JP4852545B2 - ニューブラスチン(Neublastin)変異体 - Google Patents
ニューブラスチン(Neublastin)変異体 Download PDFInfo
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- JP4852545B2 JP4852545B2 JP2007528061A JP2007528061A JP4852545B2 JP 4852545 B2 JP4852545 B2 JP 4852545B2 JP 2007528061 A JP2007528061 A JP 2007528061A JP 2007528061 A JP2007528061 A JP 2007528061A JP 4852545 B2 JP4852545 B2 JP 4852545B2
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Description
本出願は、2004年8月19日に出願された仮特許出願番号60/602,825および2005年6月24日に出願された各特許出願番号60/694,067の優先権を主張する。これらの先行出願の各々の全内容は、その全体が本明細書に参考として援用される。
本発明は、タンパク質化学、分子生物学、および神経学に関する。
ニューブラスチン(Neublastin)はアルテミン(Artemin)およびエノビン(Enovin)としても知られており、24kDaのホモ二量体の分泌タンパク質である。これは、ドーパミン作用性ニューロンのような末梢神経系および中枢神経系のニューロンの生存性を促進する(非特許文献1;非特許文献2)。ニューブラスチンをコードする遺伝子はクローニングされ、配列決定されている(非特許文献3)。
Baudet et al.,2000、Development,127:4335 Rosenblad 2000,Mol.Cell Neurosci.,15(2):199;GenBank AF120274 Baloh et al.,Neuron,21:1291 Orozco et al.,2001、Eur.J.Neurosci.,13(11):2177 Saarma,1999,Microsc.Res.Tech.,45:292 Rattenholl et al.,2000,J.Mol.Biol.,305:523 Fairlic et al.,2001,J.Biol.Chem.276(20):16911 Fairlic et al.,2001,J.Biol.Chem.276(20):16911
本発明は、ニューブラスチンがヘパリン硫酸に結合すること、およびニューブラスチンポリペプチドの中の特定のアミノ酸残基がこの結合事象に寄与していることの発見に、少なくとも一部基づく。選択されたアミノ酸残基の置換は、変異体ニューブラスチンポリペプチドによるヘパリン結合を減少させ、そして変異体の生体活性および生体利用性を増大させることが明らかにされた。
成熟した野生型ヒトニューブラスチンは113アミノ酸の長さであり、以下のアミノ酸配列を有している:
変異体ニューブラスチンポリペプチドは、治療有効量のポリペプチドと1つ以上のアジュバント、賦形剤、担体、および/または希釈剤を含む薬学的組成物へと配合することができる。許容される希釈剤、担体、および賦形剤は、通常、レシピエントの恒常性(例えば、電解質のバランス)に有害な影響を及ぼさない。許容される担体としては、生体適合性の不活性な、もしくは生体内で吸収される塩、緩衝物質、オリゴ糖もしくは多糖、ポリマー、増粘剤、保存剤などが挙げられる。1つの例示的な担体は生理食塩水(0.15MのNaCl、pH7.0〜7.4)である。別の例示的な担体は50mMのリン酸ナトリウム、100mMの塩化ナトリウムである。薬学的組成物の処方および投与のための技術のさらなる詳細は、例えば、REMINGTON’S PHARMACEUTICAL SCIENCES(Maack Publishing Co.,Easton,Pa.)に見ることができる。
変異体ニューブラスチンポリペプチドは、神経細胞またはニューロン細胞の代謝、増殖、分化、または生存を調節するために有用である。具体的には、変異体ニューブラスチンポリペプチドは、生存している動物(例えば、ヒト)の障害または疾患(これらの障害または疾患は、神経栄養因子の活性に反応する)を処置または緩和するために使用することができる。
本明細書中に開示される変異体ニューブラスチンポリペプチド(およびそれを含む薬学的組成物)は、被験体の神経障害の痛みを処置するための方法において使用することができる。この方法には、被験体に有効量の変異体ニューブラスチンポリペプチドを単独で投与する工程、または被験体に有効量の以下からなる群より選択される無痛覚症を誘導する化合物を投与する工程もまた、含まれる:オピオイド、不整脈治療剤、局所鎮痛薬、局所麻酔薬、抗痙攣剤、抗鬱剤、コルチコステロイド、および非ステロイド系抗炎症薬(NSAIDS)。1つの実施形態においては、無痛覚症を誘導する化合物は抗痙攣剤である。別の実施形態においては、無痛覚症を誘導する化合物はガバペンチン((1−アミノメチル)シクロヘキサン酢酸)またはプレガバリン(S−(+)−4−アミノ−3−(2−メチルプロピル)ブタン酸)。である。
本明細書中に開示される変異体ニューブラスチンポリペプチド(およびそれを含む薬学的組成物)は、被験体の接触性アロディニアの処置に使用することができる。用語「接触性アロディニア」は、通常、痛みが、正常であれば無害である皮膚の刺激(接触)によって引き起こされる被験体の症状をいう。
別の実施形態においては、本明細書中に開示される変異体ニューブラスチンポリペプチド(およびそれを含む薬学的組成物)は、神経障害に罹患している被験体の痛覚の欠如を軽減させるための方法において使用することができる。1つの実施形態においては、神経障害は糖尿病性神経障害である。いくつかの実施形態においては、痛覚の欠如は、熱痛覚の欠如である。この方法には、予防的処置と治療的処置の両方が含まれる。
感染およびウイルスによる神経障害の予防的処置が想定される。予防的処置は、ウイルス感染の決定後であって、神経障害の痛みの発症の前に行われる。処置の間に、変異体ニューブラスチンポリペプチドが投与されて、神経障害の痛み(ハンセン病、ライム病に伴う神経障害の痛み、ウイルス、特に、ヘルペスウイルス(およびより具体的には、ヘルペス後の神経痛を引き起こし得る帯状疱疹ウイルス)、ヒト免疫不全ウイルス(HIV)、およびパピローマウイルスからなる群より選択されるウイルスによる感染に伴う神経障害の痛みが含まれるがこれらに限定されない)の出現が防がれる。別の実施形態においては、変異体ニューブラスチンポリペプチドは、起こるであろう神経障害の痛みの重篤度を低下させるために投与される。
痛みを伴う糖尿病性神経障害の予防的処置が想定される。糖尿病性神経障害の予防的処置は、糖尿病または糖尿病に伴う症状の最初の診断の決定後であって、神経障害の痛みの発症の前に、開始される。痛みを伴う糖尿病性神経障害の予防的処置はまた、被験体に糖尿病または糖尿病に伴う症状を発症するリスクがあることが決定されると開始される場合もある。処置の間に、変異体ニューブラスチンポリペプチドが投与されて、神経障害の痛みの出現が防がれる。別の実施形態においては、変異体ニューブラスチンポリペプチドは、すでに現れている神経障害の痛みの重篤度を低下させるために投与される。
本明細書中に開示される変異体ニューブラスチンポリペプチド(およびそれを含む薬学的組成物)は、被験体(例えば、ヒト)の神経系の障害の処置または予防において、その必要がある被験体に治療有効量の変異体ニューブラスチンポリペプチド、変異体ニューブラスチンポリペプチドを含む組成物、またはポリアルキレン部分(例えば、PEG)に結合した安定な水溶性結合変異体ニューブラスチンポリペプチドを含む複合体を投与することによって使用することができる。
ヒトニューブラスチンを結晶化させ、互いに近い位置に接近している以下の4つのニューブラスチン残基:Arg14、Arg48、Arg49、およびArg51と相互作用する硫酸イオンの三者関係であるその構造を明らかにした。この三者構造の存在と、それらの相対的な互いの空間配置に基づいて、ニューブラスチンのこの領域がヘパリン硫酸結合ドメインである可能性があり得ると想定した。その後、先に解明されていたヘパリン硫酸構造を、硫酸塩の三者構造の部位でニューブラスチンに対してドッキングさせた(イン−シリコ)。ヘパリン硫酸はこの位置にきっちりとフィットし、このことは、ニューブラスチンの中のこの領域がヘパリン硫酸結合について可能性があることを示唆している。
実施例2:陽イオン性クロマトグラフィーおよびヘパリンセファロースクロマトグラフィー
変異体ニューブラスチンポリペプチドを、さらに生物学的分析を行い、ヘパリンの結合に対してそれぞれの変異が有している効果を決定した。ヘパリンセファロースと陽イオンクロマトグラフィーの両方を使用した。野生型のヒトニューブラスチンは、11.31の見かけのpIを有している塩基性タンパク質であるので、ニューブラスチンは陽イオン系の樹脂に効率よく結合する。アルギニンからグルタミン酸への1つの変換によって、見かけのpIは10.88に下がる。しかし、このpIの低下は、野生型の対照と比較して、陽イオン樹脂への結合を劇的に変化させることはなく、また、変異体の溶出プロフィールをもまた変化させることはないと予想された。
実施例3:陰イオンクロマトグラフィー
6.5の標準的なpH条件、および150mMの塩化ナトリウム濃度では、ニューブラスチンは陰イオン系樹脂には結合しない。対照的に、ヘパリン硫酸は、これらの同じ条件下で陰イオン系樹脂に結合する。
実施例4:チャイニーズハムスター卵巣細胞結合実験
ニューブラスチンは、チャイニーズハムスター卵巣(CHO)細胞の表面に非特異的に結合することが以前に示されている。ニューブラスチンCHO細胞結合アッセイを、この相互作用が、細胞表面のヘパリン硫酸分子に対するニューブラスチンの結合によって少なくとも一部媒介されているかどうかを決定するために設定した。
実施例5:野生型ニューブラスチンおよび変異体ニューブラスチンポリペプチドのヘパリン結合
ニューブラスチンのヘパリン結合部位として同定されたアルギニンの三者構造の役割をさらに研究するために、ヘパリン結合ELISAを設定した。簡単に説明すると、抗ニューブラスチンモノクローナル抗体を96ウェルプレート上にコーティングし、その後、洗浄、およびニューブラスチンの1つの形態の添加を行った。その後、ビオチニル化ヘパリンをプレートに添加した。さらなる洗浄工程の後、ニューブラスチン/ヘパリン複合体を、化学発光基質を用いてストレプトアビジン−IIRP結合体を使用して同定した。このヘパリン結合ELISAを使用して、野生型のヒトニューブラスチンの113アミノ酸の形態(配列番号1)と、104アミノ酸の形態(配列番号1の10位から13位のアミノ酸)の形態を、1アミノ酸置換(Arg48E、Arg49E、およびArg51E;配列番号2〜4)を含む変異体ニューブラスチンポリペプチド、さらには二重置換体(Arg48,49E;配列番号5)に対して比較した。
実施例6:野生型ニューブラスチンおよびヘパリン結合変異体のキナーゼ受容体活性化分析
ヘパリン結合部位変異体が細胞をベースとする生体アッセイにおいてニューブラスチン受容体によるシグナル伝達に対して効果を有しているかどうかを決定するために、変異体形態のニューブラスチンについて、野生型ニューブラスチンとともに、キナーゼ受容体活性化(KIRA)分析を行った。
実施例7:3成分複合体の分析
野生型のヒトニューブラスチンと個々のヘパリン変異体について、2つのわずかに異なるプロトコールを使用して3成分複合体分析を行った。第1のプロトコールでは、ニューブラスチンの受容体成分(GFRα3およびRET)をプール中のニューブラスチンとともに混合し、その後、捕捉抗体でコーティングしたELISAプレートに添加した(図8)。第2のプロトコールでは、これらの成分を、最初に添加したGFRα3を含むELISAプレートに対して連続して添加し、その後、ニューブラスチンを、そしてその後にRETを添加した(図9)。
実施例8:近紫外光および遠紫外光CD分析
ニューブラスチンの二次構造および三次構造に対する二重変異の効果をさらに研究するために、Arg48,49E二重変異体について、近紫外光および遠紫外光CD分析の両方を行った。微妙な差が二次構造と三次構造において検出されたが、二重変異体の立体構造は野生型ニューブラスチンの立体構造と極めてよく似ていた。
実施例9:ニューブラスチンArg48,49E二重変異体の薬物動態分析
ヒトニューブラスチンは、ラットに静脈内(IV)または皮下(SC)で投与した場合には乏しい薬物動態(PK)を示し、全体的な生体利用性は1%未満である。ヘパリンに基づくクリアランスは、この低い生体利用性の理由の1つであり得る。ヘパリンに基づくクリアランスがラットからのヒトニューブラスチンの迅速なクリアランスに関係しているかどうかを決定するために、Arg48,49E二重変異体(野生型である対照とともに)についてPK分析をおこなった。
実施例10:チャイニーズハムスター卵巣細胞の中でのニューブラスチンヘパリン結合変異体の発現
野生型ニューブラスチンをコードするプラスミド構築物と変異体ニューブラスチンをコードするプラスミド構築物をCHO細胞の中で発現させ、分泌された可溶性タンパク質の量をELISAによって測定した。これらの実験で使用したプラスミド構築物は、(i)野生型のヒトニューブラスチンのカルボキシ末端の104個のアミノ酸に対して、または(ii)Arg48,49E二重変異体(104個のアミノ酸の形態)に対して融合させた、ヒト成長ホルモンシグナルペプチド(SigPep)(プラスミドの中に含まれるイントロンを含むもの、または含まないもの)を含む融合タンパク質をコードする。
本発明は、その詳細な説明と組み合わせて記載されているが、上記の記載は本発明を例示するように意図され、その範囲を限定するように意図されない。本発明は、添付の特許請求の範囲によって定義される。他の態様、利点、および変更は、以下の特許請求の範囲に含まれる。
Claims (27)
- 配列番号1の15位〜113位のアミノ酸に対して少なくとも90%同一であるアミノ酸配列を含むポリペプチドであって、前記アミノ酸配列には:
配列番号1の48位と49位に相当する位置で置換されてアルギニン以外のアミノ酸が含まれており、前記ポリペプチドは、二量体化すると、グリア細胞株に由来する神経栄養因子ファミリー受容体α−3(GFRα3)とトランスフェクション時に再編成した(RET)受容体チロシンキナーゼを含む複合体に結合し、前記ポリペプチドは、配列番号1の野生型ニューブラスチンタンパク質と比較して低減したヘパリン結合を示す、ポリペプチド。 - 配列番号1の48位に相当する位置のアルギニン残基と配列番号1の49位に相当する位置に存在するアルギニン残基が、非保存的アミノ酸残基で置換されている、請求項1に記載のポリペプチド。
- 配列番号1の48位に相当する位置のアルギニン残基と配列番号1の49位に相当する位置に存在するアルギニン残基が、それぞれ、グルタミン酸で置換されている、請求項1に記載のポリペプチド。
- 前記アミノ酸配列が、配列番号1の15位〜113位のアミノ酸に対して少なくとも95%同一である、請求項1〜3のいずれか1項に記載のポリペプチド。
- 配列番号5の15位〜113位のアミノ酸を含む、ポリペプチド。
- 配列番号5の10位〜113位のアミノ酸を含む、ポリペプチド。
- 配列番号5のアミノ酸配列を含む、ポリペプチド。
- 配列番号5のアミノ酸配列からなる、ポリペプチド。
- 配列番号6のアミノ酸配列からなる、ポリペプチド。
- 配列番号7のアミノ酸配列からなる、ポリペプチド。
- 請求項1から10のいずれか1項に記載の2つのポリペプチドを含む、二量体。
- 自然界には存在しないポリマーに結合した請求項1から10のいずれか1項に記載のポリペプチドを含む、結合体。
- 前記自然界には存在しないポリマーがポリアルキレングリコールである、請求項12に記載の結合体。
- 前記ポリアルキレングリコールがポリエチレングリコールである、請求項13に記載の結合体。
- 前記自然界には存在しないポリマーが、前記アミノ末端において前記ポリペプチドに結合される、請求項12から14のいずれか1項に記載の結合体。
- 前記自然界には存在しないポリマーが、内部ポリマー結合部位において前記ポリペプチドに結合される、請求項12から14のいずれか1項に記載の結合体。
- 請求項1から10のいずれか1項に記載のポリペプチドと異種アミノ酸配列を含む、融合タンパク質。
- 請求項1から10のいずれかに記載のポリペプチド、請求項11に記載の二量体、請求項12から16のいずれか1項に記載の結合体、または請求項17に記載の融合タンパク質と、薬学的に許容される担体または賦形剤を含む、薬学的組成物。
- 請求項1から10のいずれか1項に記載のポリペプチドをコードする配列を含む、核酸。
- 請求項19に記載の核酸を含む、発現ベクター。
- 請求項20に記載の発現ベクターを含む、細胞。
- ポリペプチドを作製する方法であって:
請求項21に記載の細胞を提供する工程、および
核酸の発現が可能な条件下で前記細胞を培養する工程
を含む、方法。 - 哺乳動物の神経系の障害を処置するための、請求項18に記載の薬学的組成物。
- 哺乳動物の神経障害の痛みを処置するための、請求項18に記載の薬学的組成物。
- 哺乳動物の末梢神経障害を処置するための、請求項18に記載の薬学的組成物。
- 哺乳動物においてRET受容体を活性化させるための、請求項18に記載の薬学的組成物。
- 前記哺乳動物がヒトである、請求項23から26のいずれか1項に記載の薬学的組成物。
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US60/694,067 | 2005-06-24 | ||
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