JP2013518037A - 安定な成長ホルモン化合物 - Google Patents
安定な成長ホルモン化合物 Download PDFInfo
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- JP2013518037A JP2013518037A JP2012549376A JP2012549376A JP2013518037A JP 2013518037 A JP2013518037 A JP 2013518037A JP 2012549376 A JP2012549376 A JP 2012549376A JP 2012549376 A JP2012549376 A JP 2012549376A JP 2013518037 A JP2013518037 A JP 2013518037A
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Abstract
Description
本文脈では、「ヒト成長ホルモン(hGH)」、「hGH wt」、および「野生型hGH(wthGH)」という語を互換的に用い、すべて配列番号1としてのアミノ酸配列を有するタンパク質を指す。
が含まれる。
a.配列番号1により定義されるヒト成長ホルモン(hGH)と比較して、1つまたは複数のさらなるジスルフィド結合、および少なくとも1つのさらなる単一点突然変異を、前記成長ホルモン化合物に導入するステップ
を含む方法。
a.ヒト成長ホルモン(hGH)と比較して、1つまたは複数のアミノ酸残基を1つまたは複数のシステインで置換することにより1つまたは複数のさらなるジスルフィド結合を導入するステップと、
b.ヒト成長ホルモン(hGH)と比較して、1つまたは複数のアミノ酸残基を置換することにより少なくとも1つのさらなる単一点突然変異を導入するステップと
を含む方法。
a.ヒト成長ホルモン(hGH)と比較して、1つまたは複数のシステイン残基を付加することにより1つまたは複数のさらなるジスルフィド結合を導入するステップと、
b.ヒト成長ホルモン(hGH)と比較して、1つまたは複数のアミノ酸残基を置換することにより少なくとも1つのさらなる単一点突然変異を導入するステップと
を含む方法。
本明細書に記載される各種の化合物の調製および特徴づけ、ならびにそれらの生物学的活性を評価する方法について説明する以下の実施例を参照することにより、本発明をさらに明示する。本発明の範囲から逸脱しない限りにおいて、材料および方法のいずれに対しても、多くの変更を行うことが可能であることは、当業者に明らかであろう。
hGH化合物を調製するための一般的な方法
成長ホルモン化合物をコードする遺伝子を、組換えによりプラスミドベクター内へと挿入する。QuickChange部位指向性変異誘発キット(Stratagene社製)を用いることにより、システインの変異を導入する。その後、プラスミドベクターを用いて、適切な大腸菌株を形質転換する。タンパク質は、固定化金属アフィニティークロマトグラフィー精製に適する、N末端におけるヒスチジンに富むペプチドタグを伴う可溶性タンパク質として発現させる。
以下の溶液:
緩衝液A:トリエタノールアミン(119mg、0.8ミリモル)を水(40mL)に溶解させ、pHを8.5に調整した。
緩衝液B: 20mMトリエタノールアミン; 0.2M NaCl
を調製した。
hGH(8.64g)を、撹拌しながら、緩衝液A(500mL)に溶解させた。この溶液に、緩衝液A(50mL)中の1,3-ジアミノ-2-プロパノール(DAP)(8.1g; Fluka社製33262)の混合物をゆっくりと添加した。HCl水溶液を添加することにより、結果として得られる混合物のpHを8.5へと調整した。混合しながら、mTGアーゼ(2.8mL、1.3mg/mL)を添加した。最終混合物を、室温で一晩にわたり撹拌した。
緩衝液A:トリエタノールアミン(119mg、0.8ミリモル)を水(40mL)に溶解させ、pHを8.5に調整した。
緩衝液B: 3-メチルチオ-1-プロパノール(725mg、7.1ミリモル)を緩衝液A(10mL)に溶解させた。
緩衝液C: HEPES(5.96g)を水(1.0L)に溶解させ、pHを7.0に調整した。
過ヨウ素酸: NaIO4(48.1mg、0.225ミリモル)を水(1.0mL)に溶解させた。
(B)からの最終溶液(1mL、0.45マイクロモル)を、pH7.0の25mM HEPES緩衝液中において、PEG-アミン溶液(2mL、0.3マイクロモル)と混合し、結果として得られる混合物を、室温で1時間にわたりゆっくりと回転させた。1時間後に、NaCNBH3(水(0.5mL)中に100μLのNaCNBH3溶液(20mg))を、分割して(10回に分割して)添加した。混合物を、暗所内室温で18〜24時間にわたり静置した。MonoQ上において混合物を精製し、緩衝液を交換し、濃縮した。mPEG-アミン試薬は、市販されている。
精製された成長ホルモン化合物に対するタンパク質化学による特徴づけ
MALDI-MSを用いて、完全精製タンパク質を解析した。観察された質量は、アミノ酸配列から推定される理論的質量と符合した。
精製された成長ホルモン化合物の生物学的活性についての解析
細胞ベースの受容体能による増殖アッセイ、すなわちBAFアッセイにより、hGH化合物の生物学的活性を測定した。該方法は、hGH化合物に対する一般性を示す。
下垂体切除Sprague Dawleyラットにおける、in vivo用量-反応試験
雄の下垂体切除Sprague Dawleyラットにおいて、in vivoの用量-反応関係を調べることができる。下垂体切除ラットは、よく知られて認知された、成長ホルモン欠損の動物モデルであり、手術により下垂体を除去した後では、成長ホルモンの生成が生じない。これはまた、ヒトにおける成長ホルモン欠損の別の重要な臨床特徴である、循環インスリン様成長因子1(IGF-1)レベルの低下ももたらす。
表面プラズモン共鳴解析による受容体相互作用試験
表面プラズモン共鳴解析を用いて、hGH化合物の受容体相互作用について解析した。この方法は、hGH化合物について一般性があり、Q84C/Y143C hGH化合物はこれを例示する。
プロテアーゼによる野生型hGHおよびGH化合物の分解速度を測定するアッセイ
37℃で最長24時間にわたり、適切な緩衝液(例えば、PBSまたは重炭酸アンモニウム)中における関与性のプロテアーゼ(トリプシン、キモトリプシン、ペプシン、エラスターゼ、因子VIIa、因子Xa、プロテイナーゼK、カルボキシペプチダーゼ、DPPIV、中性エンドペプチダーゼ、グランザイムB、プロリンエンドペプチダーゼ、ブドウ球菌ペプチダーゼI、テルモリシン、トロンビン、Arg-Cプロテイナーゼ、Asp-Nエンドペプチダーゼ、カスパーゼ1〜10、クロストリパイン、エンテロキナーゼ、グルタミルエンドペプチダーゼ、LysC、およびLysN、または組織抽出物)により、対象の化合物を消化させた。タンパク質分解は、HPLCアッセイにより評価する。
タンパク質分解による消化:
重炭酸アンモニウム緩衝液中1mg/mlの被験化合物溶液100μLを、37℃で最長24時間にわたり、酵素により分解させる。各時点に対応する部分試料を採取し、1%TFA中への10倍希釈を介して該試料を酸化させることにより、タンパク質分解反応を停止させる。逆相HPLCによりこれらの希釈試料を解析して、タンパク質分解による消化の程度を推定する。
水中に0.1%TFA〜0.1%TFA含有100%アセトニトリルの直線勾配により溶出させる2×150mmのVydac C4逆相カラム上に、30分間にわたり、0.2ml/分の流速で、10μLの上記溶液を注射する。214nmにおけるUV吸収により、ピークの検出を実施する。時点t=Tにおけるピーク面積(AT)と、時点t=0におけるピーク面積(A0)とから、(AT/A0)×100%として、時点t=Tにおける完全化合物(%)を計算する。本明細書下記のtable 6(表6)に示す結果は、4時間後(上式におけるT=4)に得られた。
BAFアッセイ、ならびに実施例3および5に記載したタンパク質分解による消化を介する、選択された化合物についての解析
実施例3、4、および5に記載したBAFアッセイ、SPR解析、およびタンパク質分解による消化を介する、選択された化合物についての解析
Claims (15)
- 配列番号1により定義されるヒト成長ホルモン(hGH)と比較して、1つまたは複数のさらなるジスルフィド結合、および少なくとも1つのさらなる単一点突然変異を含む、成長ホルモン化合物。
- ループ部分とヘリックス部分との間を連結する、1つまたは複数のさらなるジスルフィド結合を含む、請求項1に記載の成長ホルモン化合物。
- 配列番号1中に、R16C/L117C、A17C/E174C、H21C/M170C、D26C/V102C、D26C/Y103C、N47C/T50C、Q49C/G161C、F54C/Y143C、F54C/S144C、F54C/F146C、S55C/Y143C、S57C/Y143C、I58C/Q141C、I58C/Y143C、I58C/S144C、P59C/Q137C、P61C/E66C、P61C/T67C、S71C/S132C、L73C/S132C、L73C/F139C、R77C/I138C、R77C/F139C、L81C/Q141C、L81C/Y143C、Q84C/Y143C、Q84C/S144C、S85C/Y143C、S85C/S144C、P89C/F146C、F92C/F146C、F92C/T148C、R94C/D107C、V102C/A105C、L156C/F146C、L156C/T148C、および/またはV185C/S188Cに対応する少なくとも1対の変異を含む、請求項1から2のいずれかに記載の成長ホルモン化合物。
- 1つまたは複数のさらなるジスルフィド結合を含み、そのシステインのうちの少なくとも1つが、配列番号1中のアミノ酸128〜154に対応するループ3(L3)内に存在する、請求項1から3のいずれかに記載の成長ホルモン化合物。
- L3を、ヘリックス2(H2)またはループ1(L1)と連結する、1つまたは複数のさらなるジスルフィド結合を含む、請求項4に記載の成長ホルモン化合物。
- 配列番号1中に、H21C/M170C、D26C/V102C、D26C/Y103C、F54C/Y143C、F54C/S144C、S55C/Y143C、S57C/Y143C、I58C/Q141C、I58C/Y143C、I58C/S144C、P59C/Q137C、S71C/S132C、L81C/Y143C、Q84C/Y143C、S85C/Y143C、S85C/S144C、F92C/T148C、および/またはR94C/D107Cに対応する少なくとも1対の変異を含む、請求項3に記載の成長ホルモン化合物。
- 配列番号1により定義されるヒト成長ホルモン(hGH)と比較して、プロテアーゼに対する安定性を増大させた、請求項1から6のいずれかに記載の成長ホルモン化合物。
- 少なくとも1つのさらなる単一点突然変異が、配列番号1の1〜55、57、58、60〜63、67〜87、89〜91、93、95〜100、101、102〜128、131〜132、135〜139、141、142、144、148〜182、184、185、および/または187〜191位に対応する位置に存在する、請求項1から7のいずれかに記載の成長ホルモン化合物。
- 少なくとも1つのさらなる単一点突然変異が、配列番号1の40、41、42、55、57、62、101、134、136、139、142、および/または144位に対応する位置に存在する、請求項1から8のいずれかに記載の成長ホルモン化合物。
- 少なくとも1つのさらなる単一点突然変異が、L1(配列番号1のアミノ酸36〜71に対応する)および/またはL3(配列番号1のアミノ酸128〜154に対応する)に存在する、請求項1から9のいずれかに記載の成長ホルモン化合物。
- 少なくとも1つのさらなる単一点突然変異が、L1の中央領域(配列番号1のアミノ酸40〜65に対応する)および/またはL3の中央領域(配列番号1のアミノ酸134〜148に対応する)に存在する、請求項1から10のいずれかに記載の成長ホルモン化合物。
- 配列番号1により定義されるヒト成長ホルモンと比較して、正確に1つのさらなるジスルフィド結合、および少なくとも1つのさらなる単一点突然変異を含む、請求項1から11のいずれかに記載の成長ホルモン化合物。
- タンパク質分解に対する安定性を増大させた成長ホルモン化合物を調製する方法であって、
a.配列番号1により定義されるヒト成長ホルモン(hGH)と比較して、1つまたは複数のさらなるジスルフィド結合、および少なくとも1つのさらなる単一点突然変異を、前記成長ホルモン化合物に導入するステップ
を含む方法。 - 請求項1から12のいずれかに記載の成長ホルモン化合物と、薬学的に許容される担体とを含む医薬組成物。
- 疾患または状態を治療する方法であって、循環成長ホルモン化合物量の増大から患者が利益を得る、有効量の、請求項1から12のいずれかに記載の成長ホルモン化合物または請求項14に記載の医薬組成物を患者に投与するステップを含む方法。
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MX338357B (es) | 2016-04-13 |
AU2011208620B2 (en) | 2015-04-16 |
RU2012134974A (ru) | 2014-02-27 |
US20130040883A1 (en) | 2013-02-14 |
MX2012007999A (es) | 2012-08-03 |
IL220648A0 (en) | 2012-08-30 |
WO2011089250A2 (en) | 2011-07-28 |
BR112012018162A2 (pt) | 2017-10-03 |
WO2011089250A3 (en) | 2011-10-13 |
AU2011208620A1 (en) | 2012-07-19 |
ZA201205385B (en) | 2013-04-24 |
US9211342B2 (en) | 2015-12-15 |
EP2525833A2 (en) | 2012-11-28 |
CA2787895A1 (en) | 2011-07-28 |
JP5980689B2 (ja) | 2016-08-31 |
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