JP6284478B2 - インターフェロンアルファ結合体を含む癌治療用医薬組成物 - Google Patents
インターフェロンアルファ結合体を含む癌治療用医薬組成物 Download PDFInfo
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- JP6284478B2 JP6284478B2 JP2014529611A JP2014529611A JP6284478B2 JP 6284478 B2 JP6284478 B2 JP 6284478B2 JP 2014529611 A JP2014529611 A JP 2014529611A JP 2014529611 A JP2014529611 A JP 2014529611A JP 6284478 B2 JP6284478 B2 JP 6284478B2
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Description
下記実験で用いたインターフェロンアルファは特許文献1に記載された方法により製造した。インターフェロンアルファ結合体は、前記製造されたインターフェロンアルファを用いて、特許文献2に記載された方法により製造した。具体的な代表的方法は下記の通りである。
<工程1>免疫グロブリンを用いた免疫グロブリンFc断片の製造
免疫グロブリンFc断片を、下記のとおり製造した。10mMのリン酸塩緩衝液に溶解した150kDaの免疫グロブリンG(IgG、緑十字社)200mgに、タンパク質加水分解酵素パパイン(Sigma社)2mgを処理して、37℃で2時間ゆっくり攪拌した。酵素反応後、生成された免疫グロブリンFc断片の精製のためにスーパーデクスカラム、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用いるクロマトグラフィーに適用した。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)で平衡化させたスーパーデクス200カラム(Superdex200,Pharmacia社)に投入し、同様の緩衝液を用いて流速1mL/分で前記カラムを溶出した。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は免疫グロブリンFc断片より先に溶出するという特性を用いて除去した。免疫グロブリンFc断片と分子量が類似のFabは、タンパク質Aカラムクロマトグラフィーで除去した。スーパーデクス200カラムから溶出された免疫グロブリンFc断片含有分画を、20mMのリン酸塩緩衝液(pH7.0)で平衡化させたタンパク質Aカラム(Pharmacia社)に5mL/分の流速で投入した後、同様の緩衝液で洗浄し、カラムに結合していないタンパク質を除去した。そしてタンパク質Aカラムを100mMのクエン酸ナトリウム(pH3.0)緩衝液で溶出させ、高純度の免疫グロブリンFc断片を得た。タンパク質Aカラムから得たFc分画を、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、前記Fc分画が負荷されたカラムは10mMのアセテート緩衝液(pH4.5)を直線濃度勾配(塩化ナトリウム濃度0.15M→0.4M)で溶出させ、高純度のFc分画を提供した。高純度のFc分画は12%SDS-PAGEで分析した。
両末端にアルデヒド反応基を有する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アルファ-2b(hIFNα-2b,MW:20kDa)が5mg/mLの濃度で溶解した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になるように混合した。前記混合物に還元剤であるシアノ水素化ホウ素ナトリウム(NaCNBH3,Sigma社)を最終濃度が20mMになるように添加し、4℃でゆっくり攪拌しながら3時間反応させて、PEGがインターフェロンアルファのアミノ末端部位に結合されるようにした。PEGとインターフェロンアルファの1:1複合体を得るために、前記反応混合物をスーパーデクスAL(SuperdexR,Pharmacia社)カラムを用いたサイズ排除クロマトグラフィーに適用した。
前記工程2で精製されたIFNα-PEG複合体を免疫グロブリンFc断片のN末端に結合させるために、工程1で製造された免疫グロブリンFc断片(約53kDa)を10mMのリン酸塩緩衝液に溶解した後、IFNα-PEG複合体:Fcのモル比がそれぞれ1:1、1:2、1:4および1:8になるように、IFNα-PEG複合体と混合した。反応液のリン酸塩緩衝液濃度を100mMに合わせた後、還元剤としてNaCNBH3を最終濃度が20mMになるように、反応液に添加して4℃で20時間ゆっくり攪拌しながら反応させた。この実験から反応性が最もよく、二量体のような副産物が最も少なく生産される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。
前記工程3の反応後、反応混合物をスーパーデクスサイズ排除クロマトグラフィーに適用し、未反応物質および副産物を除去して生成されたIFNα-PEG-Fcタンパク質結合体を精製した。反応混合物を濃縮し、スーパーデクスカラムに投入した後、10mMのリン酸塩緩衝液(pH7.3)を流速2.5mL/分でカラムに通過させ、結合していないFcおよび未反応物質を除去し、カラム溶出によってIFNα-PEG-Fcタンパク質結合体の分画を収集した。収集されたIFNα-PEG-Fcタンパク質結合体の分画には、少量の不純物として未反応Fcおよびインターフェロンアルファ二量体を含んでいるため、陽イオン交換樹脂クロマトグラフィーを行って前記不純物を除去した。IFNα-PEG-Fcタンパク質結合体の分画を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)に投入し、1Mの塩化ナトリウム(NaCl)を用いて10mMの酢酸ナトリウム(pH4.5)の緩衝液を用いて直線濃度勾配(塩化ナトリウム濃度0M→0.5M)でカラムから溶出させた。最後に、陰イオン交換カラムを用いてIFNα-PEG-Fcタンパク質結合体を精製した。10mMのTris-HCl(pH7.5)緩衝液で平衡化させたPolyWAX LPカラム(PolyLC社)に、前記IFNα-PEG-Fcタンパク質結合体の分画を投入し、1Mの塩化ナトリウムを用いて10mM Tris-HCl(pH7.5)緩衝液で直線濃度勾配(塩化ナトリウム濃度0M→0.3M)を用いてカラムで溶出させ、高純度形態のIFNα-PEG-Fcタンパク質結合体を分離した。
<工程1>Fc-PEG複合体の製造
両末端にアルデヒド反応基を有する、3.4kDaのポリエチレングリコールであるALD-PEG-ALD(Shearwater社)と、前記実施例1-1の工程1で製造された免疫グロブリンFc断片が15mg/mLの量で溶解した100mMのリン酸塩緩衝液を、1:1、1:2.5、1:5、1:10および1:20のFc:PEGのモル比で混合した。この混合液に還元剤であるNaCNBH3を最終濃度20mMで添加した後、4℃でゆっくり攪拌しながら3時間反応させた。PEGおよびFcの1:1の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クスκカラム(Pharmacia社)を用いたサイズ排除クロマトグラフィーに適用した。溶出液として10mMのリン酸カリウム緩衝液(pH6.0)を用いてカラムからFc-PEG複合体を溶出させ、PEGと結合していない免疫グロブリンFc断片、未反応PEGおよび2つの免疫グロブリンFc断片がPEGと結合された二量体の副産物を除去した。精製されたFc-PEG複合体を約15mg/mLに濃縮した。この実験から反応性が最もよく、二量体のような副産物が最も少なく生成され、Fc:PEGの最適反応モル比は1:3〜1:10であることが見出された。
前記工程1で精製されたFc-PEG複合体をIFNα N末端に結合させるために、10mMのリン酸塩緩衝液に溶解したインターフェロンアルファとFc-PEG複合体を、1:1、1:1.5、1:3および1:6のFc-PEG複合体:IFNαモル比で混合した。反応液のリン酸塩緩衝液濃度を100mMになるように混合した後、還元剤としてNaCNBH3を反応液に最終濃度が20mMになるように添加した後、4℃で20時間ゆっくり攪拌しながら反応させた。反応完了後、実施例1-1の工程4と同様の精製方法により未反応物質および副産物を除去し、高純度のFc-PEG-IFNαタンパク質結合体を分離した。
ダウディ細胞を用いて、培養培地と試験培地はRPMI1640に10%のFBSおよび10%のPSを添加した培地を用いた。96ウェルの丸底プレートでインターフェロンアルファと本発明のインターフェロンアルファ結合体を4倍ずつ試験培地に10種類の濃度で希釈した。希釈した試験培地をそれぞれ50μLずつ96ウェルの扁平な底プレートに移した。ダウディ細胞を1000rpmに5分間遠心分離した後、PBS50mLでコニカルチューブを洗浄した。前記細胞を1000rpmに5分間遠心分離した後、試験用培地を入れて細胞の数を計数した。ダウディ細胞を5×105cell/mLの濃度で希釈した後、各ウェル当り100μLずつ入れ、37℃で72時間培養した。その後、CCK-8を各ウェル当り20μLずつ入れ、3時間後に450nmで吸光度を測定した。
前記実施例1で製造したインターフェロンアルファ結合体のin vivo抗癌効果を測定するために、ヒト卵巣癌細胞(SK-OV-3)を皮下に移植したマウスで腫瘍のサイズの変化を確認した。
前記実施例1で製造したインターフェロンアルファ結合体のIn vivo抗癌効果を測定するために、ヒト膵贓癌細胞(BxPC3)を皮下に移植したマウスで腫瘍のサイズの変化を確認した。
前記実施例1で製造したインターフェロンアルファ結合体のIn vivo抗癌効果を測定するために、ヒト膵贓癌細胞(Panc-1)を皮下に移植したマウスで腫瘍のサイズの変化を確認した。
前記実施例1で製造したインターフェロンアルファ結合体のIn vivo抗癌効果を測定するために、ヒト膵贓癌細胞(Miapaca-2)を皮下に移植したマウスで腫瘍のサイズの変化を調べた。
Claims (21)
- インターフェロンアルファと免疫グロブリン不変領域が非ペプチド性ポリマーによって結合されたインターフェロンアルファ結合体及びRaf阻害剤を含む癌の予防または治療用の医薬組成物であって、前記非ペプチド性ポリマーはポリエチレングリコールであり、前記Raf阻害剤はゲムシタビンである、医薬組成物。
- 前記インターフェロンアルファは、生体内の受容体に結合して野生型インターフェロンアルファと同一であるかまたは対応する生物学的活性を示す物質であって、野生型インターフェロンアルファ、またはこれらの断片である請求項1に記載の組成物。
- 前記癌は、k−ras変異を有する癌である請求項1に記載の組成物。
- 前記組成物は膵贓癌、黒色腫、腎癌または卵巣癌の治療に用いられる請求項1に記載の組成物。
- 前記免疫グロブリン不変領域は、免疫グロブリンFc領域である請求項1に記載の組成物。
- 前記インターフェロンアルファは、インターフェロンアルファ2aまたはインターフェロンアルファ2bである請求項1に記載の組成物。
- 前記非ペプチド性ポリマーは、結合体でインターフェロンアルファのN末端に結合される請求項1に記載の組成物。
- 前記非ペプチド性ポリマーは、結合体でインターフェロンアルファのN末端のアミン基またはチオール基に結合される請求項1に記載の組成物。
- 前記免疫グロブリン不変領域は、非糖鎖化されたものである請求項1に記載の組成物。
- 前記免疫グロブリン不変領域は、CH1、CH2、CH3およびCH4ドメインからなる群から選択される1〜4個のドメインからなるものである請求項1に記載の組成物。
- 前記免疫グロブリン不変領域は、CH1、CH2、CH3およびCH4ドメインからなる群から選択される重鎖不変領域および軽鎖不変領域の二量体からなる請求項1に記載の組成物。
- 前記免疫グロブリン不変領域は、ヒンジ領域を含む請求項1に記載の組成物。
- 前記免疫グロブリン不変領域は、IgG、IgA、IgD、IgEまたはIgMに由来したものである請求項1に記載の組成物。
- 前記免疫グロブリン不変領域のそれぞれのドメインがIgG、IgA、IgD、IgEおよびIgMからなる群から選択される免疫グロブリンに由来した異なる起源を有するドメインハイブリッドである請求項1に記載の組成物。
- 前記免疫グロブリン不変領域は、同一の起源のドメインからなる単鎖免疫グロブリンからなる二量体または多量体である請求項1に記載の組成物。
- 前記免疫グロブリン不変領域は、IgG4 Fc領域である請求項1に記載の組成物。
- 前記免疫グロブリン不変領域は、ヒト非糖鎖化IgG4 Fc領域である請求項1に記載の組成物。
- 前記非ペプチド性ポリマーは1kDa〜100kDaの範囲の分子量を有する請求項1に記載の組成物。
- 前記非ペプチド性ポリマーの反応基が、アルデヒド基、プロピオンアルデヒド基、ブチルアルデヒド基、マレイミド基およびスクシンイミド誘導体からなる群から選択されるものであり、前記スクシンイミド誘導体がスクシンイミジルプロピオン酸エステル、スクシンイミジルカルボキシメチル、ヒドロキシスクシンイミジルまたは炭酸スクシンイミジルである請求項1に記載の組成物。
- 前記非ペプチド性ポリマーは、両末端にアルデヒド反応基を有する請求項1に記載の組成物。
- 癌が膵贓癌である請求項1記載の組成物。
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PCT/KR2012/007113 WO2013036032A1 (en) | 2011-09-05 | 2012-09-05 | A pharmaceutical composition for treating cancer, comprising interferon alpha conjugate |
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Families Citing this family (18)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10350188B2 (en) * | 2011-11-04 | 2019-07-16 | Myron R. Szewczuk | Use of Neu1 sialidase inhibitors in the treatment of cancer |
KR20130049671A (ko) | 2011-11-04 | 2013-05-14 | 한미사이언스 주식회사 | 생리활성 폴리펩타이드 결합체 제조 방법 |
AR090281A1 (es) | 2012-03-08 | 2014-10-29 | Hanmi Science Co Ltd | Proceso mejorado para la preparacion de un complejo polipeptidico fisiologicamente activo |
US20140329889A1 (en) * | 2013-05-03 | 2014-11-06 | The Regents Of The University Of California | Cyclic di-nucleotide induction of type i interferon |
AR096890A1 (es) * | 2013-07-12 | 2016-02-03 | Hanmi Pharm Ind Co Ltd | Conjugando fc de inmunoglobulina, que mantiene la afinidad de unión del fragmento fc de la inmunoglobulina a fcrn |
US20170128589A1 (en) * | 2014-03-31 | 2017-05-11 | Hanmi Pharm. Co., Ltd. | Method for improving solubility of protein and peptide by using immunoglogulin fc fragment linkage |
WO2015182625A1 (ja) * | 2014-05-26 | 2015-12-03 | 国立大学法人京都大学 | Ras活性阻害薬及びその用途 |
ES2630106T3 (es) * | 2014-10-07 | 2017-08-18 | Cyprumed Gmbh | Formulaciones farmacéuticas para la administración oral de fármacos peptídicos o proteicos |
US10226484B2 (en) | 2014-12-01 | 2019-03-12 | Peter Y Novak | Pharmaceutical composition for improving health, cure abnormalities and degenerative disease, achieve anti-aging effect of therapy and therapeutic effect on mammals and method thereof |
EP3546473A1 (en) * | 2014-12-16 | 2019-10-02 | Kayla Therapeutics | Cyclic [(2',5')p(3',5')p]-dinucleotides for cytokine induction |
WO2016096577A1 (en) * | 2014-12-16 | 2016-06-23 | Invivogen | Combined use of a chemotherapeutic agent and a cyclic dinucleotide for cancer treatment |
CN107530411B (zh) | 2015-04-30 | 2021-08-13 | 东丽株式会社 | 免疫诱导剂 |
WO2017052329A1 (en) * | 2015-09-24 | 2017-03-30 | Hanmi Pharm. Co., Ltd. | Protein complex by use of a specific site of an immunoglobulin fragment for linkage |
US10183041B2 (en) * | 2017-04-12 | 2019-01-22 | Vector Vitale Ip Llc | Antibacterial composition and its use in treating bacterial infections |
KR101880015B1 (ko) * | 2017-12-08 | 2018-07-19 | 아주대학교산학협력단 | 인터페론 감마를 유효성분으로 함유하는 신경섬유육종 예방 또는 치료용 조성물 |
CN112245570A (zh) * | 2019-07-22 | 2021-01-22 | 厦门特宝生物工程股份有限公司 | 一种基于干扰素的疾病治疗方法 |
CN117255695A (zh) * | 2021-01-21 | 2023-12-19 | 厦门特宝生物工程股份有限公司 | 一种基于干扰素的癌症治疗方法和药物组合 |
WO2022256211A1 (en) * | 2021-06-04 | 2022-12-08 | St. Jude Children's Research Hospital, Inc. | Interferons and nuclear export inhibitors for use in methods of treating cancer |
Family Cites Families (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
PL176408B1 (pl) | 1992-02-10 | 1999-05-31 | Interferon Sciences Inc | Kompozycja naturalnego alfa interferonu z ludzkich leukocytów krwi obwodowej i sposób wytwarzania kompozycji naturalnego alfa interferonu z ludzkich leukocytów krwi obwodowej |
US6096871A (en) | 1995-04-14 | 2000-08-01 | Genentech, Inc. | Polypeptides altered to contain an epitope from the Fc region of an IgG molecule for increased half-life |
CA2249195A1 (en) | 1996-03-18 | 1997-09-25 | Board Of Regents, The University Of Texas System | Immunoglobin-like domains with increased half lives |
KR100360594B1 (ko) | 2000-01-19 | 2002-11-13 | 한미약품공업 주식회사 | 인간 인터페론 알파의 발현 분비벡터 및 이를 이용한인터페론 알파의 생산 방법 |
RU2179859C1 (ru) | 2001-05-22 | 2002-02-27 | Центральный научно-исследовательский рентгено-радиологический институт | Способ лечения почечно-клеточного рака |
US20050176108A1 (en) | 2003-03-13 | 2005-08-11 | Young-Min Kim | Physiologically active polypeptide conjugate having prolonged in vivo half-life |
US20040197312A1 (en) | 2003-04-02 | 2004-10-07 | Marina Moskalenko | Cytokine-expressing cellular vaccine combinations |
AU2004282984B2 (en) | 2003-11-13 | 2011-07-14 | Hanmi Science Co., Ltd. | Protein complex using immunoglobulin fragment andmethod for the preparation thereof |
WO2005123113A2 (en) | 2004-06-14 | 2005-12-29 | Intermune, Inc. | Interferon compositions and methods of use thereof |
JP2008509889A (ja) * | 2004-06-30 | 2008-04-03 | イージェン コーポレーション | ペグ化インターフェロンα−1b |
EP1968589A2 (en) | 2005-10-31 | 2008-09-17 | Bayer Pharmaceuticals Corporation | Combinations comprising sorafenib and interferon for the treatment of cancer |
CA2698173C (en) * | 2007-09-04 | 2015-02-03 | Biosteed Gene Expression Tech. Co., Ltd. | Interferon alpha 2b modified by polyethylene glycol, the preparation and use thereof |
CA2698396C (en) * | 2007-09-04 | 2014-01-21 | Biosteed Gene Expression Tech. Co., Ltd. | Interferon alpha2a modified by polyethylene glycol, the preparation and use thereof |
ES2336873B1 (es) * | 2007-11-07 | 2011-01-24 | Proyecto De Biomedicina Cima, S.L. | Composicion farmaceutica para el tratamiento de cancer. |
WO2010011096A2 (en) * | 2008-07-23 | 2010-01-28 | Hanmi Pharmaceutical Co., Ltd. | A polypeptide complex comprising non-peptidyl polymer having three functional ends |
KR101303388B1 (ko) * | 2010-10-26 | 2013-09-03 | 한미사이언스 주식회사 | 지속형 인터페론 알파 결합체의 액상 제제 |
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EP2753348A4 (en) | 2015-05-27 |
BR112014005091A2 (pt) | 2017-06-13 |
KR20140084023A (ko) | 2014-07-04 |
KR101990656B1 (ko) | 2019-06-18 |
CN103611163A (zh) | 2014-03-05 |
JP2014526460A (ja) | 2014-10-06 |
AU2012305062B2 (en) | 2017-06-22 |
US20140219961A1 (en) | 2014-08-07 |
EP2753348B1 (en) | 2019-12-11 |
RU2014108725A (ru) | 2015-10-20 |
EP2753348A1 (en) | 2014-07-16 |
RU2622077C2 (ru) | 2017-06-09 |
AU2012305062A1 (en) | 2014-03-27 |
US9789202B2 (en) | 2017-10-17 |
WO2013036032A1 (en) | 2013-03-14 |
CA2847837A1 (en) | 2013-03-14 |
MX2014002555A (es) | 2014-09-22 |
MX358491B (es) | 2018-08-22 |
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