709−712頁(1999年))。カンジダアンタークティカ(Candida antarctica)リパーゼで触媒される三級ブチルアルコール中での位置選択的二糖類アシル化が報告された(ウーデンベルグバンオーステローム等(Woudenberg van−Oosterom, et al.)、バイオテクノロジーアンドバイオエンジニアリング(Biotechnol. Bioeng.)、49巻、328−333頁(1996年))。カンジダアンタークティカ(Candida antarctica)リパーゼの固定化版が又三級ブタノール中でのヒドロキシプロピルセルロースのアシル化に用いられた(セレッティ等(Sereti, et al.)、バイオテクノロジーアンドバイオエンジニアリング(Biotechnol. Bioeng.)、72(4)巻、495−500頁(2001年))。本発明で用いる他リパーゼとしては、リポタンパク質リパーゼ、トリアシルグリセロールリパーゼ、ジグリセライドリパーゼ及びポストヘパリンリパーゼが挙げられる。
エステラーゼ
アシラーゼ
アセチル基転移酵素
糖転移
糖転移酵素
フコシル基転移酵素
ガラクトシルトランスフェラーゼ
シアル酸転移酵素
表3 受容体基質としてGalβ1,4GalcNAc配列使用のシアル酸転移酵素
グーチー等(Goochee, et al.)、バイオ/テクノロジー(Bio/Technology)、9巻、1347―1355頁(1991年)
山本等(Yamamoto, et al.)、ジャーナルオブバイオケミストリー(J. Biochem.)、120巻、104―110頁(1996年)。
ギルバート等(Gilbert, et al.)、ジャーナルオブバイオロジカルケミストリー(J. Biol. Chem.)、271巻、28271−28276頁(1996年)
GalNAc転移酵素
細胞結合糖転移酵素
スルホトラスフェラーゼ
グリコシダーゼ
固定化酵素
組み換え法によるグリコシル化
FGFペプチド複合物の精製
薬剤組成と投与
実施例
線維芽細胞成長因子―20配列情報
表4 ヒト線維芽細胞成長因子―20(SEQ ID NO:1)
MAPLAEVGGF LGGLEGLGQQ VGSHFLLPPA GERPPLLGER RSAAERSARG
GPGAAQLAHL HGILRRRQLY CRTGFHLQIL PDGSVQGTRQ DHSLFGILEF
ISVAVGLVSI RGVDSGLYLG MNDKGEL YGS EKLTSECIFR EQFEENWYNT
YSSNIYKHGD TGRRYFVALN KDGTPRDGAR SKRHQKFTHF LPRPVDPERV
PELYKDLLMY T
表5 異なるタンパク質領域を示す野生型ヒトFGF―20配列
線維芽細胞成長因子―21配列情報
表6 ヒト線維芽細胞成長因子―21(SEQ ID NO:146)
MHP IPDSSPLLQF GGQVRQRYLY TDDAQQTEAH LEIREDGTVG
GAADQSPESL LQLKALKPGV IQILGVKTSR FLCQRPDGAL YGSLHFDPEA
CSFRELLLED GYNVYQSEAH GLPLHLPGNK SPHRDPAPRG PARFLPLPGL
PPALPEPPGI LAPQPPDVGS SDPLSMVGPS QGRASPSYAS
表7 異なるタンパク質領域を示す野生型ヒトFGF―21配列
実施例1
1.領域1
MAPTP3LAEV; SEQ ID NO:9
MVTP3LAEV; SEQ ID NO:10
MAP3TTEV; SEQ ID NO:11
MAP3TQGAMPL4AEV; SEQ ID NO:12
MAP3 TSSL4AEV; SEQ ID NO:13
MAP3 TALPL4AEV; SEQ ID NO:14
MAP3 TQAPL4AEV; SEQ ID NO:338
MAP3 TEIPL4AEV; SEQ ID NO:339
MAP3 TINTPL4AEV; SEQ ID NO:340
MAP3 TINTL4AEV; SEQ ID NO:341
MAP3 TTVSL4AEV; SEQ ID NO:342
MAP3 TQEVL4AEV; SEQ ID NO:343
MAP3 TQAVL4AEV; SEQ ID NO:344
2.領域2
領域2(a):これら変異体では野生型VGSHFLLP28P29A30GERPP(SEQ ID NO:15)は1234XYZP28P29A30で置換され、ここで1,2,3,4,X、Y、Zは独立に任意の非荷電アミノ酸又はグルタミン酸(E)から選択し、少なくともその一つはスレオニン(T)かセリン(S)であり、且つGalNAc転移酵素用基質であり、GalNacはO−連結グリコシル化部位創生のために少なくともスレオニン又はセリンに付加する。記号a及びbは独立に0又は1である。好ましい変異として以下が挙げられる。
TETP28P29A30GERPP; SEQ ID NO:18
GTETP28P29A30GERPP; SEQ ID NO:19
VGTETP28P29A30GERPP; SEQ ID NO:20
TGTP28P29AEERPP; SEQ ID NO:21
TATP28P29AEERPP; SEQ ID NO:22
領域2(b):これら変異体では野生型P28P29A30GERPP(SEQ ID NO:16)はP28P291234(5)aPPで置換され、ここで1,2,3,4,X、Y、Zは領域2(a)で記載したとおりである。好ましい変異として以下が挙げられる。
P28P29TGEAPP; SEQ ID NO:23
P28P29TGEVPP; SEQ ID NO:24
P28P29TQGAPP; SEQ ID NO:25
P28P29ATVAPP; SEQ ID NO:26
P28P29ATILPP; SEQ ID NO:27
P28P29AGTAPP; SEQ ID NO:28
P28P29TQGAMPP; SEQ ID NO:29
P28P29GSTAPP; SEQ ID NO:30
P28P29AGTSPP; SEQ ID NO:31
P28P29AGETPP; SEQ ID NO:32
P28P29ATETPP; SEQ ID NO:33
P28P29GTETPP; SEQ ID NO:34
P28P29TGERPP; SEQ ID NO:35
P28P29TINTPP; SEQ ID NO:345
P28P29TTVSPP; SEQ ID NO:346
P28P29TQALPP; SEQ ID NO:347
領域2(c):これら変異体では野生型P34P3PLLGERRS(SEQ ID NO:17)はP34P35123456で置換され、ここで1,2,3,4,5,6は独立に任意の非荷電アミノ酸又はグルタミン酸(E)から選択し、少なくともその一つはスレオニン(T)かセリン(S)であり、且つGalNAc転移酵素用基質であり、GalNacはO−連結グリコシル化部位創生のために少なくともスレオニン又はセリンに付加する。好ましい変異として以下が挙げられる。
P34P35TQGAMP; SEQ ID NO:36
P34P35TQGAMRS; SEQ ID NO:37
P34P35TQGAMAS; SEQ ID NO:38
P34P35TQGAMFS; SEQ ID NO:39
P34P35TSSSTRS; SEQ ID NO:40
P34P35TSSSTKS; SEQ ID NO:41
P34P35TGERRS; SEQ ID NO:42
P34P35TTGVRRS; SEQ ID NO:43
P34P35TTGEARS; SEQ ID NO:44
P34P35TAGERRS; SEQ ID NO:45
P34P35TINTRRS; SEQ ID NO:348
P34P35TTVSRRS; SEQ ID NO:349
3.領域3
領域3(a):これら変異体では野生型RSARGGP52(SEQ ID NO:46)は123456P52で置換され、ここで1,2,3,4,5,6は独立に任意の非荷電アミノ酸又はグルタミン酸(E)から選択し、少なくともその一つはスレオニン(T)かセリン(S)であり、且つGalNAc転移酵素用基質であり、GalNAcはO−連結グリコシル化部位創生のために少なくともスレオニン又はセリンに付加する。好ましい変異として以下が挙げられる。
RSATETP52; SEQ ID NO:48
RSGTETP52; SEQ ID NO:49
RSGTETP52; SEQ ID NO:50
RVGTETP52; SEQ ID NO:51
GVGTETP52; SEQ ID NO:52
GSATETP52; SEQ ID NO:53
GVGVTETP52; SEQ ID NO:54
GVTETP52; SEQ ID NO:55
QTELP52; SEQ ID NO:56
GVTSAP52; SEQ ID NO:57
SVVTP52; SEQ ID NO:58
領域3(b):これら変異体では野生型P52GAAQLA(SEQ ID NO:47)はP52123456で置換され、ここで1,2,3,4,5,6は独立に任意の非荷電アミノ酸又はグルタミン酸(E)から選択し、少なくともその一つはスレオニン(T)かセリン(S)であり、且つGalNAc転移酵素用基質であり、GalNAcはO−連結グリコシル化部位創生のために少なくともスレオニン又はセリンに付加する。好ましい変異として以下が挙げられる。
P52TGAQLA; SEQ ID NO:59
P52TQGAMP; SEQ ID NO:60
P52TQGAMA; SEQ ID NO:61
P52TTAQLA; SEQ ID NO:62
P52GATQLA; SEQ ID NO:63
P52TSSSTA; SEQ ID NO:64
P52TSSSLA; SEQ ID NO:65
P52TINTLA; SEQ ID NO:350
P52TTVSLA; SEQ ID NO:351
P52TQAQLA; SEQ ID NO:352
4.領域4
領域4(a):これら変異体では野生型HLQILP81(SEQ ID NO:66)は12345P81で置換され、ここで1,2,3,4,5は独立に任意の非荷電アミノ酸又はグルタミン酸(E)から選択し、少なくともその一つはスレオニン(T)かセリン(S)であり、且つGalNAc転移酵素用基質であり、GalNAcはO−連結グリコシル化部位創生のために少なくともスレオニン又はセリンに付加する。好ましい変異として以下が挙げられる。
QTELP81; SEQ ID NO:69
LIVTP81; SEQ ID NO:70
LTELP81; SEQ ID NO:71
LTELP81; SEQ ID NO:72
GVTSAP81; SEQ ID NO:73
HLTETP81; SEQ ID NO:74
VLTETP81; SEQ ID NO:75
VGTETP81; SEQ ID NO:76
VGVGTETP81; SEQ ID NO:77
VTSAP81; SEQ ID NO:78
VSTP81; SEQ ID NO:79
EATP81; SEQ ID NO:80
領域4(b):これら変異体では野生型P81DGSVQGT(SEQ ID NO:67)はP8112345GTで置換され、ここで1,2,3,4,5は独立に任意の非荷電アミノ酸又はグルタミン酸(E)から選択し、少なくともその一つはスレオニン(T)かセリン(S)であり、且つGalNAc転移酵素用基質であり、GalNAcはO−連結グリコシル化部位創生のために少なくともスレオニン又はセリンに付加する。好ましい変異として以下が挙げられる。
P81TGSVGT; SEQ ID NO:81
P81TQGVQGT; SEQ ID NO:82
P81TGSVGPGT; SEQ ID NO:83
P81TQGAMPGT; SEQ ID NO:84
P81TTSVQGT; SEQ ID NO:85
P81TTAVQGT; SEQ ID NO:86
P81TINTQGT; SEQ ID NO:353
P81TTVSQGT; SEQ ID NO:354
領域4(c):これら変異体では野生型P81DGS(SEQ ID NO:68)は変異されてN−連結グリコシル化部位を創生する。好ましい例としては以下が挙げられる。
IL P81NGSVH; SEQ ID NO:87
IF P81NGSV; SEQ ID NO:88
P81NGT; SEQ ID NO:89
L P81NGTVH; SEQ ID NO:90
P81NGTV; SEQ ID NO:91
IL P81NGT; SEQ ID NO:92
QIL P81NGT; SEQ ID NO:93
QIL P81NGTVH; SEQ ID NO:94
5.領域5
LNVTET P175RDGARSKRH; SEQ ID NO:95
LNVTET P175DDGARSKRH; SEQ ID NO:96
LNVTET P175LDGARSKRH; SEQ ID NO:97
LNAITT P175RDGARSKRH; SEQ ID NO:98
LNAITT P175LDGARSKRH; SEQ ID NO:99
LNQEAT P175LDGARSKRH; SEQ ID NO:100
LNQTEL P175LDGARSKRH; SEQ ID NO:101
LNQTEL P175ADGARSKRH; SEQ ID NO:102
LNKDGT P175TDGARSKRH; SEQ ID NO:103
LNKDGT P175TSGARSKRH; SEQ ID NO:104
LNKDGT P175TDGAASKRH; SEQ ID NO:105
LNKDGT P175TSGAASKRH; SEQ ID NO:106
LNKDGT P175TQGAMPKRH; SEQ ID NO:107
LNKDGT P175TQGAMSKRH; SEQ ID NO:108
LNKDGT P175TTTARSKRH; SEQ ID NO:109
LN KDGTP175TINTRSKRH; SEQ ID NO:355
LN KDGTP175TINTSSKRH; SEQ ID NO:356
LN KDGTP175TTVSRSKRH; SEQ ID NO:357
LN KDGTP175TTVSASKRH; SEQ ID NO:358
6.領域6
領域6(a):領域6(a)ではこれら野生型LP192RPVD P197ERVP201ELYKD(SEQ ID NO:110)はP1921P23P197で置換され、ここで1,2,3は独立に任意の非荷電アミノ酸又はグルタミン酸(E)から選択し、少なくともその一つはスレオニン(T)かセリン(S)であり、且つGalNAc転移酵素用基質であり、GalNAcはO−連結グリコシル化部位創生のために少なくともスレオニン又はセリンに付加する。好ましい変異として以下が挙げられる。
LP192APTD P197ERVP201ELYKD; SEQ ID NO:112
LP192NPTA P197ERVP201ELYKD; SEQ ID NO:113
LP192RPTA P197ERVP201ELYKD; SEQ ID NO:114
LP192APTQ P197ERVP201ELYKD; SEQ ID NO:115
LP192TPVD P197ERVP201ELYKD; SEQ ID NO:116
LP192TPSD P197ERVP201ELYKD; SEQ ID NO:117
LP192VPTD P197ERVP201ELYKD; SEQ ID NO:118
LP192TPAD P197ERVP201ELYKD; SEQ ID NO:119
領域6(b):領域6(b)ではこれら野生型P197ERVP201ELYKD(SEQ ID NO:111)はP197123P20145678で置換され、ここで1,2,3、4、5、6、7、8は独立に任意の非荷電アミノ酸又はグルタミン酸(E)から選択し、少なくともその一つはスレオニン(T)かセリン(S)であり、且つGalNAc転移酵素用基質であり、GalNacはO−連結グリコシル化部位創生のために少なくともスレオニン又はセリンに付加する。好ましい変異として以下が挙げられる。
P197TAS P201ELYKD; SEQ ID NO:120
P197TAS P201ALYKD; SEQ ID NO:121
P197NTL P201ELYKD; SEQ ID NO:122
P197ETV P201ELYKD; SEQ ID NO:123
P197QET P201ELYKD; SEQ ID NO:124
P197TQG P201ELYKD; SEQ ID NO:125
P197TQG P201ALYKD; SEQ ID NO:126
P197QGT P201ALYKD; SEQ ID NO:127
P197ATE P201ELYKD; SEQ ID NO:128
P197TTQ P201ELYKD; SEQ ID NO:129
P197TTE P201ELYKD; SEQ ID NO:130
P197ERVP201TLYKD; SEQ ID NO:131
P197ERVP201TLYAD; SEQ ID NO:132
P197ERVP201TQGAD; SEQ ID NO:133
P197ERVP201TQGAMP; SEQ ID NO:134
P197ERVP201TQGA; SEQ ID NO:135
P197TQAP201ELYKD; SEQ ID NO:359
P197TEIP201ELYKD; SEQ ID NO:360
7.領域7
L208MY T211P(x); SEQ ID NO:136
L208TE T211P(x); SEQ ID NO:137
VTE T211P(x); SEQ ID NO:138
GVTE T211PL(x); SEQ ID NO:139
PELYVGVTC T211PL(x); SEQ ID NO:140
L208MY T211(x); SEQ ID NO:141
L208MY T211PTASP; SEQ ID NO:142
L208MY T211PATEP; SEQ ID NO:143
L208MY T211PTP(x); SEQ ID NO:144
L208MY T211PTAP(x); SEQ ID NO:145
実施例2
実施例3
1.領域1
領域1(a):これら変異体で野生型M1HP3(SEQ ID NO:158)はM1XnBoOrJqP3で置換され、ここでB,O、Jは独立に任意の非荷電アミノ酸から選択し、Xは任意の非荷電アミノ酸又はヒスチジン(H)であり、少なくとも一つはT又はSであり且つGalNAc転移酵素用基質であり、GalNAcは少なくともT又はSに付加する。記号n、o、p、q、rは独立に0−3を表す。好ましい変異は以下に挙げられる。
M1VTP3 SEQ ID NO:161
M1QTP3 SEQ ID NO:162
M1ATTP3 SEQ ID NO:163
M1IATP3 SEQ ID NO:164
領域1(b):これら変異体で野生型M1HPIP(SEQ ID NO:159)はM1XnPBoPで置換され、ここでBは独立に任意の非荷電アミノ酸から選択し、Xは任意の非荷電アミノ酸又はヒスチジン(H)であり、少なくとも一つはT又はSであり且つGalNAc転移酵素用基質であり、GalNAcは少なくともT又はSに付加する。記号n、oは独立に0−3を表す。好ましい変異は以下に挙げられる。
M1FPTP SEQ ID NO:165
M1HPTPSEQ ID NO:166
M1APTPSEQ ID NO:167
M1FPSP SEQ ID NO:168
M1HPSPSEQ ID NO:169
M1APSPSEQ ID NO:170
M1SPTP SEQ ID NO:171
領域1(c):これら変異体で野生型P5DSS(SEQ ID NO:160)はP5BoOrJqで置換され、ここでB、O、Jは独立に任意の非荷電アミノ酸から選択し、少なくとも一つはT又はSであり且つGalNAc転移酵素用基質であり、GalNAcは少なくともT又はSに付加する。記号o、q、rは独立に0−3を表す。好ましい変異は以下に挙げられる。
P5TSS; SEQ ID NO:172
P5TQA; SEQ ID NO:173
P5TAQ; SEQ ID NO:174
P5TIE; SEQ ID NO:175
P5SSS; SEQ ID NO:176
2.領域2
P9P10TQF; SEQ ID NO:177
P9P10INT; SEQ ID NO:178
P9P10QGA; SEQ ID NO:179
P9P10QGF; SEQ ID NO:180
P9P10TVS; SEQ ID NO:181
P9P10QAF; SEQ ID NO:182
3.領域3
で置換され、ここでφ、Z,X,B,J、O、U、1,2、3は独立に任意の非荷電アミノ酸から選択し、Z又はJは独立にグルタミン酸(E)から選び、2とXは独立にリシン(K)又はアルギニン(R)として選び、且つ少なくとも一つはT又はSであり且つGalNAc転移酵素用基質であり、GalNAcは少なくともT又はSに付加する。記号t、m、n、o、q、r、s、tは独立に0−3を表す。好ましい変異は以下に挙げられる。
ADQSP50TSLL; SEQ ID NO:183
ADQSP50TTVS; SEQ ID NO:184
ADQSP50TINT; SEQ ID NO:185
ADQSP50TQAL; SEQ ID NO:186
ADQSP50TQGA; SEQ ID NO:187
ADQSP50TQAL; SEQ ID NO:188
ATQSP50ESLL; SEQ ID NO:189
ATESP50ESLL; SEQ ID NO:190
ATETP50ESLL; SEQ ID NO:191
VTQSP50ESLL; SEQ ID NO:192
VTETP50ESLL; SEQ ID NO:193
ATESP50ASLL; SEQ ID NO:194
4.領域4
SP61TVIQ; SEQ ID NO:195
AP61TVIQ; SEQ ID NO:196
SP61TTVS; SEQ ID NO:197
SP61TINT; SEQ ID NO:198
SP61TQAQ; SEQ ID NO:199
SP61TQGA; SEQ ID NO:200
SP61TVIA; SEQ ID NO:201
SP61TTVS; SEQ ID NO:202
SP61TINT; SEQ ID NO:203
5.領域5
SP79TGAL; SEQ ID NO:204
AP79TGAL; SEQ ID NO:205
SP79TINT; SEQ ID NO:206
SP79TTVS; SEQ ID NO:207
SP79TQAL; SEQ ID NO:209
SP79TQGA; SEQ ID NO:210
SP79TQGAM; SEQ ID NO:211
6.領域6
SLTFTP91; SEQ ID NO:212
SLTETP91; SEQ ID NO:213
SVTETP91; SEQ ID NO:213
7.領域7
領域7(a):これら変異体では野生型AHGLP116LHLP120(SEQ ID NO:215)は1tφZmBoP116 JqXnOrP120で置換され、ここで1,φ、Z、B、J、Oは独立に任意の非荷電アミノ酸から選択し、少なくとも一つはT又はSであり且つGalNAc転移酵素用基質であり、GalNAcは少なくともT又はSに付加する。記号t、m、o、q、n、rは独立に0−3を表す。好ましい変異は以下に挙げられる。
ATGTP116LHLP120 SEQ ID NO:220
ATETP116LHLP120 SEQ ID NO:221
VTETP116LHLP120 SEQ ID NO:222
VTGLP116LHLP120 SEQ ID NO:223
ATGLP116LHLP120 SEQ ID NO:224
AHGLP116TQAP120 SEQ ID NO:225
AHGLP116TAQP120 SEQ ID NO:226
AHGLP116TEIP120 SEQ ID NO:227
AHGL;P116TSSP120 SEQ ID NO:228
AHGLP116TALP120 SEQ ID NO:229
ASGLP116TQAP120 SEQ ID NO:230
ASGLP116TEIP120 SEQ ID NO:231
領域7(b):これら変異体では野生型HLP120GNKSP125HR(SEQ ID NO:216)は1tLP120XnOrUs2aP125BoJqで置換され、ここでX、B、J、O、U、1,2は独立に任意の非荷電アミノ酸から選択し、B,J、1は独立にヒスチジン(H)、リシン(K)又はアルギニン(R)から選び、少なくとも一つはT又はSであり且つGalNAc転移酵素用基質であり、GalNAcは少なくともT又はSに付加する。記号t、n、r、s、a、o、qは独立に0−3を表す。好ましい変異は以下に挙げられる。
HLP120TTAVP125HR; SEQ ID NO:232
HLP120TSGEP125HR; SEQ ID NO:233
HLP120GSTAP125HR; SEQ ID NO:234
HLP120GNTSP125HR; SEQ ID NO:235
HLP120GTESP125HR; SEQ ID NO:236
HLP120LTQTP125HR; SEQ ID NO:237
HLP120GTQTP125HR; SEQ ID NO:238
HLP120LTQTP125AR; SEQ ID NO:239
HLP120TNASP125HR; SEQ ID NO:240
HLP120TQGSP125HR; SEQ ID NO:241
HLP120VTSQP125HR; SEQ ID NO:242
HLP120TINTP125HR; SEQ ID NO:243
HLP120TSVSP125HR; SEQ ID NO:244
領域7(c):これら変異体では野生型KSP125HRDP129APR(SEQ ID NO:217)は1tSP 125XnOrUsP129BoP Jqで置換され、ここでB、U,1は独立に任意の非荷電アミノ酸から選択し、X、O、Jは独立に任意の非荷電アミノ酸、ヒスチジン(H)、リシン(K)又はアルギニン(R)から選び、少なくとも一つはT又はSであり且つGalNAc転移酵素用基質であり、GalNAcは少なくともT又はSに付加する。記号t、n、r、s、o、qは独立に0−3を表す。好ましい変異は以下に挙げられる。
KSP125TAQP129APR; SEQ ID NO:245
KSP125TADP129APR; SEQ ID NO:246
ASP125TAQP129APR; SEQ ID NO:247
SSP125TADP129APR; SEQ ID NO:248
KSP125TSDP129APR; SEQ ID NO:249
KSP125TEIP129APR; SEQ ID NO:250
KSP125TEIP129APR; SEQ ID NO:251
KSP125TEDP129APR; SEQ ID NO:252
ASP125TEDP129APR; SEQ ID NO:253
SSP125TADP129APR; SEQ ID NO:254
SSP125TAQP129APR; SEQ ID NO:255
KSP125TQAP129APR; SEQ ID NO:256
SSP125TQAP129APR; SEQ ID NO:257
ASP125TEIP129APR; SEQ ID NO:258
KSP125HRDP129TPR; SEQ ID NO:259
KSP125HRDP129SPR; SEQ ID NO:260
KSP125HRDP129TPA; SEQ ID NO:261
KSP125HRDP129TPS; SEQ ID NO:262
KSP125HSDP129TPA; SEQ ID NO:263
KSP125HADP129TPS; SEQ ID NO:264
KSP125HADP129TPA; SEQ ID NO:265
領域7(d):これら変異体では野生型RGP134ARFLP139LP(SEQ ID NO:218)は1tGP 134XnOrUs2aP139BoPで置換され、ここでX、B、O、U,1、2は独立に任意の非荷電アミノ酸から選択し、O、1は独立にリシン(K)又はアルギニン(R)から選び、少なくとも一つはT又はSであり且つGalNAc転移酵素用基質であり、GalNAcは少なくともT又はSに付加する。記号t、n、r、s、a、oは独立に0−3を表す。好ましい変異は以下に挙げられる。
RGP134TSFLP139LP; SEQ ID NO:266
RGP134TSGEP139LP; SEQ ID NO:267
RGP134GSTAP139LP; SEQ ID NO:268
RGP134ANTSP139LP; SEQ ID NO:269
RGP134ATESP139LP; SEQ ID NO:270
RGP134ATQTP139LP; SEQ ID NO:271
RGP134ATQTP139LP; SEQ ID NO:272
RGP134LTQTP139LP; SEQ ID NO:273
RGP134TQFLP139LP; SEQ ID NO:274
RGP134TSFLP139LP; SEQ ID NO:275
RGP134VTSQP139LP; SEQ ID NO:276
SGP134TSFLP139LP; SEQ ID NO:277
AGP134TSGEP139LP; SEQ ID NO:278
SGP134TSALP139LP; SEQ ID NO:279
領域7(e):これら変異体では野生型RGP134ARFLP139LP(SEQ ID NO:219)は1tGP 134XnOrUs2aP139BoPで置換され、ここでX、B、O、U,1、2は独立に任意の非荷電アミノ酸から選択し、O、1は独立にリシン(K)又はアルギニン(R)から選び、少なくとも一つはT又はSであり且つGalNAc
転移酵素用基質であり、GあlNAcは少なくともT又はSに付加する。記号t、n、r、s、a、oは独立に0−3を表す。好ましい変異は以下に挙げられる。
RGP134ARFLP139TP; SEQ ID NO:280
RGP134ARFLP139SP; SEQ ID NO:281
RGP134ASFLP139TP; SEQ ID NO:282
8.領域8
TPP151GILAP156Q; SEQ ID NO:283
SPP151GILAP156Q; SEQ ID NO:284
EPP151TILAP156Q; SEQ ID NO:285
EPP151TTLAP156Q; SEQ ID NO:286
EPP151TQLAP156Q; SEQ ID NO:287
EPP151TQGAP156Q; SEQ ID NO:288
EPP151TSGEP156Q; SEQ ID NO:289
EPP151GSTAP156Q; SEQ ID NO:290
EPP151TTAVP156Q; SEQ ID NO:291
EPP151GNTSP156Q; SEQ ID NO:292
EPP151GTESP156Q; SEQ ID NO:293
EPP151GTETP156Q; SEQ ID NO:294
EPP151VTSQP156Q; SEQ ID NO:295
EPP151AVQTP156Q; SEQ ID NO:296
EPP151LTQTP156Q; SEQ ID NO:297
EPP151VTSQP156Q; SEQ ID NO:298
EPP151SSGAP156Q; SEQ ID NO:299
EPP151TINTP156Q; SEQ ID NO:300
EPP151TTVSP156Q; SEQ ID NO:301
EPP151TQAAP156Q; SEQ ID NO:302
EPP151GILAP156T; SEQ ID NO:303
EPP151GILAP156S; SEQ ID NO:304
9.領域9
TVGSSDP166; SEQ ID NO:305
DVGSSTP166; SEQ ID NO:306
DVGTETP166; SEQ ID NO:307
DAASAAP166; SEQ ID NO:308
DAATAAP166; SEQ ID NO:309
DVGTSDP166; SEQ ID NO:310
DVATSDP166; SEQ ID NO:311
TGDSSDP166; SEQ ID NO:312
TDASGAP166; SEQ ID NO:313
DVGTSGP166; SEQ ID NO:314
10.領域10
TSMVGP; SEQ ID NO:315
TSGVGP; SEQ ID NO:316
TSGAMP; SEQ ID NO:317
TQGAMP; SEQ ID NO:318
TSMVGP; SEQ ID NO:319
TQGAMP; SEQ ID NO:320
11.領域11
領域11(a):これら変異体では野生型SQGRSP178(SEQ ID NO:321)はXnOrUs2aBoP178で置換され、ここでB、O、U,2は独立に任意の非荷電アミノ酸、グルタミン酸(E)又はアスパラギン酸(D)から選択し、少なくともXはT又はSのいずれかを選び且つGalNAc転移酵素用基質であり、GalNAcは少なくともT又はSに付加する。記号n、r、s、a、oは独立に0−3を表す。好ましい変異は以下に挙げられる。
SQGASP178; SEQ ID NO:323
TQGASP178; SEQ ID NO:324
TQGAMP178; SEQ ID NO:325
TQGAMp178; SEQ ID NO:326
領域11(b):これら変異体では野生型カルボキシル末端RSP178SYAS(SEQ ID NO:322)はZSP178XnOrUs1Bo23で置換され、ここでZ,X,B、O、U,1,2、3は独立に任意の非荷電アミノ酸、グルタミン酸(E)又はアスパラギン酸(D)から選択し、少なくともXはT又はSのいずれかを選び、Zは独立にアルギニン(R)又はリシン(K)で選んでも良く、且つGalNAc転移酵素用基質であり、GalNAcは少なくともT又はSに付加する。記号n、r、s、oは独立に0−3を表す。好ましい変異は以下に挙げられる。
ASP178SYAS; SEQ ID NO:327
RSP178TSAVAA; SEQ ID NO:328
ASP178TSAVAA; SEQ ID NO:329
ASP178SSGAPPPS; SEQ ID NO:330
ASP178SSGAPP; SEQ ID NO:331
ASP178SSGAP; SEQ ID NO:332
RSP178SSGAPPPS; SEQ ID NO:333
ASP178TINT; SEQ ID NO:334
ASP178TSVS; SEQ ID NO:335
ASP178TQAF; SEQ ID NO:336
ASP178TINTP; SEQ ID NO:337
実施例4
大腸菌でのFGF―20とFGF―21の可溶性発現
実験
結果
FGF―20
FGF―21
Claims (16)
- 線維芽細胞成長因子(FGF)複合物が
変異FGF−21ペプチド及び修飾基を含み、
該変異FGF−21ペプチドは、対応する野生型FGF−21には存在しない新規導入のO連結グリコシル化部位を含み、該対応する野生型FGF−21は、SEQ ID NO.146と少なくとも95%同一のアミノ酸配列を含み、該変異FGF−21ペプチドはSEQ ID NO.324と同一のアミノ酸配列を含み、
該修飾基は、無傷グリコシル結合基により該ペプチドのアミノ酸残基位で該ペプチドと共有結合し、該修飾基はポリマー型修飾基である、
FGF複合物。 - 該グリコシル結合基が以下の式による構造を有する請求項1のFGF複合物で、
ここでR2は水素原子、CH2OR7、COOR7又はOR7であり、ここで
R7は水素原子、置換アルキル又は非置換アルキル又は置換ヘテロアルキル又は非置換ヘテロアルキルを表し、
R3及びR4及びは水素原子、置換アルキル又は非置換アルキル、OR8、NHC(O)R9から独立に選ぶ構成員であり、
ここでR8及びR9は水素原子、置換アルキル又は非置換アルキル、置換ヘテロアルキル又は非置換ヘテロアルキル又はシアリル酸から独立に選び、
Laは結合、置換アルキル又は非置換アルキル、置換ヘテロアルキル及び非置換ヘテロアルキルから選ぶリンカーであり、
R16及びR17は独立に選択したポリマー型アームであり、
X2及びX4はポリマー成分R16及びR17を炭素原子に連結する独立に選んだ結合断片であり且つ
X5は非反応性基であるFGF複合物。 - 該グリコシル結合基が以下の式による構造を有する請求項2のFGF複合物。
- 該グリコシル結合基が以下の式による構造を有する請求項1から3のいずれか一項記載のFGF複合物。
ここで、式中、bは0及び1より選択される整数、sは、1から10より選択される指数、fは1から2500より選択される指数である。 - 対応する野生型線維芽細胞成長因子−21に存在しない新規導入のO連結グリコシル化部位を含む変異線維芽細胞成長因子−21であって、
該対応する野生型線維芽細胞成長因子−21は、SEQ ID NO.146と少なくとも95%同一のアミノ酸配列を含み、該変異線維芽細胞成長因子−21はSEQ ID NO.324と同一のアミノ酸配列を含む、
変異線維芽細胞成長因子−21。 - 変異線維芽細胞成長因子−21が一つより多い新規導入グリコシル化部位を含む請求項5の変異線維芽細胞成長因子−21。
- グリコシルリンカーによりグリコシル化部位と結合した水溶性ポリマーを含む請求項5の変異線維芽細胞成長因子−21。
- 該グリコシルリンカーが無傷グリコシルリンカーである請求項7の変異線維芽細胞成長因子−21。
- 対応する野生型線維芽細胞成長因子−21に存在しない新規導入のO連結グリコシル化部位を含む変異線維芽細胞成長因子−21の作成方法で、
(a)該変異線維芽細胞成長因子−21を組み換え産生する段階と、
(b)該変異線維芽細胞成長因子−21を新規導入グリコシル化部位でグリコシル化する段階を含み、
該グリコシル化が無細胞試験管内プロセスである変異線維芽細胞成長因子−21の作成方法であって、
該対応する野生型線維芽細胞成長因子−21は、SEQ ID NO:146と少なくとも95%同一のアミノ酸配列を含み、該変異線維芽細胞成長因子−21はSEQ ID NO.324と同一のアミノ酸配列を含む、
方法。 - 変異線維芽細胞成長因子−21が一つより多い新規導入グリコシル化部位を含む請求項9の方法。
- 変異線維芽細胞成長因子−21の有効量と薬学的に許容可能な補助物質を含有する薬剤組成物であって、
該変異線維芽細胞成長因子−21は、該対応する野生型線維芽細胞成長因子−21に存在しない新規導入のO連結グリコシル化部位を含み、
該対応する野生型線維芽細胞成長因子−21は、SEQ ID NO:146と少なくとも95%同一のアミノ酸配列を含み、該変異線維芽細胞成長因子−21はSEQ ID NO.324と同一のアミノ酸配列を含む、
薬剤組成物。 - 該変異線維芽細胞成長因子−21が一つより多い新規導入グリコシル化部位を含む請求項11の組成物。
- 対応する野生型線維芽細胞成長因子−21に存在しない新規導入のO連結グリコシル化部位を含む変異線維芽細胞成長因子−21の複合糖質の作成方法で、
(a)該変異線維芽細胞成長因子−21を組み換え産生する段階と、
(b)該変異線維芽細胞成長因子−21を新規導入グリコシル化部位で修飾糖により酵素的にグリコシル化する段階を含み、
該グリコシル化が無細胞試験管内プロセスである複合糖質作成法であって、
該対応する野生型線維芽細胞成長因子−21は、SEQ ID NO:146と少なくとも95%同一のアミノ酸配列を含み、該変異線維芽細胞成長因子−21はSEQ ID NO.324と同一のアミノ酸配列を含む、
方法。 - 該修飾糖が水溶性ポリマーで修飾する請求項13の方法。
- 該修飾糖がポリエチレングリコール及びm−ポリエチレングリコールからなる一群から選んだ水溶性ポリマーで修飾する請求項14の方法。
- 変異線維芽細胞成長因子が一つより多い新規導入グリコシル化部位を含む請求項15の方法。
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JP2016164162A (ja) | 2016-09-08 |
CY1120007T1 (el) | 2018-12-12 |
SI2586456T1 (sl) | 2016-05-31 |
ES2572779T3 (es) | 2016-06-02 |
HK1222330A1 (zh) | 2017-06-30 |
EP2586456B1 (en) | 2016-01-20 |
WO2006050247A2 (en) | 2006-05-11 |
EP2586456A1 (en) | 2013-05-01 |
EP1814573A2 (en) | 2007-08-08 |
JP2008518601A (ja) | 2008-06-05 |
CA2585758C (en) | 2017-08-01 |
PL2586456T3 (pl) | 2016-07-29 |
WO2006050247A3 (en) | 2007-05-10 |
US10874714B2 (en) | 2020-12-29 |
US9200049B2 (en) | 2015-12-01 |
US20160158319A1 (en) | 2016-06-09 |
EP1814573B1 (en) | 2016-03-09 |
DK2586456T3 (en) | 2016-03-21 |
ES2566670T3 (es) | 2016-04-14 |
CA2585758A1 (en) | 2006-05-11 |
EP1814573A4 (en) | 2009-12-02 |
US20080176790A1 (en) | 2008-07-24 |
US20120172300A1 (en) | 2012-07-05 |
HUE026826T2 (en) | 2016-07-28 |
EP3061461A1 (en) | 2016-08-31 |
US20210100876A1 (en) | 2021-04-08 |
JP2014012004A (ja) | 2014-01-23 |
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