JP6087429B2 - 変形されたヒト腫瘍壊死因子受容体−1ポリペプチドの新規用途 - Google Patents
変形されたヒト腫瘍壊死因子受容体−1ポリペプチドの新規用途 Download PDFInfo
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- JP6087429B2 JP6087429B2 JP2015518318A JP2015518318A JP6087429B2 JP 6087429 B2 JP6087429 B2 JP 6087429B2 JP 2015518318 A JP2015518318 A JP 2015518318A JP 2015518318 A JP2015518318 A JP 2015518318A JP 6087429 B2 JP6087429 B2 JP 6087429B2
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Description
位置92、95、97、及び98の4個のアミノ酸残基の位置におけるアミノ酸の変形を含むアミノ酸配列(4重変異体)、
位置68、92、95、97、及び98の5個のアミノ酸残基の位置におけるアミノ酸の変形を含むアミノ酸配列(5重変異体)、または
位置68、92、95、97、及び98の5個のアミノ酸残基の位置及び、追加的に位置161、または207のアミノ酸残基の位置におけるアミノ酸の変形を含むアミノ酸配列(6重変異体)、を持つことが好ましい。
92位でSのI、またはMへの置換、
95位でHのFへの置換、
97位でRのPへの置換、及び
98位でHのA、またはGへの置換、が必須的に含まれて、
好ましくは追加的に、
68位でLのVへの置換、
161位でKのQ、またはNへの置換、及び
207位でのDのNへの置換、から選択された一つ以上のアミノ酸残基の変形がさらに含まれてもよい。前記変形で、好ましくは前記92位のSは、Mに置換されて、98位のHは、Gに置換されて、161位のKは、Nに置換される。
前記4重変異体で追加的に68位でLのVへの置換を含む5重変異体、または
前記5重変異体で追加的に161位でKのQ、またはNへの置換、または、207位でのDのNへの置換を含む6重変異体が本発明に係る眼球乾燥症の予防及び/または治療用組成物の有効成分として利用されることが好ましい。
前記ポリペプチド複合体は、変形されたTNFRI又は変形されたTNFRI切片の少なくとも2つが結合、好ましくは共有結合された構造を有する。
配列番号1に記載された天然型TNFRIのアミノ酸配列(TNFRI)でS92I/H95F/R97P/H98A、S92M/H95F/R97P/H98A、L68V/S92M/H95F/R97P/H98A、L68V/S92I/H95F/R97P/H98A/K161N、L68V/S92M/H95F/R97P/H98A/K161N、L68V/S92M/H95F/R97P/H98A/D207N、L68V/S92I/H95F/R97P/H98G/K161Q、または、L68V/S92M/H95F/R97P/H98G/K161N中から選択されるアミノ酸変形を含むアミノ酸配列;
配列番号1に記載された天然型TNFRIのアミノ酸配列の41番〜211番からなるアミノ酸配列(TNFRI171)でS92I/H95F/R97P/H98A、S92M/H95F/R97P/H98A、L68V/S92M/H95F/R97P/H98A、L68V/S92I/H95F/R97P/H98A/K161N、L68V/S92M/H95F/R97P/H98A/K161N、L68V/S92M/H95F/R97P/H98A/D207N、L68V/S92I/H95F/R97P/H98G/K161Q、または、L68V/S92M/H95F/R97P/H98G/K161N中から選択されるアミノ酸変形を含むアミノ酸配列;
配列番号1に記載された天然型TNFRIのアミノ酸配列の41番〜166番からなるアミノ酸配列(TNFRI126)でS92I/H95F/R97P/H98A、S92M/H95F/R97P/H98A、L68V/S92M/H95F/R97P/H98A、L68V/S92I/H95F/R97P/H98A/K161N、L68V/S92M/H95F/R97P/H98A/K161N、L68V/S92M/H95F/R97P/H98A/D207N、L68V/S92I/H95F/R97P/H98G/K161Q、または、L68V/S92M/H95F/R97P/H98G/K161N中から選択されるアミノ酸変形を含むアミノ酸配列;または
配列番号1に記載された天然型TNFRIのアミノ酸配列の41番〜145番からなるアミノ酸配列(TNFRI105)でS92I/H95F/R97P/H98A、S92M/H95F/R97P/H98A、または、L68V/S92M/H95F/R97P/H98A中から選択されるアミノ酸変形を含むアミノ酸配列。
配列番号1に記載された天然型TNFRIのアミノ酸配列(TNFRI)でL68V/S92I/H95F/R97P/H98A/K161N、L68V/S92M/H95F/R97P/H98A/D207N、または、L68V/S92M/H95F/R97P/H98G/K161N中から選択されるアミノ酸変形を含むアミノ酸配列;
配列番号1に記載された天然型TNFRIのアミノ酸配列の41番〜211番からなるアミノ酸配列(TNFRI171)でL68V/S92I/H95F/R97P/H98A/K161N、L68V/S92M/H95F/R97P/H98A/D207N、または、L68V/S92M/H95F/R97P/H98G/K161N中から選択されるアミノ酸変形を含むアミノ酸配列;または
配列番号1に記載された天然型TNFRIのアミノ酸配列の41番〜166番からなるアミノ酸配列(TNFRI126)でL68V/S92I/H95F/R97P/H98A/K161N、または、L68V/S92M/H95F/R97P/H98G/K161N中から選択されるアミノ酸変形を含むアミノ酸配列。
配列番号1に記載された天然型TNFRIのアミノ酸配列(TNFRI)でL68V/S92M/H95F/R97P/H98G/K161N、または、L68V/S92M/H95F/R97P/H98A/D207Nであるアミノ酸変形を含むアミノ酸配列;
配列番号1に記載された天然型TNFRIのアミノ酸配列の41番〜211番からなるアミノ酸配列(TNFRI171)でL68V/S92M/H95F/R97P/H98G/K161N、または、L68V/S92M/H95F/R97P/H98A/D207Nであるアミノ酸変形を含むアミノ酸配列;または
配列番号1に記載された天然型TNFRIのアミノ酸配列の41番〜166番からなるアミノ酸配列(TNFRI126)でL68V/S92M/H95F/R97P/H98G/K161Nであるアミノ酸変形を含むアミノ酸配列。
(1)TNFRI変異体の設計
本出願人の韓国特許出願第2010−0089395号(公開番号第2012−0027666号)及び韓国特許出願第2011−0138751号(公開番号第2012−0072323号)から下記の表1のアミノ酸変形を含む変形されたTNFRI(「TNFRI変異体」)を候補として選定した。
位置特異的TNFRI変異体を作製するために位置指定突然変異体作製(site-directed mutagenesis)方法によってTNFRI変異体を作製した。前記表1に記載されたアミノ酸変形を含むTNFRI変異体作製に用いられたプライマー及び鋳型を下記の表2に示した。
PCR産物は、DpnI酵素で37℃で2時間処理して、大腸菌由来のDNAを分解して、PCRによって増幅されたDNAを確保した。DNA溶液2μLを取ってXL1−blueコンピテント細胞(competent cell)(RBC,Cat.No:RH119−J80)に入れて、42℃で1分間熱衝撃(heat shock)を加えて、形質転換して、アンピシリンが含まれたLB固体培地で静置培養してコロニーを得た。このコロニーをアンピシリンが含まれたLB液体培地で培養した後、プラスミドを分離して、塩基配列分析を介して位置特異的TNFRI変異体が完成されたことを確認した。
(イ)TNFRI及びTNFRI変異体の発現
前記製造例で作製されたプラスミド溶液1μLを取って、BL21Star(DE3)(Invitrogen、Cat.No:C6010−03)コンピテント細胞に入れて、42℃で1分間熱衝撃を加えて形質転換して、アンピシリンが含まれたLB固体培地で静置培養してコロニーを得た。発現ベクターを含んでいる大腸菌BL21Star(DE3)を100μg/mL濃度のアンピシリンが入っている50mL YP培地(yeast extract:Merck,Cat.No:103753,peptone:BD,Cat.No:243620,NaCl:Merck、Cat.No:1064049025)に接種して37℃で16時間通気培養した。培養された培地は、100μg/mL濃度のアンピシリンが含まれた250mL YP培地がある1Lフラスコに600nmの吸光度が0.1になるよう接種した。37℃で培養して600nmの吸光度が3〜4である時、最終濃度が1.0mM濃度になるようIPTGを添加して発現を誘導した。発現誘導後37℃で3時間さらに通気培養を継続した後、細胞を6000rpmで20分間遠心分離して細胞を収集した。
収集した細胞を再懸濁溶液(50mMトリス、0.5mMEDTA(pH8.5))で再懸濁させた。懸濁された細胞は、sonicator(Sonics,Cat.No:VCX750)を使って破砕した。細胞破砕後、8000xg、10℃、30分間の遠心分離と、上澄み液を捨て、沈殿したペレットを洗浄溶液1(50mMトリス、10mM EDTA、0.5%トリトンX−100(Triton X-100)(pH8.0))で懸濁させて、8000xg、10℃、20分間遠心分離した。上澄み液を捨て、ペレットを再懸濁溶液で再懸濁させて、8000xg、10℃、20分間遠心分離した。前記洗浄されたペレットは直ちに使るか−80℃で凍結保存した。
前記得られたペレットに6mL変性溶液(6〜8M尿素(Urea)または6〜8M塩化グアニジン(Guanidine-HCl)、10mMジチオトレイトール(DTT)、2.0mM EDTA、0.2M NaCl)を添加して溶解した。溶解後、0.45μmシリンジフィルターを使って溶解しなかったペレットを取り除いた。可溶化させたペレット溶液をリフォールディング(refolding)溶液(50mMトリス、1.0mM EDTA、0.5M L−アルギニン(Arginine)、6.0mM GSH、4.0mM GSSG、240mM NaCl、10mM KCl(pH9.0))に20倍に希釈して4℃で12〜24時間穏やかに攪拌リフォールディングを誘導した。
リフォールディングされたTNFRI及びTNFRI変異体を精製するために、リフォールディング溶液を3kDのAmicon Ultra(Millipore,Cat.No:UFC900324)を用いて20倍に濃縮した。濃縮後、Superdex 75 prep grade(GE)レジンをXK25/70(GE,Cat.No:19−0146−01)カラムにパッキングしたゲル透過クロマトグラフィー(GPC:gel permeation chromatography)を用いて精製した。
眼球乾燥症治療でTNFαの阻害に伴う治療効果を確認するために、TNFα阻害剤をマウスを利用した眼球乾燥症動物モデルに投与した。TNFα阻害剤として、エタネルセプトとTNFRI変異体を用いて、TNFRI変異体とエタネルセプトの治療効果を比較した。陽性対照群としてシクロスポリンAを用いた。
実施例2.1 角膜損傷回復効果確認
TNFRI変異体であるHL036337をバッファーを利用して、各々0.625mg/mLと6.25mg/mL濃度で調製して、点眼適用の場合は、1回当たり8mg/mLずつ、1日4回適用し、皮下投与の場合は、0.5mg/kgと5mg/kgで1日1回投与した。また、対照群であるエタネルセプトは、5mg/kgで1日1回皮下適用した。
前記実施例1のように製造された眼球乾燥症動物モデルに7日間試験物質を投与して、症状改善程度を観察した。エタネルセプトは、皮下投与方式で投与され、TNFRI変異体は、皮下と点眼投与方式で投与された。
角膜損傷程度は前記実施例1と同様に評価した。
その結果、エタネルセプトを皮下投与した場合には、症状改善効果が殆どない反面、TNFRI変異体を皮下及び点眼投与した場合、全角膜傷の回復効果を示しており、特に点眼投与時角膜傷を回復させる効果が優れたことが分かった(図2参照)。
試験物質投与による涙量増加程度を確認しようとフルオレセイン試験紙を下まぶたに入れて涙量を測定した。涙量による等級は、表4のとおりである。Grade0の場合は涙が殆どない状態を意味し、Grade1は、3mm、Grade2は、4〜5mm、Grade3は、6mmだけ試験紙が濡れることを意味する。
抗炎症効能を確認するための炎症関連サイトカイン測定は、角膜組織からmRNAを抽出した後、qPCR法で測定してIFN−γ、IL−1、IL−4、IL−6、IL−21とIL−22のmRNAのレベルを確認した。
各物質の投与方法は、前記実施例2.1と同様であった。その結果、眼球乾燥症誘発によって炎症に関連したサイトカイン(IFN−γ、IL−1、IL−6、IL−4、IL−21、IL−22)が、角膜で顕著に増加することを確認することができた。しかし、TNFRI変異体であるHL036337を皮下に適用した場合には、炎症に関連したサイトカインが減少することが確認されて、特に点眼で適用時には炎症が改善されて、略正常レベルに回復する優れた効果を見せた。その反面、エタネルセプトを皮下に適用すると、殆ど炎症減少効果が観察されなかった(図4参照)。
TNFRI変異体であるHL036326及びHL036330もHL036337と似た程度で角膜での抗炎症効果を示すことを確認した。
眼球表面での炎症サイトカインの量を測定するために、Luminex100を利用して測定して、IFN−γ、IL−6、IL−21とIL−22の量を測定した。
各物質の投与方法は、前記実施例2.1と同様であった。その結果、眼球乾燥症誘発によって炎症に関連したサイトカイン(IFN−γ、IL−6、IL−21、IL−22)が眼球表面で顕著に増加した。しかし、TNFRI変異体であるHL036337を点眼で適用時優れた炎症改善効果が観察された反面、エタナセプトを皮下に適用する時炎症減少効果が殆ど観察されなかった(図5参照)。
TNFRI変異体であるHL036326及びHL036330もHL036337と似た程度で眼球表面での抗炎症効果を示すことを確認した。
眼球乾燥症治療剤として使用中の0.05%のシクロスポリンAと0.1%メチルプレドニゾロン(methyl prednisolone)点眼液との効果を比較するために、涙腺での炎症サイトカインの量を測定した。炎症関連サイトカイン測定は、涙腺組織からmRNAを抽出した後、qPCR法で測定してIFN−γ、IL−6 mRNAのレベルを確認した。
TNFRI変異体であるHL036326及びHL036330もHL036337と似た程度で涙腺での抗炎症効果を示すことを確認した。
Claims (11)
- 配列番号1に記載された天然型TNFRIのアミノ酸配列(TNFRI)で、
i)L68V/S92I/H95F/R97P/H98A/K161N、L68V/S92M/H95F/R97P/H98A/D207N、または、L68V/S92M/H95F/R97P/H98G/K161N中から選択されるアミノ酸変形を含むアミノ酸配列;
ii)配列番号1に記載された天然型TNFRIのアミノ酸配列の41番〜211番からなるアミノ酸配列(TNFRI171)でL68V/S92I/H95F/R97P/H98A/K161N、L68V/S92M/H95F/R97P/H98A/D207N、または、L68V/S92M/H95F/R97P/H98G/K161N中から選択されるアミノ酸変形を含むアミノ酸配列;及び
iii)配列番号1に記載された天然型TNFRIのアミノ酸配列の41番〜166番からなるアミノ酸配列(TNFRI126)でL68V/S92I/H95F/R97P/H98A/K161N、または、L68V/S92M/H95F/R97P/H98G/K161N中から選択されるアミノ酸変形を含むアミノ酸配列
からなる群から選択されるアミノ酸配列を含む変形されたTNFRIの1種以上を含むことを特徴とする眼球乾燥症の予防または治療用組成物。 - 配列番号1に記載された天然型TNFRIのアミノ酸配列(TNFRI)で
i)L68V/S92M/H95F/R97P/H98G/K161N、または、L68V/S92M/H95F/R97P/H98A/D207Nであるアミノ酸変形を含むアミノ酸配列;及び
ii)配列番号1に記載された天然型TNFRIのアミノ酸配列の41番〜211番からなるアミノ酸配列(TNFRI171)でL68V/S92M/H95F/R97P/H98G/K161N、または、L68V/S92M/H95F/R97P/H98A/D207Nであるアミノ酸変形を含むアミノ酸配列
からなる群から選択されるアミノ酸配列を含む変形されたTNFRIの1種以上を含むことを特徴とする請求項1に記載の眼球乾燥症の予防または治療用組成物。 - 配列番号18又は20から選択されるアミノ酸配列を含む変形されたTNFRIの1種以上を含むことを特徴とする請求項1に記載の眼球乾燥症の予防または治療用組成物。
- 前記変形されたTNFRIは、大腸菌発現系での産生のための変形がさらに含まれたことを特徴とする請求項1から3のいずれかに記載の眼球乾燥症の予防または治療用組成物。
- 大腸菌発現系での産生のための変形は、アミノ酸配列のアミノ末端に信号配列またはメチオニン(Met)が付加されたことを特徴とする請求項4に記載の眼球乾燥症の予防または治療用組成物。
- 請求項1から3のいずれかに記載の変形されたTNFRIの二つ以上が共有結合によって連結された形態の変形されたTNFRI複合体1種以上を含む眼球乾燥症の予防または治療用組成物。
- 前記変形されたTNFRIは、糖化、アシル化、メチル化、リン酸化、ハシル化、カルバミル化、硫酸化、プレニル化、酸化、グアニジル化、アミジン化、カルバミル化、トリニトロフェニル化、硝酸化、またはペグ化されていることを特徴とする請求項1から3のいずれかに記載の眼球乾燥症の予防または治療用組成物。
- 請求項1から3のいずれかに記載の変形されたTNFRIを暗号化する遺伝子を含む眼球乾燥症の予防または治療用組成物。
- 請求項1から3のいずれかに記載の組成物を含む局所点眼用製剤。
- 点眼剤または眼軟膏であることを特徴とする請求項9に記載の局所点眼用製剤。
- 変形されたTNFRIを含む眼球乾燥症の予防または治療用組成物であって、前記の変形されたTNFRIが、配列番号1に記載された天然型TNFRIのアミノ酸配列の41番〜211番からなるアミノ酸配列(TNFRI171)でL68V/S92M/H95F/R97P/H98G/K161Nであるアミノ酸変形を含むアミノ酸配列を含む前記組成物。
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US6204270B1 (en) | 1999-11-12 | 2001-03-20 | Eyal S. Ron | Ophthalmic and mucosal preparations |
US20040136990A1 (en) | 2002-07-19 | 2004-07-15 | Abbott Biotechnology Ltd. | Treatment of pain using TNFalpha inhibitors |
US20090098136A1 (en) | 2007-10-15 | 2009-04-16 | Alcon Research, Ltd. | Use of tnf receptor antagonists for treating dry eye |
CN101591388A (zh) * | 2008-05-30 | 2009-12-02 | 上海复旦张江生物医药股份有限公司 | 一种可溶性tnf受体突变体 |
JP5746191B2 (ja) | 2009-10-19 | 2015-07-08 | ハナル バイオファーマ カンパニーリミテッドHanAll Biopharma Co., Ltd. | 修飾されたヒト腫瘍壊死因子受容体−1ポリペプチドまたはその断片及びその製造方法 |
KR101273893B1 (ko) | 2010-09-13 | 2013-06-14 | 한올바이오파마주식회사 | 변형된 인간 종양 괴사 인자 수용체-1 폴리펩티드 또는 그의 절편 및 그의 제조방법 |
JP5819439B2 (ja) | 2010-12-23 | 2015-11-24 | ハノル バイオファーマ カンパニー リミテッド | 修飾されたヒト腫瘍壊死因子受容体−1ポリペプチドまたはその断片及びその製造方法 |
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US9580490B2 (en) | 2017-02-28 |
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JP2015525237A (ja) | 2015-09-03 |
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US20150119338A1 (en) | 2015-04-30 |
BR112014031923A2 (pt) | 2017-11-28 |
CN104394881B (zh) | 2016-10-26 |
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