JP5020934B2 - 非ペプチド性重合体で改質された免疫グロブリンFc断片およびこれを含む薬学的組成物 - Google Patents
非ペプチド性重合体で改質された免疫グロブリンFc断片およびこれを含む薬学的組成物 Download PDFInfo
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- JP5020934B2 JP5020934B2 JP2008505221A JP2008505221A JP5020934B2 JP 5020934 B2 JP5020934 B2 JP 5020934B2 JP 2008505221 A JP2008505221 A JP 2008505221A JP 2008505221 A JP2008505221 A JP 2008505221A JP 5020934 B2 JP5020934 B2 JP 5020934B2
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- QYSPLQLAKJAUJT-UHFFFAOYSA-N piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 description 1
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- 238000002741 site-directed mutagenesis Methods 0.000 description 1
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- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
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- 230000002459 sustained effect Effects 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 239000012085 test solution Substances 0.000 description 1
- 229960002180 tetracycline Drugs 0.000 description 1
- 229930101283 tetracycline Natural products 0.000 description 1
- 235000019364 tetracycline Nutrition 0.000 description 1
- 150000003522 tetracyclines Chemical class 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229960003165 vancomycin Drugs 0.000 description 1
- MYPYJXKWCTUITO-LYRMYLQWSA-N vancomycin Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=C2C=C3C=C1OC1=CC=C(C=C1Cl)[C@@H](O)[C@H](C(N[C@@H](CC(N)=O)C(=O)N[C@H]3C(=O)N[C@H]1C(=O)N[C@H](C(N[C@@H](C3=CC(O)=CC(O)=C3C=3C(O)=CC=C1C=3)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)O2)=O)NC(=O)[C@@H](CC(C)C)NC)[C@H]1C[C@](C)(N)[C@H](O)[C@H](C)O1 MYPYJXKWCTUITO-LYRMYLQWSA-N 0.000 description 1
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Classifications
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- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
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- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
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- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6813—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin the drug being a peptidic cytokine, e.g. an interleukin or interferon
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- A62C13/00—Portable extinguishers which are permanently pressurised or pressurised immediately before use
- A62C13/76—Details or accessories
- A62C13/78—Suspending or supporting devices
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- C—CHEMISTRY; METALLURGY
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- C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
- C07K2317/52—Constant or Fc region; Isotype
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- C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
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Description
(a)両末端に反応基を持つリンカー、薬物および非ペプチド性重合体で改質されたFc断片を反応させ、これらを相互共有結合によって連結させる段階と、
(b)リンカーの両末端に、薬物および非ペプチド性重合体で改質されたFc断片がそれぞれ共有結合によって連結された結合体を分離する段階とを含む。
(a1)リンカーの一方の末端に、非ペプチド性重合体で改質されたFc断片および薬物を共有結合によって連結させる段階と、
(a2)前記反応混合物から、リンカーによって結合した非ペプチド性重合体で改質されたFc断片または薬物の複合体を分離する段階と、
(a3)前記で分離された複合体の非ペプチド性重合体の他方の末端に、Fc断片または薬物を共有結合によって連結し、リンカーの両末端が、それぞれ非ペプチド性重合体で改質されたFc断片および薬物と結合した結合体を生成する段階とを含むことができる。
<段階1>免疫グロブリンを用いた天然型キャリア(免疫グロブリンFc断片)の製造
天然型免疫グロブリンFc断片を製造するために、10mMリン酸塩緩衝液に溶解された分子量150kDaの免疫グロブリンG(IgG、緑十字)200mgにタンパク質加水分解酵素パパイン(Sigma社)を2mg処理して37℃で2時間徐々に攪拌しながら反応させた。酵素反応の後、生成された天然型免疫グロブリンFc断片を精製するために、スーパーデックスカラム、タンパク質Aカラム、および陽イオン交換樹脂カラムクロマトグラフィーを順次行った。具体的に、反応液を10mMリン酸ナトリウム緩衝液(PBS、pH7.3)で平衡化させたスーパーデックス200カラム(Pharmacia社)に点滴し、同一の緩衝液を用いて流速1mL/分で溶出させた。天然型免疫グロブリンFc断片より分子量が相対的に大きい未反応免疫グロブリン(IgG)とF(ab’)2などは前方で溶出されるので、これを先に除去した。天然型免疫グロブリンFc断片と類似な分子量のFabは、次のようにタンパク質Aカラムクロマトグラフィーを行って除去した。20mMリン酸塩緩衝液(pH7.0)で平衡化させたタンパク質Aカラム(Pharmacia社)に、スーパーデックス200カラムから溶出された天然型免疫グロブリンFc断片含有画分を5mL/分の流速で負荷した後、カラムに結合していないタンパク質を除去するために同一の緩衝液で十分洗浄した。ここに100mMクエン酸ナトリウム(pH3.0)緩衝液を流して高純度の天然型免疫グロブリンFc断片を溶出させた。タンパク質Aカラムで精製されたFc画分を最後に陽イオン交換樹脂カラム(polyCAT、PolyLc社)を用いて最終精製したが、10mMアセテート緩衝液(pH4.5)を直線濃度勾配(塩化ナトリウム濃度0.15M→0.4M)の方法で流して高純度の天然型免疫グロブリンFc画分を得た。
<IgG4 Fc誘導体発現ベクターの製造>
ヒト免疫グロブリンIgG4重鎖不変領域を製造するために、天然型ヒンジ領域においてアミノ末端から9個のアミノ酸が除去された誘導体(dCysG4Fc)を製造した。
gag tcc aaa tat ggt Ccc cca tgc cca Tca tgc Cca (配列番号10)
ctc agg ttt ata cca Ggg ggt acg ggt Agt acg ggt (配列番号11)
Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro (配列番号9)
ヒト免疫グロブリンIgG1重鎖不変領域を製造するために、天然型ヒンジ領域においてアミノ末端から12個のアミノ酸が除去された誘導体(dCysG1Fc)を製造した。配列番号7と8のプライマー対を用いて前記と同一の方法を行った。配列番号7は、15個のアミノ酸配列(Glu Pro Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys Pro)から構成されたヒンジ領域タンパク質配列中の13番目のアミノ酸配列であるプロリンから始まる配列である。配列番号7および8のプライマー対で増幅された遺伝子は、全体IgG1 Fc遺伝子配列のうち、ヒンジ領域のプロリン−システイン−プロリンから始まるアミノ末端とCH2、CH3ドメインから構成されるように設計した。
pH8.0の50mMトリス塩酸緩衝液20mLで、天然型(G1Fc)または組み換えキャリア(dCysG4Fc、dCysG1Fc)100mgにポリエチレングリコールスクシニミジルプロピオネート(PEG−SPA、平均分子量5,000、12,000および20,000Da、Shearwater社)とポリエチレングリコールN−ヒドロキシスクシニミジル(PEG−NHS、平均分子量40,000Da、Shearwater社)それぞれをキャリアとPEGのモル比が1:2となるように添加した。反応混合物を4℃で2時間反応させた後、モノ−PEG化キャリアおよびジ−PEG化キャリアを精製した。反応液を、10mMトリス塩酸緩衝液(pH7.5)で平衡化したQセファロースHP(Pharmacia社)カラムに10mL/分の速度で適用させた。平衡緩衝液でカラムを十分洗浄した後、0.5MのNaClを用いた直線濃度勾配方法を用いて溶出し、溶出順序に従って高純度のジ−PEG化キャリアおよびモノ−PEG化キャリアを天然型(モノ−PEG化G1Fc、ジ−PEG化G1Fc)と組み換え(モノ−PEG化dCysG1Fc、モノ−PEG化dCysG4Fc)の2つの形態でそれぞれ精製して総10個のキャリア誘導体を製造した。モノ−PEG化G1FcはG1Fc−20K、G1Fc−40Kの2つの形態で製造し、ジ−PEG化G1FcはG1Fc−(20K)2の形態で製造した。モノ−PEG化dCysG1FcはdCysG1Fc−5K、dCysG1Fc−12K、dCysG1Fc−20Kの3つの形態で製造し、モノ−PEG化dCysG4FcはdCysG4Fc−20Kの形態で製造した(表1)。
<段階1>インターフェロン−PEG複合体の製造
両末端にアルデヒド反応基を持つ分子量3.4kDaのポリエチレングリコールであるALD−PEG−ALD(Shearwater社)を、ヒトインターフェロンα−2b(hIFNα−2b、分子量20kDa)が5mg/mLの濃度で溶解された100mMリン酸塩緩衝液にIFNα:PEGのモル比が1:1、1:2.5、1:5、1:10および1:20となるように添加した。ここに還元剤としての水素化シアノホウ素ナトリウム(NaCNBH3、Sigma社)を最終濃度20mMとなるように添加し、4℃で徐々に攪拌しながら3時間反応させた。インターフェロンアルファのアミノ末端部位に選択的にPEGが連結され、PEGとインターフェロンアルファが1:1の割合で結合した複合体を得るために、前記反応混合物をもってスーパーデックス(SuperdexR、Pharmacia社)サイズ排除クロマトグラフィーを行った。溶出液として10mMリン酸カリウム緩衝液(pH6.0)を用いてIFNα−PEG複合体を精製し、PEGと結合していないインターフェロンアルファ、未反応PEGおよび2つのインターフェロンアルファがPEGと連結された二量体副産物を除去した。精製されたIFNα−PEG複合体を5mg/mLの濃度で濃縮した。この実験より、反応性が最もよく且つ二量体などの副産物が少ないIFNα:PEGの最適反応モル比は1:2.5〜1:5であることを確認した。
前記段階1で精製されたIFNα−PEG複合体を天然型キャリア(またはPEG化天然型キャリア)のN末端に結合させるために、実施例1で準備された天然型免疫グロブリンFc断片(G1Fc、分子量約53kDa)を10mMリン酸塩緩衝液に溶解させた後、IFNα−PEG連結体:Fcのモル比がそれぞれ1:1、1:2、1:4および1:8となるようにIFNα−PEG複合体と混合して反応させた。反応液を100mMリン酸塩緩衝液の状態にし、還元剤としてNaCNBH3を最終濃度が20mMとなるように添加した後、4℃で20時間徐々に攪拌しながら反応させた。この実験より、反応性が最もよく且つ二量体などの副産物が少ないIFNα−PEG複合体:Fcの最適反応モル比は1:2であることを確認した。モノ−20kDa PEG、ジ−20kDa PEG、およびモノ−40kDa PEGでそれぞれ改質された天然型免疫グロブリンFc断片(G1Fc−20K、G1Fc−(20K)2、G1Fc−40K)を用いて前記と同一の方法でIFNα−PEG−キャリア結合体を製造した。
前記段階2の結合反応の後、未反応物質および副産物を除去し、生成されたIFNα−PEG−キャリアタンパク質結合体を精製するために、PolyWAX LPカラム(PolyLC社)を10mM Tris−HCl(pH7.5)緩衝液で平衡化させた後、反応液を負荷し、1M塩化ナトリウムを含む10mM Tris−HCl(pH7.5)緩衝液を直線濃度勾配(塩化ナトリウム濃度0M→0.3M)方法によって流して、純粋なIFNα−PEG−キャリア結合体を精製した。IFNα−PEG−キャリア結合体の画分を10mM酢酸ナトリウム(pH4.5)で平衡化させたPolyCAT LPカラム(PolyLC社)に仕込み、1M塩化ナトリウム(NaCl)を含む10mM酢酸ナトリウム(pH4.5)緩衝液を直線濃度勾配(塩化ナトリウム濃度0M→0.5M)方法によって流して、IFNα−PEG−G1Fc、IFNα−PEG−G1Fc−20K、IFNα−PEG−G1Fc−(20K)2、IFNα−PEG−G1Fc−40K結合体をそれぞれ精製した。
インターフェロンアルファの代わりにヒト顆粒球コロニー刺激因子(G−CSF)を用いて、実施例2の段階1と同一の方法で17S−G−CSF−PEG複合体を製造および精製した。精製された17S−G−CSF−PEG複合体を、前記実施例1で製造されたPEG化組み換えキャリア(dCysG4Fc−20K)のN末端に結合させた。融合 反応は前記実施例2の段階2と同一の方法を使用した。融合反応の後、未反応物質及び副産物を除去し、生成された17S−G−CSF−PEG−dCysG4Fc−20K結合体を精製するために、Q HP 26/10カラム(Pharmacia社)50mLを使用した。カップリング反応液を脱塩カラムHiPrep 26/10(Pharmacia社)を用いて10mM Tris緩衝液(pH8.0)で交換した後、Q HP 26/10 50mLカラムに8mL/分の流速で負荷して結合させた後、直線濃度勾配(塩化ナトリウム濃度0M→0.2M)方法によって高純度の17S−G−CSF−PEG−dCysG4Fc−20K結合体の画分を得ることができた。
インターフェロンアルファの代わりにヒト成長ホルモン(hGH、分子量22kDa)を用いて、実施例3と同一の方法で高純度のhGH−PEG−dCysG4Fc−20K結合体の画分を得ることができた。
<1−1>タンパク質結合体の確認
前記実施例で製造したタンパク質結合体は、4〜20%濃度勾配のゲルおよび10%ゲルを用いた還元性または非還元性SDS−PAGEおよびELISA(R&D System社)方法によって確認した。
前記実施例で製造したそれぞれのタンパク質結合体の量はスーパーデックスカラム(Superdex 26/60、Pharmacia社)と10mMリン酸カリウム緩衝液(pH6.0)を溶出液として用いるサイズ排除クロマトグラフィー上でピーク面積を対照区と比較して換算する方法によって計算した。既に定量されているIFNα、hGH、17S−G−CSFおよびFcでそれぞれサイズ排除クロマトグラフィーを行った後、濃度とピーク面積間の換算係数を測定した。各タンパク質結合体の一定量を用いて同一のサイズ排除クロマトグラフィーを行い、ここで得られたピーク面積から、免疫グロブリンFc断片に該当するピーク面積を差し引いた値を、各タンパク質結合体に存在する生理活性タンパク質の定量値として決定した。
前記実施例で獲得したタンパク質結合体IFNα−PEG−Fc、IFNα−PEG−DG(deglycosylated)FcおよびIFNα−PEG−組み換えAG(aglycosylated)Fc誘導体試料の純度を分析するために、逆相HPLCを行った。逆相カラム(Vydac社、259VHP54カラム)を用いて分析し、0.5%TFA存在の下にアセトニトリル溶媒を用いて100%まで濃度勾配(40〜100%)方法によって280nmの波長で純度を分析した。その結果、図2から分かるように、結合していないインターフェロンまたは免疫グロブリンFcは存在せず、IFNα−PEG−G1Fc結合体、17S−G−CSF−PEG−dCysG4Fc−20K結合体およびhGH−PEG−dCysG4Fc−20K結合体はいずれも96%以上の純度で純粋に精製されたことが分かった。
各群当たり5匹のSDラットに天然型生理活性タンパク質(対照群)と前記実施例3および4で製造した結合体の血液内安定性および薬物動力学係数を比較した。対照群および17S−G−CSF−PEG−dCysG4Fc−20K結合体とhGH−PEG−G4Fc−20K結合体(試験群)を各100μg/kgずつ皮下注射した後、対照群は注射0.5、1、2、4、6、12、24、30、48、72および96時間後に採血し、試験群は注射1、6、12、24、30、48、72,96、120、240および288時間後に採血した。ヘパリン含有チューブに血液試料を集めて凝固を防止し、エッペンドルフ高速マイクロ遠心分離機で5分間遠心分離して細胞を除去した。血漿内タンパク質量は各生理活性タンパク質に対する抗体を用いてELISA方法で測定した。
前記実施例で製造した誘導体と大腸菌形質転換体から発現して精製された免疫グロブリン不変領域タンパク質がヒトClqと結合するか否かを確認するために、下記の如く活性酵素免疫測定分析法(ELISA)を行った。実験群として、形質転換体HM10932およびHM10927から生産された免疫グロブリン不変領域断片試料と前記実施例で製造した誘導体を使用し、比較群として、糖が結合している免疫グロブリン(IVIG−グロブリンS、緑十字PBM)を使用した。前記実験群と比較群の試料を10mMカーボネート緩衝液(pH9.6)に1μg/mLの濃度で準備した。準備された試料を96ウェルプレート(Nunc)にウェル当たり200ngの量で分注した後、4℃で一晩コートし、その後ウェルプレートをPBS−T溶液(137mM NaCl、2mM KCl、10mM Na2HPO4、2mM KH2PO4、0.05%ツイン20)で3回洗浄した。牛血清アルブミンを1%の濃度でPBS−T溶液に溶解させて準備した遮断緩衝液250μLを各ウェルに添加した後、常温で1時間放置し、同一のPBS−T溶液で3回洗浄した。標準液と試料を適切な濃度でPBS−T溶液で希釈した後、抗体がコートされたウェルに点滴して常温で1時間放置させて反応させた後、さらにPBS−T溶液で3回洗浄した。遮断反応済みのプレートに2μg/mL Clq(R&D System社、米国)を添加した後、2時間常温で反応させ、反応済みのプレートを前記PBS−T溶液で6回洗浄した。ヒトの抗ヒトClq抗体−ペルオキシダーゼコンジュゲート(Biogenesis社、米国)を遮断緩衝溶液に1000:1で希釈して各ウェルに200μLずつ点滴した後、1時間常温で反応させた。反応が完了した後、各ウェルをPBS−T溶液で3回洗浄し、その後発色溶液AとB(カラー−A−安定化ペルオキシダーゼ[Color A-Stabilized peroxidase]溶液およびカラーB−安定化色原体[Color B-stabilized chromogen]溶液、DY999、R&D System社)を同量で混合して各ウェルに200μLずつ添加し、30分間放置した。その後、反応停止溶液としての2M硫酸を50μLずつ添加して反応を停止させた。反応済みのウェルプレートは、マイクロプレートリーダー(Molecular Device社)を用いて450nmの波長で標準液と検液の吸光度を測定し、その結果を図7および図8にそれぞれ示した。
Claims (15)
- 非ペプチド性重合体で改質された免疫グロブリンFc断片、リンカー、及び薬物を含み、前記非ペプチド性重合体で改質された免疫グロブリンFc断片がリンカーを介して薬物と共有結合によって連結された結合体。
- 前記Fc断片がIgG、IgA、IgD、IgE、IgM、これらの組み合わせ(combination)またはこれらのハイブリッド(hybrid)のFc断片であることを特徴とする、請求項1に記載の結合体。
- 前記Fc断片がIgG1、IgG2、IgG3、IgG4、これらの組み合わせ(combination)またはこれらのハイブリッド(hybrid)のFc断片であることを特徴とする、請求項2に記載の結合体。
- 前記Fc断片がIgG4 Fc断片であることを特徴とする、請求項3に記載の結合体。
- 前記Fc断片が非糖化したことを特徴とする、請求項1に記載の結合体。
- 前記リンカーが非ペプチド性重合体であることを特徴とする、請求項1に記載の結合体。
- 前記非ペプチド性重合体が、ポリエチレングリコール、ポリプロピレングリコール、エチレングリコール−プロピレングリコールの共重合体、ポリオキシエチレン、ポリウレタン、ポリホスファゼン、ポリサッカライド、デキストラン、ポリビニルアルコール、ポリビニルピロリドン、ポリビニルエチルエーテル、ポリアクリルアミド、ポリアクリレート、ポリシアノアクリレート、脂質重合体、キチン類、ヒアルロン酸、ヘパリン、およびこれらの組み合わせよりなる群から選択されたことを特徴とする、請求項6に記載の結合体。
- 前記非ペプチド性重合体がポリエチレングリコールであることを特徴とする、請求項7に記載の結合体。
- 前記薬物が生理活性ポリペプチドであることを特徴とする、請求項1に記載の結合体。
- 前記生理活性ポリペプチドが、ホルモン、サイトカイン、酵素、抗体、成長因子、転写調節因子、血液因子、ワクチン、構造タンパク質、リガンドタンパク質、受容体、細胞表面抗原、および受容体拮抗物質よりなる群から選択されることを特徴とする、請求項9に記載の結合体。
- 前記生理活性ポリペプチドが、ヒト成長ホルモン、成長ホルモン放出ホルモン、成長ホルモン放出ペプチド、インターフェロン類、インターフェロン受容体類、コロニー刺激因子類、グルカコン様ペプチド類(GLP−1など)、Gプロテイン関連受容体(G-protein-coupled receptor)、インターロイキン類、インターロイキン受容体類、酵素類、インターロイキン結合タンパク質類、サイトカイン結合タンパク質類、マクロファージ活性因子、マクロファージペプチド、B細胞因子、T細胞因子、タンパク質A、アレルギー抑制因子、細胞怪死糖タンパク質、免疫毒素、リンホトキシン、腫瘍怪死因子、腫瘍抑制因子、転移成長因子、α−1アンチトリプシン、アルブミン、α−ラクトアルブミン、アポリポタンパク質−E、赤血球生成因子、高糖化赤血球生成因子、アンジオポイエチン類、ヘモグロビン、トロンビン、トロンビン受容体活性ペプチド、トロンボモジュリン、血液因子VII、VIIa、VIII、IX、およびXIII、プラズミノゲン活性因子、フィブリン結合ペプチド、ウロキナーゼ、ストレプトキナーゼ、ヒルジン、タンパク質C、C−反応性タンパク質、レニン抑制剤、コラゲナーゼ抑制剤、スーパーオキシドジスムターゼ、レプチン、血小板由来成長因子、上皮細胞成長因子、表皮細胞成長因子、アンジオスタチン、アンジオテンシン、骨形成成長因子、骨形成促進タンパク質、カルシトニン、インスリン、アトリオペプチン、軟骨誘導因子、エルカトニン、結合組織活性因子、組織因子経路抑制剤、濾胞刺激ホルモン、黄体形成ホルモン、黄体形成ホルモン放出ホルモン、神経成長因子類、副甲状腺ホルモン、リレキシン、シクレチン、ソマトメジン、インスリン様成長因子、副腎皮質ホルモン、グルカゴン、コレシストキニン、膵臓ポリペプチド、ガストリン放出ペプチド、副腎皮質刺激ホルモン放出因子、甲状腺刺激ホルモン、オートタキシン、ラクトフェリン、ミオスタチン、受容体類、受容体拮抗物質、細胞表面抗原、モノクローナル抗体、ポリクローナル抗体、および抗体断片類よりなる群から選択されることを特徴とする、請求項10に記載の結合体。
- 前記生理活性ポリペプチドが、ヒト成長ホルモン、コロニー刺激因子、インターフェロンアルファ、およびヒト赤血球生成因子よりなる群から選択されることを特徴とする、請求項11に記載の結合体。
- 請求項1に記載の結合体およびその薬学的に許容される担体を含む、薬物の生体内持続性および安定性増加用薬学的組成物。
- 免疫グロブリンFc断片を改質するための非ペプチド性重合体が、ポリエチレングリコール、ポリプロピレングリコール、エチレングリコール−プロピレングリコールの共重合体、ポリオキシエチレン、ポリウレタン、ポリホスファゼン、ポリサッカライド、デキストラン、ポリビニルアルコール、ポリビニルピロリドン、ポリビニルエチルエーテル、ポリアクリルアミド、ポリアクリレート、ポリシアノアクリレート、脂質重合体、キチン類、ヒアルロン酸、ヘパリン、およびこれらの組み合わせよりなる群から選択されたことを特徴とする、請求項1に記載の結合体。
- 免疫グロブリンFc断片を改質するための非ペプチド性重合体がポリエチレングリコールであることを特徴とする、請求項14に記載の結合体。
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