JP5425150B2 - 薬物のキャリアとして有用なIgGFc断片およびその製造方法 - Google Patents
薬物のキャリアとして有用なIgGFc断片およびその製造方法 Download PDFInfo
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- Preparation Of Compounds By Using Micro-Organisms (AREA)
Description
本発明において、「キャリア」とは、薬物と共に結合する物質を意味し、一般に薬物に結合して薬物の生理活性を増減または除去する。ところが、本発明におけるキャリアは、本発明の目的上、結合する薬物の生理活性減少を最小化すると同時に薬物の生体内安定性は増加させるためのものである。
本発明において、「薬物」は、ヒトまたは動物に投与される場合、治療的活性を示す物質を意味し、ポリペプチド、化合物、抽出物、核酸などを含むが、これに制限されない。薬物は、好ましくはポリペプチド薬物である。
また、本発明の結合体は、いろいろの架橋剤(coupling agent)で結合可能である。このような架橋剤の種類は、当該分野に公知となっており、例えば1,1−ビス(ジアゾアセチル)−2−フェニルエタン、グルタルアルデヒド、N−ヒドロキシスクシンイミドエステル、例えば4−アジドサリチル酸とのエステル、イミドエステル、例えばジスクシンイミジルエステル、例えば3,3’−ジチオビス(スクシンイミジルプロピオネート)および二官能性(bifunctional)マレイミド、例えばビス−N−マレイミド−1,8−オクタンを含むが、これに制限されない。
(実施例1)ヒト免疫グロブリンIgG4 Fc発現ベクターの製作
(1−1)二量体IgG4 Fc発現ベクターの製作
ヒト免疫グロブリンIgG4のFc遺伝子をクローニングするために、ヒトの血液から収得した血球細胞のRNAを鋳型として次のようにRT−PCRを行った。まず、Qiamp RNA血液キット(Qiagen社)を用いて約6mLの血液から全体RNAを分離した後、このRNAを鋳型とし、One−Step RT−PCRキット(Qiagen社)を用いて遺伝子を増幅した。この際、前記遺伝子配列を収得するために配列番号1と配列番号2で表わされるプライマー対を使用した。配列番号1は、IgG4ヒンジ領域の12個(Glu Ser Lys Tyr Gly Pro Pro Cys Pro Ser Cys Pro、配列番号:3)のアミノ酸配列のうち10番目のアミノ酸配列であるセリンから始まる配列であり、配列番号2は、終結コドンを含むBamHI制限酵素認識部位を挿入したものである。前記プライマー対で増幅された遺伝子は、配列番号4で表わされる塩基配列を持つことが確認され、全体IgG4 Fc中のヒンジ領域のセリン−システイン−プロリンで始まるアミノ末端とCH2およびCH3ドメインから構成される。
単量体の形態で発現されるIgG4 Fc断片をクローニングするために、配列番号9および2を用いて、前記実施例(1−1)で製作したpSTIIdCG4Fcプラスミドを鋳型としてPCRを行った。前記のPCRによって増幅された遺伝子は、IgG4 Fc配列で二量体の形成に必要なヒンジ領域が除去されたまま、IgG4 CH2−3遺伝子のみが増幅されて単量体の形態で存在する。前記(1−1)と同一の発現ベクターpmSTIIに同一の過程でクローニングしてプラスミドpSTIIG4Moを製作した。前記発現ベクターを大腸菌BL21(DE3)に形質転換させて大腸菌形質転換体BL21/pSTIIG4Mo(HM10933)を製造し、これを韓国微生物保存センター(KCCM)に2004年9月15日付で寄託した(寄託番号:KCCM−10598)。前記発現ベクターによって発現される蛋白質は、配列番号10のアミノ酸配列を持ち、ヒンジ領域がないため、CH2ドメインから発現されて単量体の形態で存在する。
(2−1)二量体IgG1 Fc発現ベクターの製作
IgG1のFc遺伝子をクローニングするために、前記実施例(1−1)で行った方法と同様に、ヒトの血液から収得した血球細胞のRNAを鋳型としてOne−Step RT−PCRキット(Qiagen社)を用いてRT−PCRを行った。この際、前記遺伝子配列を収得するために、配列番号11と配列番号12で表わされるプライマー対を使用した。
単量体の形態で発現されるIgG1 Fcを製造するために、配列番号16および12のプライマー対を用いて、前記実施例(2−1)で製作したプラスミドpSTIIdCG4Fcを鋳型として遺伝子を増幅した。増幅された遺伝子の断片を実施例(2−1)と同様の方法で発現ベクターpmSTIIに挿入し、配列番号17で表わされる塩基配列を含有するPSTIIG1Moを製作した。前記発現ベクターを大腸菌BL21(DE3)に形質転換させて大腸菌形質転換体BL21/pSTIIG1Mo(HM10930)を製造し、これを韓国微生物保存センター(KCCM)に2004年9月15日付で寄託した(寄託番号:KCCM−10595)。前記発現ベクターによって発現される蛋白質は、二量体の形成を可能とするシステイン残基を含有するヒンジ領域が除去されたため、CH2ドメインから発現されて単量体の形態で存在し、配列番号18で表わされるアミノ酸配列を持つ。
ヒトIgG2のFc遺伝子をクローニングするために、前記実施例(1−1)で行った方法と同様に、ヒトの血液から収得した血球細胞のRNAを鋳型としてOne−Step RT−PCRキット(Qiagen社)を用いてRT−PCRを行った。この際、前記遺伝子配列を収得するために、配列番号19と配列番号20で表わされるプライマー対を使用した。配列番号19は12個のアミノ酸配列(Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro;配列番号:21)からなるヒンジ領域蛋白質配列のうち10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り、配列番号19および20のプライマー対で増幅された遺伝子は、全体IgG2 Fc遺伝子配列中のヒンジ領域のプロリン−システイン−プロリンで始まるアミノ末端とCH2、CH3ドメインからなり、配列番号22の遺伝子配列を持つ。前記増幅されたIgG2 Fc遺伝子配列を大腸菌シグナル配列を含む発現ベクターにクローニングするために、前述したpmSTIIベクターを使用した。前記実施例(1−1)で行ったクローニング過程と類似の方法で、プラスミドpmSTIIをStuI/BamHI制限酵素で処理した後、アガロースゲル電気泳動を行い、大腸菌熱安定性エンテロトキシンシグナル配列誘導体を含む大きい断片(4.7kb)を回収した。前記増幅されたIgG2 Fc遺伝子をBamHI制限酵素で処理した後、前記回収された発現ベクターの断片に挿入してpSTIIdCG2Fcを製作した。このように製作された発現ベクターによって発現される産物は、宿主細胞で発現するときに配列番号23のアミノ酸配列を持ち、ヒンジ領域のシステイン残基間のジスルフィド結合によって二量体を形成することができる。それぞれ製作された発現ベクターを大腸菌BL21(DE3)に形質転換させて大腸菌形質転換体BL21/pSTIIdCG2Fc(HM10936)を製造した。
(4−1)免疫グロブリンFcの発現の確認
前記実施例1、2および3で収得した微生物形質転換体を発酵器(Marubishi社)に接種して発酵させた後、免疫グロブリンFc断片の発現の有無を確認した。
まず、LB培地100mLに前記形質転換体をそれぞれ一晩中振盪培養した後、発酵器に接種して本培養を行った。発酵器の温度は、35℃あるいは30℃を維持し、嫌気性状態になることを防止するために、空気を20vvmで投入しながら500rpmで攪拌した。発酵の間、微生物の成長のために足りないエネルギー源を補うために、葡萄糖(glucose)と酵母抽出液(yeast extract)とを微生物の発酵状態に応じて投与した。吸光度600nmでOD値が80〜110となる時期に誘導物質(inducer)IPTGを20μM〜4mMとなるように投与して発現を誘導した。これを、さらに40〜45時間高濃度で培養して吸光度600nmでのOD値が100〜120となるようにした。
前記実施例において大腸菌の細胞質内で水溶性二量体の形態で発現されるFcは、シグナル配列が融合しているために分泌されず、細胞質内に存在するとき、シグナル配列のプラセシングなしで融合したままで存在するかを確認するために、N末端アミノ酸配列の分析を基礎科学支援研究所のソウル分所に依頼した。分析する試料は下記のように準備した。
免疫グロブリンに強い親和性があると知られているプロテインA親和性カラム(protein-A affinity column)を用いて下記のような方法で精製した。
(実施例5)インターフェロンアルファ(IFNα)−PEG−免疫グロブリンFc領域(Fc)結合体の製造I
(段階1)免疫グロブリンを用いた免疫グロブリンFc領域の製造
免疫グロブリンFc領域を製造するために、10mMの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(Immunoglobulin G;IgG、緑十字)200mgを、蛋白質加水分解酵素パパイン(Papain、Sigma社)2mgを用い、37℃で2時間徐々に攪拌しながら処理した。酵素反応後、生成された免疫グロブリンFc領域を精製するために、Superdexカラム、プロテイン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を順次行った。具体的には、反応液を、10mMのリン酸ナトリウム緩衝液(PBS、pH7.3)によって平衡化させたSuperdex200カラム(Pharmacia社)に滴下し、同一の緩衝液を用いて1mL/分の流速で溶出させた。免疫グロブリンFc領域より分子量が相対的に大きい未反応免疫グロブリン(IgG)やF(ab’)2などは、早く溶出するので、これを先に除去した。免疫グロブリンFc領域と類似の分子量を持つFabは、次のように、プロテインAカラムクロマトグラフィを行って除去した(図4)。20mMのリン酸塩緩衝液(pH7.0)で平衡化させたプロテインAカラム(Pharmacia社)にSuperdex200カラムから溶出した免疫グロブリンFc領域含有分画を5mL/分の流速で負荷した後、カラムに結合していない蛋白質を除去するために同一の緩衝液で十分洗浄した。次に、100mMのクエン酸ナトリウム(Na citrate、pH3.0)緩衝液を流して高純度の免疫グロブリンFc領域を溶出させた。最後に、プロテインAカラムで精製されたFc分画を陽イオン交換樹脂カラム(polyCAT、PolyLC社)を用いて精製した。プロテインAカラムで精製されたFc分画を滴下した前記陽イオン交換樹脂カラムは、10mMの酢酸塩緩衝液(pH4.5)を用いた直線濃度勾配(塩化ナトリウムの濃度0.15M→0.4M)法によって溶出し、高純度のFc分画を得た。前記高純度のFc分画を12%SDS−PAGEによって解析した(図5のレーン2)。
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ALD−PEG−ALD(Shearwater社)を、ヒトインターフェロンアルファ−2b(hIFNα−2b、分子量20kDa)が5mg/mLの濃度で溶解された100mMのリン酸塩緩衝液に、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。ここに還元剤のナトリウムシアノボロハイドライド(NaCNBH3、Sigma社)を最終濃度が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を連結され、PEGとインターフェロンアルファが1:1で結合した連結体を得るために、前記反応混合物をSuperdexRカラム(Pharmacia社)を用いたサイズ排除(size exclusion)クロマトグラフィにかけた。溶出液として10mMのリン酸カリウム緩衝液(pH6.0)を用いてIFNα−PEG連結体を精製し、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連結体を5mg/mLの濃度に濃縮した。これより、反応性が最も良くて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2で精製されたIFNα−PEG連結体に免疫グロブリンFc領域のN末端に結合させるために、段階1で準備された免疫グロブリンFc領域(約53kDa)を10mMの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連結体と混合して反応させた。反応液を100mMのリン酸塩緩衝液に調製し、還元剤としてNaCNBH3を最終濃度が20mMとなるように添加し、4℃で20時間徐々に攪拌しながら反応させた。これにより、反応性が最も良くて二量体などの副産物が少ないIFNα−PEG連結体:Fcの最適反応モル比は1:2であることを確認した。
前記段階3の結合反応後、未反応物質および副産物を除去し、生成されたIFNα−PEG−Fc蛋白質結合体を精製するためにSuperdexサイズ排除クロマトグラフィを行った。反応混合物を濃縮した後、10mMのリン酸塩緩衝液(pH7.3)を用いて流速2.5mL/分でカラムを通過させ、結合していないFcおよび未反応物質を除去し、IFNα−PEG−Fc蛋白質結合体分画を得た。得られたIFNα−PEG−Fc蛋白質結合体分画には不純物として少量の未反応Fcおよびインターフェロンアルファ二量体が混在しているので、これを除去するためにさらに陽イオン交換樹脂クロマトグラフィを行った。IFNα−PEG−Fc蛋白質結合体分画を10mMの酢酸ナトリウム(pH4.5)で平衡化させたPolyCAT LPカラム(PolyLC社)に仕込み、1Mの塩化ナトリウム(NaCl)を含む10mMの酢酸ナトリウム(pH4.5)緩衝液を用いた直線濃度勾配(塩化ナトリウムの濃度0M→0.5M)法で溶出してさらに精製した。最後に、陰イオン交換カラムを用いてIFNα−PEG−Fc蛋白質結合体を精製した。PolyWAX LPカラム(PolyLC社)を10mMのTris−HCl(pH7.5)緩衝液で平衡化させた後、精製されたIFNα−PEG−Fc蛋白質結合体分画を負荷し、1Mの塩化ナトリウムを含む10mMのTris−HCl(pH7.5)緩衝液を用いた直線濃度勾配(塩化ナトリウムの濃度0M→0.3M)法で溶出して純粋なIFNα−PEG−Fc蛋白質結合体を精製した。
(段階1)Fc−PEG連結体の製造
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ALD−PEG−ALD(Shearwater社)を、前記実施例5の段階1で準備された免疫グロブリンFc領域が15mg/mLの濃度で溶解された100mMのリン酸塩緩衝液に、免疫グロブリンFc:PEGのモル比がそれぞれ1:1、1:2.5、1:5、1:10および1:20となるように添加した。還元剤のNaCNBH3を最終濃度が20mMとなるように添加した後、4℃で徐々に攪拌しながら3時間反応させた。免疫グロブリンFc領域のアミノ末端部位に選択的にPEG:Fcが1:1で結合した連結体を得るために、前記反応混合物を持ってSuperdex(SuperdexR、Pharmacia社)サイズ排除クロマトグラフィを行った。溶出液として10mMのリン酸カリウム緩衝液(pH6.0)を用いてFc−PEG連結体を精製し、PEGと結合していない免疫グロブリンFc領域、未反応PEGおよび2つの免疫グロブリンFc領域がPEGに連結された二量体副産物を除去した。精製されたFc−PEG連結体を約15mg/mLの濃度で濃縮した。これより、反応性が最も良くて二量体などの副産物が少ないFc:PEGの最適反応モル比は1:3〜1:10であることを確認した。
前記段階1で精製されたFc−PEG連結体をIFNαのN末端に結合させるために、10mMのリン酸塩緩衝液に溶解されたインターフェロンアルファを使用し、Fc−PEG連結体:IFNαのモル比がそれぞれ1:1、1:1.5、1:3および1:6となるように添加して反応させた。反応液を100mMのリン酸塩緩衝液に調製し、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。反応後、実施例5の段階4と同一の方法で精製して未反応物質および副産物を除去し、これから生成されたFc−PEG−IFNα蛋白質結合体を純粋に分離した。
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)を使用し、hGH:PEGのモル比を1:5とする以外は、実施例5と同一の方法でhGH−PEG−Fc蛋白質結合体を製造および精製した。
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)を使用し、G−CSF:PEGのモル比を1:5とする以外は、実施例5と同一の方法でG−CSF−PEG−Fc蛋白質結合体を製造および精製した。
インターフェロンアルファの代わりにヒト赤血球生成因子(Erythropoietin;EPO)を使用し、EPO:PEGのモル比を1:5とする以外は、実施例5と同一の方法でEPO−PEG−Fc蛋白質結合体を製造および精製した。
両末端の反応基が全てスクシンイミジルプロピオネート(Succinimidyl propionate;SPA)であるPEGを用いてIFNα−PEG−Fc蛋白質結合体を次のように製造した。インターフェロンアルファ10mgが溶解された100mMのリン酸塩緩衝液に、両末端にSPA反応基を持つ分子量3.4kDaのポリエチレングリコールSPA−PEG−SPA(Shearwater社)をIFNα:PEGのモル比がそれぞれ1:1、1:2.5、1:5、1:10および1:20となるように添加し、常温で徐々に攪拌しながら2時間反応させた。インターフェロンアルファのリジン残基のアミノ基部位に選択的にPEGが1:1で結合したPEG−IFNα連結体を得るために、反応混合物をもってSuperdexサイズ排除クロマトグラフィを行った。溶出液として10mMのリン酸カリウム緩衝液(pH6.0)を用いてIFNα−PEG連結体を精製し、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PEGの両末端に2つのインターフェロンアルファが連結された二量体副産物を除去した。IFNα−PEG連結体を免疫グロブリンFcのリジン残基のアミノ基部位に結合させるために精製されたIFNα−PEG連結体を約5mg/mLの濃度で濃縮した後、実施例5の段階3および4と同一の方法でIFNα−PEG−Fc結合体を製造および精製した。これより、反応性が最も良くて二量体などの副産物が少ないインターフェロンアルファ: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。
両末端にアルデヒド反応基を持つ分子量10kDaのポリエチレングリコールALD−PEG−ALD(Shearwater社)を用いて実施例5の段階2と同一の方法でIFNα−10K PEG連結体を製造および精製した。この際、反応性が最も良くて二量体などの副産物が少ないインターフェロンアルファ:10K PEGの最適モル比は1:2.5〜1:5であることが確認された。精製されたIFNα−PEG連結体を約5mg/mLとなるように濃縮した後、これを用いて実施例5の段階3および4と同一の方法によってIFNα−10K PEG−Fc蛋白質結合体を製造および精製した。
(段階1)Fab’の発現および精製
抗腫瘍壊死因子−アルファFab’を発現する大腸菌形質転換体BL21/poDLHF(寄託番号:KCCM−10511)をLB培地100mLに接種して一晩中振盪培養した後、5Lの発酵器(Marubishi)に接種して温度30℃、空気投入量20vvm、攪拌速度500rpmの条件下で培養した。発酵が進むにつれて、微生物の成長のために足りないエネルギー源を補うために、葡萄糖(glucose)と酵母抽出液(yeast extract)とを微生物の発酵状態に応じて投与し、吸光度600nmでのOD値が80となる時期にIPTGを投与して蛋白質の発現を誘導した。これを40〜45時間高濃度で培養して吸光度600nmでのOD値が120〜140となるようにした。得られた発酵液を遠心分離(20,000g、30分)して沈殿物は捨て、上澄み液のみを取った。
免疫グロブリンFcのN末端のアミノ基にリンカーPEGを結合させるために、前記実施例5の段階1と同一の方法で製造された免疫グロブリンFcを100mMのリン酸ナトリウム緩衝液(pH6.0)に5mg/mLの濃度で溶解させ、ここにNHS−PEG−MAL(3.4kDa、Shearwater社)をFc:PEGのモル比が1:10となるように添加した後、4℃で徐々に攪拌しながら12時間反応させた。
Fab’の遊離システイン基に免疫グロブリンFc−PEG連結体を結合させるために、段階1で精製されたFab’を100mMのリン酸ナトリウム緩衝液(pH7.3)に2mg/mLの濃度で溶解させた後、同一の緩衝液に段階2で準備された免疫グロブリンFc−PEG連結体をFab’:連結体のモル比が1:5となるように入れた。最終蛋白質の濃度が50mg/mLとなるように濃縮し、4℃で徐々に攪拌しながら24時間反応させた。
(段階1)Fab’−PEG連結体(N末端)の製造および精製
前記実施例12の段階1で得た、精製されたFab’40mgを100mMのリン酸ナトリウム緩衝液(pH6.0)に5mg/mLの濃度で溶解させた後、ブチルALD−PEG−ブチルALD(3.4kDa、Nektar社)をFab’:PEGのモル比が1:5となるように添加した。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℃で徐々に攪拌しがら2時間反応させた。
段階1で精製されたFab’−PEG連結体を免疫グロブリンFcのN末端に結合させるために、100mMのリン酸ナトリウム緩衝液(pH6.0)に10mg/mLの濃度で溶解させた後、同一の緩衝液に溶解された免疫グロブリンFcをFab’−PEG連結体:Fcのモル比が1:5となるように入れた。最終蛋白質の濃度が50mg/mLとなるように濃縮し、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℃で徐々に攪拌しながら24時間反応させた。
前記実施例5と同一の方法で製造した免疫グロブリンFc200mgを、100mMのリン酸塩緩衝液(pH7.5)に2mg/mLの濃度となるように溶解した後、脱糖鎖化酵素PNGase F(NEB社)を300U/mgとなるように添加した。反応混合物を37℃で24時間徐々に攪拌しながら反応させた。反応終了後、脱糖鎖化免疫グロブリンFcを精製するために、反応物をSPセファロースFFカラム(Pharmacia社)に負荷し、10mMの酢酸塩緩衝液(pH4.5)条件で1MのNaClを使用した直線濃度勾配(0.1M→0.6M)法で溶出させ、天然型免疫グロブリンFc分画を先に溶出させた後、脱糖鎖化免疫グロブリンFc(deglycosylated FC:DG Fc)を溶出させて得た。
前記実施例5の段階2で精製されたIFNα−PEG連結体に、前記実施例14で製造された脱糖鎖化免疫グロブリンFcを結合させるために、IFNα−PEG連結体を10mMのリン酸塩緩衝液に溶解されたDG FcにIFNα−PEG連結体:DG Fcのモル比がそれぞれ1:1、1:2、1:4および1:8となるように添加して反応させた。反応液を100mMのリン酸塩緩衝液に調製し、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。
前記実施例5および15と同一の方法により、実施例1で製造されたAG Fc誘導体であるIgG4 delta−CysのN末端にIFNα−PEG連結体を結合させた。実施例1で製造されたAG Fc誘導体であるIgG4 delta−CysをIFNα−PEG連結体と結合させた。結合反応後、未反応物質および副産物を除去し、生成されたIFNα−PEG−AG Fc蛋白質結合体(I)を精製するために、Q HP 26/10カラム(Pharmacia社)50mLを用いて1次精製した後、高圧カラムのpolyCAT 21.5×250カラム(PolyLC社)で高純度の結合体を精製した。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のTris緩衝液(pH8.0)で交換した後、Q HP26/10 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(塩化ナトリウムの濃度0M→0.2M)法によって所望の分画を得た。溶出した分画を10mMの酢酸塩緩衝液(pH5.2)で平衡化されたpolyCAT21.5×250カラムに15mL/分の流速でさらに結合させた後、直線濃度勾配(塩化ナトリウムの濃度0.1M→0.3M)法で溶出させて高純度の分画を得ることができた。同一の方法により、実施例12で製造された別のAG Fc誘導体であるIgG4単量体を用いてIFNα−PEG−AG Fc蛋白質結合体(II)を製造した。
前記実施例16と同一の方法により、EPO−PEG連結体とAG Fc誘導体であるIgG4 delta−Cysとが連結された結合体を製造した。
100mMのリン酸カリウム緩衝液(pH6.0)にインターフェロンアルファ5mgを溶解して最終体積が5mLとなるように調製した後、PEGの分子量40kDaの活性化メトキシ−PEG−アルデヒド(Shearwater社)をインターフェロンアルファ:40K PEGのモル比が1:4となるように前記溶液に添加した。前記反応溶液に還元剤NaCNBH3を最終濃度が20mMとなるように添加した後、4℃で18時間徐々に攪拌させながら反応させた。インターフェロンアルファに反応していないPEGを不活性化させるために、エタノールアミンを最終濃度が50mMとなるように添加した。
同一の方法により、ヒト成長ホルモン、顆粒球コロニー刺激因子およびその誘導体のアミノ末端に40K PEGが結合したhGH−40K PEG、G−CSF−40K PEGおよび40K PEG−17S−G−CSF誘導体の連結体を製造した。
実施例1の段階2で精製されたIFNαF−PEG連結体をアルブミンのアミノ末端に結合させるために、10mMのリン酸塩緩衝液に溶解されたヒトアルブミン(human serum albumin、HSA、約67kDa、緑十字)をIFNα−PEG連結体:アルブミンのモル比が1:1、1:2、1:4および1:8となるように添加した後、反応させた。反応液を100mMのリン酸塩緩衝液に調製し、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。これにより、反応性が最も良くて二量体などの副産物が少ないIFNα−PEG連結体:アルブミンの最適反応モル比は、1:2であることを確認した。
実施例8の段階1で精製されたFab’に存在する遊離システイン基を活性化させるために、活性化緩衝液(20mMの酢酸ナトリウム(pH4.0)、0.2mMのDTT)に1時間放置した。PEG修飾緩衝液である50mMのリン酸カリウム(pH6.5)で緩衝液を交換した後、マレイミド−PEG(分子量40kDa、Shearwater社)をFab’:40K PEGのモル比が1:10となるように添加した後、4℃で徐々に攪拌しながら24時間反応させた。
(1−1)蛋白質結合体の確認
前記実施例で製造した蛋白質結合体は、4〜20%の濃度勾配ゲルおよび12%のゲルを用いた非還元性SDS−PAGEおよびELISA(R&D system社)法で確認した。
前記実施例で製造したそれぞれの蛋白質結合体の量は、Superdexカラム(HiLoad 26/60 Superdex 75、Pharmacia社)と10mMの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でのピーク面積を対照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、G−CSF、17S−G−CSF、EPOおよびFcを用いてそれぞれサイズ排除クロマトグラフィを行った後、濃度とピーク面積間の換算係数を測定した。各蛋白質結合体の一定量を使用して同一のサイズ排除クロマトグラフィを行い、ここから得られたピーク面積から免疫グロブリンFc領域に該当するピーク面積を差し引いた値を、各蛋白質結合体に存在する生理活性蛋白質の定量値として決定した。図7は精製されたIFNα−PEG−Fc結合体のサイズ排除クロマトグラフィカラムの分析結果を示すもので、二量体以上の多量体不純物がない単一ピークを確認した。
それぞれの実施例で得た蛋白質結合体に対してサイズ排除クロマトグラフィを行い、280nmの吸光を測定した。その結果、IFNα−PEG−Fc、hGH−PEG−Fc、G−CSF−PEG−Fcおよび17Ser−G−CSF−PEG−Fcは、分子量70〜80kDaの物質の滞留時間帯で単一ピークを示した。
各群当たり5匹のSDラットにおいて、天然型生理活性蛋白質(対照群)と前記実施例および比較例で製造した−40K PEG連結体、−PEG−アルブミン結合体、−PEG−Fc結合体、−PEG−DG Fc結合体、および−PEG−組み換えAG Fc誘導体結合体の血液内安定性および薬物動態学的係数(pharmacokinetic parameters)を比較した。対照群および−40K PEG連結体、−PEG−アルブミン結合体、−PEG−Fc結合体、−PEG−DG Fc結合体、および−PEG−組み換えAG Fc誘導体結合体(試験群)を各100μg/kgずつ皮下注射した後、対照群は注射してから0.5.1、2、4、6、12、24、30、48、72および96時間後に採血し、試験群は注射してから1、6、12、24、30、48、72、96、120、240および288時間後に採血した。ヘパリンを含有する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。血漿内の蛋白質量は、各生理活性蛋白質に対する抗体を用いてELISA方法によって測定した。
IFNα、hGH、G−CSFまたはEPOの天然型蛋白質、これらの−40K PEG連結体、−PEG−アルブミン結合体、−PEG−Fc結合体、および−PEG−DG Fc結合体の薬物動態の分析結果を下記表3〜表7に示した。下記表において、Tmaxは最高薬物濃度に到達する時間を、T1/2は薬物の血中半減期を、MRT(mean residence time)は薬物分子の平均的な体内滞留時間をそれぞれ意味する。
実施例12および13で製造されたFab’−S−PEG−N−Fc、Fab’−N−PEG−N−Fc結合体および比較例3で製造されたFab’−S−40K PEG連結体の血中半減期を測定するために、Fab’を対照群として前記結合体または連結体を用いて実験例2と同一の方法で薬物動態学的な調査を行い、その結果を図15に示した。
図15より、Fab’−S−PEG−N−FcおよびFab’−N−PEG−N−Fc結合体が、Fab’またはFab’−S−40K PEG連結体に比べて2〜3倍延長された血中半減期を示すことが分かる。
(4−1)インターフェロンアルファ蛋白質結合体の細胞内活性比較
インターフェロンアルファ蛋白質結合体の細胞内活性比較のために、IFNα−PEG−Fc(実施例5)、IFNα−PEG−DG Fc(実施例15)、IFNα−PEG−組み換えAG Fc誘導体(実施例16)、IFNα−40K PEG(比較例1)およびIFNα−PEG−アルブミン(比較例2)の抗ウイルス活性を水泡性口内炎ウイルスで飽和させたMDBK(Madin Darby Bovine Kidney、ATCC CCL−22)を使用する細胞培養生検で測定した。この際、PEGが結合していないインターフェロンアルファ−2b(NIBSC国際標準品)を標準物質として使用した。
ヒト成長ホルモン蛋白質結合体の細胞内活性を比較するために、hGH−PEG−Fc、hGH−40K PEGおよびhGH−PEG−アルブミンの細胞内活性を比較試験した。
顆粒球コロニー刺激因子誘導体の蛋白質結合体の細胞内活性を比較するために、天然型G−CSF(Filgrastim、第一薬品(株))、17Ser−G−CSF誘導体、20K PEG−G−CSF(Neulasta社)、40K PEG−17S−G−CSF、17Ser−G−CSF−PEG−アルブミンおよび17S−G−CSF−PEG−Fcの細胞内活性を測定した。
実施例8および9で製造されたFab’−S−PEG−N−Fc、Fab’−N−PEG−N−Fc結合体、および比較例3で製造されたFab’−S−40K PEG連結体の試験管内活性実験を行った。マウス繊維亜細胞株L929(ATCC CRL−2148)を用いてTNFαの細胞毒性を測定する実験を基本骨格として、Fab’がTNFαの細胞壊死活性をどれくらい中和させるかを測定した。
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されて精製された免疫グロブリン不変領域蛋白質とがヒトClqに結合するか否かを確認するために、下記のように固相酵素免疫検定法(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試料と前記実施例で製造した誘導体とを使用し、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)を始めとして、商業化されて治療用抗体として使われているいろいろの抗体を使用した。前記実験群と比較群の試料を10mMのカーボネート緩衝液(pH9.6)に1μg/mLの濃度で調製した。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℃で一晩中コートし、その後ウェルプレートをPBS−T溶液(137mMのNaCl、2mMのKCl、10mMのNa2HPO4、2mMのKH2PO4、0.05%のツイン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ブロッキングバッファ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溶液によって希釈した後、抗体がコートされたウェルに加えて常温で1時間放置させて反応させ、その後さらにPBS−T溶液で3回洗浄した。ブロッキング反応が完了したプレートに2μg/mLのClq(R&D systems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抗体とペルオキシダーゼとの結合体(Biogenesis社、米国)をブロッキングバッファに1000:1に希釈して各ウェルに200μLずつ加えた後、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回洗浄した後、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 peroxide]溶液およびカラーB−安定化クロモゲン[Color B-stabilized chromogen]溶液、DY999、R&D systems社)を同量で混合し、当該混合液を各ウェルに200μLずつ添加し、30分間放置した。その後、反応停止溶液である2Mの硫酸を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、標準液と検液の450nmの波長の吸光度を測定し、その結果を図17、図18にそれぞれ示した。
[1]非ペプチド性リンカーを使用して薬物との結合体を形成するための薬物キャリアとして、薬物とは独立的に組換え的な方法によって製造されたものである、IgG Fc断片。
[2]前記IgGがIgG2またはIgG4である1に記載のFc断片。
[3]前記IgGがIgG4である2に記載のFc断片。
[4]非糖鎖化された1に記載のFc断片。
[5]非糖鎖化されたIgG4 Fc断片である4に記載のFc断片。
[6]ヒト由来の非糖鎖化されたIgG4Fc断片である5に記載のFc断片。
[7]配列番号8、10または23のアミノ酸配列を持つ1に記載のFc断片。
[8]1のFc断片をコードする遺伝子。
[9]配列番号4、9または22である8に記載の遺伝子。
[10]9の遺伝子の中から選択される配列を持つ組み換えベクター。
[11]10の組み換えベクターで形質転換された形質転換体。
[12]11の形質転換された組み換え微生物を培養してFc蛋白質を収得する方法。
[13]1のFc断片をキャリアとして含む薬剤学的組成物。
Claims (12)
- 非ペプチド性リンカーによってポリペプチド薬物との結合体を製造するためのキャリアとしての、IgG Fc断片の使用(ただし、該結合体は、組換え的な方法によって製造された融合蛋白質でない。)であり、
上記IgG Fc断片が配列番号8、10または23のアミノ酸配列を有するFc断片である、IgG Fc断片の使用。 - 前記IgG Fc断片が非糖鎖化されたものである請求項1に記載の使用。
- 前記IgG Fc断片がCH1、CH2、CH3及びCH4ドメインよりなる群から選択される1〜4個のドメインから構成される請求項1に記載の使用。
- 前記IgG Fc断片がヒンジ領域をさらに含む請求項3に記載の使用。
- 前記IgG Fc断片がIgG1、IgG2、IgG3、IgG4、これらの組み合わせ及びこれらのハイブリッドのFc断片よりなる群から選択される請求項1に記載の使用。
- 前記IgG Fc断片がIgG4 Fc断片である請求項5に記載の使用。
- 前記IgG Fc断片がヒト非糖鎖化IgG4 Fc断片である請求項6に記載の使用。
- 前記IgG Fc断片が配列番号4、9または22の塩基配列によってコードされる請求項1に記載の使用。
- 前記IgG Fc断片が原核細胞宿主を使用して製造した組換え型IgG Fc断片であり、前記ポリペプチド薬物が真核細胞宿主を使用して製造した組換え型ポリペプチド薬物である請求項1に記載の使用。
- 前記IgG Fc断片が非糖鎖化されたものであり、前記ポリペプチド薬物が糖鎖化されたものである請求項1に記載の使用。
- 前記IgG Fc断片がポリペプチド薬物に対して1:1〜1:10のモル比で使用される請求項1に記載の使用。
- 前記非ペプチド性リンカーがポリ(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とプロピレングリコールの共重合体、ポリオキシエチル化ポリオール、ポリビニルアルコール、多糖類、デキストラン、ポリビニルエーテル、生分解性高分子、脂質重合体、キチン及びヒアルロン酸よりなる群から選択される請求項1に記載の使用。
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AR081066A1 (es) * | 2010-04-02 | 2012-06-06 | Hanmi Holdings Co Ltd | Conjugado de insulina donde se usa un fragmento de inmunoglobulina |
AR081755A1 (es) * | 2010-04-02 | 2012-10-17 | Hanmi Holdings Co Ltd | Formulacion de accion prolongada de la hormona estimuladora de los foliculos donde se usa un fragmento de inmunoglobulina, metodo de preparacion y metodo para tratar a un sujeto que sufre un trastorno reproductivo |
AR080993A1 (es) * | 2010-04-02 | 2012-05-30 | Hanmi Holdings Co Ltd | Formulacion de accion prolongada de interferon beta donde se usa un fragmento de inmunoglobulina |
KR20120002129A (ko) * | 2010-06-30 | 2012-01-05 | 한미홀딩스 주식회사 | 면역글로불린 단편을 이용한 제7인자(Factor Ⅶa)약물 결합체 |
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