JP2010526093A - 血管新生を増大させるための組成物および方法 - Google Patents
血管新生を増大させるための組成物および方法 Download PDFInfo
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Abstract
Description
本発明は、タンパク質化学、分子生物学、および血管生物学に関する。
ニューブラスチン(アルテミンおよびエノビンとしても公知)は、24kDaのホモダイマーの分泌タンパク質であり、末梢神経系および中枢神経系のニューロンの成長および生存を促進する(Baudetら,2000,Development,127:4335;Masureら,1999,Eur.J.Biochem.,266:892;Rosenbladら,2000,Mol.Cell Neurosci.,15(2):199)。ニューブラスチンmRNAは、胚性の腎および肺において主に発現され、そして成体においては、下垂体、気管、および胎盤において最も高く発現される(Baudetら,2000,Development,127:4335)。
本発明は、少なくとも一部、哺乳動物へのニューブラスチンの投与が、新血管新生および動脈閉塞後の虚血筋組織への血流の増大を促進するという発見に基づく。
本発明は、損なわれた血流もしくは不適切な血流を示す組織において血管新生を増大させるための組成物および方法を提供する。添付の実施例に開示されるように、ニューブラスチンの投与は、哺乳動物における新血管新生を促進し、そして虚血筋組織への血流を増大させることが分かった。
成熟野生型ヒトニューブラスチンは、113アミノ酸長であり、以下のアミノ酸配列を有する:AGGPGSRARAAGARGCRLRSQLVPVRALGLGHRSDELVRFRFCSGSCRRARSPHDLSLASLLGAGALRPPPGSRPVSQPCCRPTRYEAVSFMDVNSTWRTVDRLSATACGCLG(配列番号1)。配列番号1のアミノ酸配列を有するポリペプチドもしくはその生物学的に活性な改変体が、本明細書に記載される方法において使用され得る。改変ニューブラスチンポリペプチドは、以下の節において詳述されるように、1または数個の付加、置換、および/または欠失を含み得る。野生型ニューブラスチンポリペプチドおよびその生物学的に活性な改変体は、本明細書においてまとめて「ニューブラスチンポリペプチド」といわれる。
ニューブラスチンポリペプチドは、治療上有効量の上記ポリペプチド、ならびに1種以上のアジュバント、賦形剤、キャリア、および/もしくは希釈剤を含む薬学的組成物へと組み込まれ得る。受容可能な希釈剤、キャリアおよび賦形剤は、代表的には、レシピエントのホメオスタシス(例えば、電解質バランス)に悪影響を及ぼさない。受容可能なキャリアとしては、生体適合性の、不活性の、もしくは生体吸収性の塩、緩衝化剤、オリゴ糖もしくはポリサッカリド、ポリマー、粘性改良剤、保存剤などが挙げられる。1つの例示的キャリアは、生理食塩水(0.15M NaCl,pH7.0〜7.4)である。別の例示的キャリアは、50mM リン酸ナトリウム、100mM 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に関するさらなる詳細は、例えば、REMINGTON’S PHARMACEUTICAL SCIENCES(Maack Publishing Co.,Easton,Pa.)に見いだされ得る。
本明細書に記載されるニューブラスチンポリペプチドは、組織において損なわれた血流もしくは不適切な血流を示す哺乳動物において血管新生を増大させるために使用され得る。例えば、ニューブラスチンポリペプチドは、虚血障害(例えば、筋虚血、虚血心臓(例えば、心筋梗塞から生じる)、褥瘡、静脈瘤から生じる虚血、糖尿病の虚血合併症(例えば、脚の病変のような皮膚病変)、虚血腎、虚血脳(例えば、脳卒中から生じる)、または虚血肝を有するか、これらを有すると疑われるか、またはこれらを発症する危険性を有する哺乳動物(例えば、ヒト)を処置するために使用され得る。さらに、ニューブラスチンポリペプチドは、移植気管を受け入れており、かつ上記器官の血管新生を必要とする哺乳動物において血管新生を増大するために使用され得る。ニューブラスチンポリペプチドの投与によって処置もしくは予防され得る特定の医学的状態の例は、以下の節において総説されている。
脳卒中(例えば、虚血性脳卒中、血栓性脳卒中、塞栓性脳卒中、全身性灌流脳卒中(systemic hypoperfusion stroke)、出血性脳卒中、脳内出血性脳卒中、もしくはクモ膜下出血性脳卒中)は、脳の1つ以上の領域への損なわれた血流もしくは不適切な血流によって特徴づけられる障害である。上記灌流における障害は、静脈であり得るが、もっとも頻繁には、動脈である。脳への血流の喪失もしくは低下は、虚血性領域に対する損傷を生じ、このことによって、局所的の機能もしくは全体の脳機能が重度に損なわれ得る。本明細書に記載されるニューブラスチンポリペプチドは、脳の1つ以上の領域への血流を増大させて、それによって、脳卒中によって引き起こされる損傷を予防もしくは低下させるように、(例えば、静脈内送達、皮下送達、経鼻的送達、または頭蓋内局所送達によって)被験体に投与され得る。上記被験体が脳卒中を有する危険性がある(例えば、脳の動脈の部分的閉塞を有すると診断された被験体)場合、ニューブラスチンは、脳卒中の発生を予防する、もしくは重篤度を軽減するために、上記被験体に投与され得る。
虚血性心疾患は、心筋への損なわれた血流もしくは不十分な血流によって特徴づけられ、1つ以上の冠状動脈における例えば、アテローム硬化症(冠状動脈疾患)、心不整脈、急性心筋梗塞、心筋活動の喪失、もしくは心臓弁欠陥(defective heart valve)によって引き起こされ得る。心臓への血流の喪失もしくは低下は、虚血性心筋組織に対する損傷を生じ、このことによって、心臓に対する永続する損傷および/もしくは影響を受けた被験体の死亡が引き起こされ得る。本明細書に記載されるニューブラスチンポリペプチドは、心臓の1種以上の虚血領域へ血流を増大させて、それによって、上記虚血によって引き起こされる損傷を予防もしくは低下させるように、被験体へ(例えば、心筋注射もしくは心外膜注射によって静脈内に、皮下に、もしくは局所に)投与され得る。上記被験体が虚血性心疾患を発症させる危険性がある場合、ニューブラスチンは、心臓虚血の発生を予防するか、もしくはその重篤度を低下させるために投与され得る。
潰瘍は、その影響を受けた領域(例えば、脚)への損なわれた血流もしくは不適切な血流から生じる皮膚病変である。このような潰瘍は、糖尿病の血管の合併症(例えば、脚の糖尿病性潰瘍)、静脈の不十分(下腿潰瘍)、もしくは過剰圧(例えば、褥瘡もしくは床ずれ)の結果であり得る。皮膚の領域への血流の喪失もしくは低下は、皮膚および周りの組織の慮域の損傷および/もしくは死滅を生じる。本明細書に記載されるニューブラスチンポリペプチドは、上記潰瘍もしくはその周りの組織の部位における血流を増大させ、それによって、上記潰瘍の重篤度もしくは存続を低下させるように、被験体に投与され得る(例えば、被験体の潰瘍に局所投与される)。上記被験体が、潰瘍を発症する危険性がある(例えば、長期間の伏臥位もしくは仰臥位にある麻痺した被験体または糖尿病に起因して心血管合併症を有する被験体)場合、ニューブラスチンは、潰瘍の発生を予防するか、もしくは潰瘍の重篤度を低下させるために、上記被験体に(例えば、糖尿病患者の脚および足に局所投与することによって)投与され得る。
静脈瘤(静脈不全症)は、静脈(一般には脚の静脈)がヘモグロビン減少血液を心臓へ戻すことができないことによって特徴づけられる障害である。静脈不全症は、血栓(血塊)または静脈弁への損傷もしくは静脈弁の弾性の喪失から生じ得る。本明細書に記載されるニューブラスチンポリペプチドは、脚の血流の、心臓への戻りを増大させ、それによって、静脈瘤の重篤度、もしくは静脈瘤に起因する合併症を低下させるように、被験体に(例えば、被験体の脚に局所的に、皮下に、もしくは影響を受けている静脈へ静脈内に)投与され得る。上記被験体が静脈瘤を発症させる危険性がある(例えば、静脈瘤の1つ以上の危険因子を有する被験体)場合、ニューブラスチンは、静脈瘤の発生を予防するか、もしくは静脈瘤の重篤度を低下させるために、被験体に投与され得る。
器官移植は、完全もしくは一部の器官が、ある被験体から別の被験体へ移されるプロセスである。移植される器官としては、例えば、心臓、肺、肝臓、腎臓、小腸、膵臓、手、指(手指もしくは足指)、または皮膚(例えば、顔面移植のような皮膚移植片;以下を参照のこと)が挙げられる。器官移植が首尾良くいくためには、移植器官と宿主との間で血管新生が発生しなければならない。従って、本明細書に記載されるニューブラスチンポリペプチドは、移植器官と宿主との間で血管新生、および移植器官への増大した血流を促進し、それによって、移植の失敗を予防するように、被験体に投与され得る。
本明細書に記載されるニューブラスチンポリペプチドは、単一療法として、または損なわれた血流もしくは不適切な血流によって特徴づけられる障害を有する被験体に治療的利益を提供する1種以上のさらなる薬剤とともに、複数治療レジメンの一部として、被験体に投与され得る。例えば、ニューブラスチンポリペプチドは、さらなる血管新生因子(例えば、アンギオゲニン、アンギオポエチン−1、Del−1、線維芽細胞増殖因子(例えば、aFGF、bFGF、もしくはFGF2)、フォリスタチン、顆粒球コロニー刺激因子(G−CSF)、肝細胞増殖因子(HGF)、インターロイキン−8(IL−8)、レプチンミッドカイン、胎盤増殖因子、血小板由来内皮細胞増殖因子(PD−ECGF)、血小板由来増殖因子−BB(PDGF−BB)、プレイオトロフィン(PTN)、プログラニュリン、プロリフェリン、トランスホーミング増殖因子−α(TGF−α)、トランスホーミング増殖因子−β(TGF−β)、腫瘍壊死因子−α(TNF−α)、および/もしくは血管内皮増殖因子(VEGF))とともに同時投与され得る。さらに、ニューブラスチンポリペプチドは、血管新生を増大させないが、別の面で損なわれた血流もしくは不適切な血流によって特徴づけられる障害を有する被験体に対して有益な1種以上の治療剤と組み合わせて投与され得る。例えば、ニューブラスチンポリペプチドは、抗血栓剤(例えば、アスピリン、ストレプトキナーゼ、ウロキナーゼ、組織プラスミノゲンアクチベーター、ヘパリン、もしくはヒルジン)、疼痛薬物、抗生物質、コレステロール低下剤(例えば、スタチン)、β遮断剤、および/もしくは抗高血圧薬(例えば、利尿剤、アンジオテンシン変換酵素インヒビター、血管拡張薬、もしくはα遮断剤)のうちのいずれか1つとともに同時投与され得る。ニューブラスチンポリペプチドが、レシピエントへ移植された器官(例えば、移植された心臓、肝臓、腎臓、肺、四肢(例えば、指)、もしくは指)の血管新生を増大させるために使用される場合、上記ニューブラスチンポリペプチドは、必要に応じて、1種以上の免疫抑制剤とともに同時投与され得る。
ニューブラスチン処置の効力は、本明細書に記載される方法のいずれかによって(例えば、新たな血管増殖のレベルを直接モニターするか、または損なわれた血流もしくは不適切な血流によって特徴づけられる障害の特定の特徴の特定の特徴もしくは症状を評価することによって)、評価され得る。例えば、被験体の脳の血管系の量もしくは密度は、MRI(例えば、Dunnら(2004)Magn Reson.Med.51(1):55−61を参照のこと)もしくは超音波技術(例えば、Fosbergら(2004)Ultrasonics 42(1):325−330によって記載されるものの適合)を使用して、(例えば、処置の前後に)測定され得る。新血管新生を促進することにおけるニューブラスチン処置の効果はまた、例えば、Frecceroら(2003)Microvasc Res.66(3):183−9;およびRendellら(1989)Diabetes 38(7):819−824に記載されるように、レーザードップラー技術を使用して、血流における増加をモニターすることによって評価され得る。レーザードップラー技術によって皮膚血流を測定するために有用な例示的デバイスは、DRT4(Moor Instruments,Devon,UK)である。さらに、移植器官(例えば、移植された腎臓、心臓、もしくは皮膚)の血管新生を促進するためのニューブラスチンの効力は、移植した器官機能の増大もしくは処置後の器官の健康状態における増大によって(例えば、生検によって)測定され得る。
以下の実施例は、虚血障害のニューブラスチン処置の効果を研究するために有用なインビボ動物モデル系を説明する。そのような処置の効力は、虚血処置の直接的分析によって、例えば免疫組織化学技術を使用する虚血筋肉における毛細管密度を測定することによって、および/または虚血筋肉における血流を測定することによって、評価され得る。損なわれた血流もしくは不適切な血流によって特徴づけられる障害の予防または発症遅延を評価するために、ニューブラスチンポリペプチドはまた、その障害を誘発する前の動物に投与され得る。血管新生を増加させるためのニューブラスチン処置の効力を評価するのに有用なさらなる動物モデル(例えば、マウスモデル)としては、例えば、Couffinhalら(1988)Am J.Pathol.152(6):1667−1679;Caoら(1998)Proc.Natl.Acad.Sci.USA 95(24):14389−14394;およびSalvenら(2002)FASEB J.16:1471−1473に記載されるものが挙げられる。糖尿病における創傷治癒不全のための動物モデルは、例えば、Tsuboiら(1992)J.Dermatol.19(11):673−75に記載される。
後肢虚血のマウスモデルを使用して、ニューブラスチン投与が哺乳動物における血管新生を増大させるか否かを決定した。マウス後肢の右大腿動脈を、外科的に結紮した。ニューブラスチンを、1ミリグラム/キログラム(mg/kg)もしくは0.1mg/kgの投与量で1週間に3回皮下投与した。あるいは、1セットのマウスに、ビヒクルのみ(ニューブラスチンなし)をコントロールとして投与した。10匹のマウスを、各群において評価した。21日(3週間)後に、上記マウスを屠殺し、その腓腹筋を取り出した。
ニューブラスチン処置が虚血組織(例えば、皮膚)において血流を増大させるか否かを決定するために、マウス大腿動脈を、上記のように結紮した。ラットニューブラスチン(タンパク質の成熟113アミノ酸形態)を、1mg/kgもしくは0.1mg/kgで1週間に3回、3週間にわたって皮下投与した。コントロールとして、1セットのマウスを、ビヒクルのみで処置した。
本発明は、その詳細な説明とともに記載されてきたが、以下の説明は、添付の特許請求の範囲によって定義される。本発明の範囲を例示し、限定しない。他の局面、利点、および改変は、以下の特許請求の範囲内である。
Claims (31)
- 組織における血管新生を増大させるための方法であって、該方法は、
組織において損なわれた血流もしくは不適切な血流を示す哺乳動物を選択する工程;および
該哺乳動物に、該組織における血管新生を増大するに有効な量のポリペプチドを投与する工程であって、ここで該ポリペプチドは、配列番号1のアミノ酸15〜113に対して少なくとも80%であるアミノ酸配列を含み、該ポリペプチドは、二量体化された場合、GFRα3およびRETを含む複合体に結合する、工程
を包含する、方法。 - 前記組織は虚血組織である、請求項1に記載の方法。
- 前記虚血組織は、虚血筋組織である、請求項2に記載の方法。
- 前記哺乳動物の心臓は、損なわれた血流を示し、前記ポリペプチドの投与は、該心臓の血管新生を増大させる、請求項1に記載の方法。
- 前記哺乳動物は、脳卒中を経験したことがあり、該脳卒中の結果として、前記組織において損なわれた血流もしくは不適切な血流を示す、請求項1に記載の方法。
- 前記哺乳動物は、心筋梗塞を経験したことがあり、該心筋梗塞の結果として、前記組織において損なわれた血流もしくは不適切な血流を示す、請求項1に記載の方法。
- 前記哺乳動物は、冠状動脈疾患を有しており、該冠状動脈疾患の結果として、前記組織において損なわれた血流もしくは不適切な血流を示す、請求項1に記載の方法。
- 前記哺乳動物は、移植臓器を受け入れており、前記ポリペプチドの投与は、該移植臓器における血管新生を増大させる、請求項1に記載の方法。
- 前記移植臓器は心臓である、請求項8に記載の方法。
- 前記移植臓器は真皮である、請求項8に記載の方法。
- 前記哺乳動物は、虚血疾患を有する、請求項1に記載の方法。
- 前記哺乳動物は心血管疾患を有する、請求項1に記載の方法。
- 前記組織は、前記哺乳動物の四肢に位置する、請求項1に記載の方法。
- 前記哺乳動物は糖尿病を有する、請求項12または13に記載の方法。
- 前記組織は、皮膚病変を含む、請求項1に記載の方法。
- 前記皮膚病変は、糖尿病性潰瘍と関連している、請求項15に記載の方法。
- 前記糖尿病性潰瘍は、糖尿病性下肢潰瘍である、請求項16に記載の方法。
- 前記哺乳動物に、抗血栓剤、血管新生を増大させるニューブラスチン以外の因子、コレステロール低下剤、β遮断剤、抗高血圧剤、もしくは免疫抑制剤のうちの1種以上を投与する工程をさらに包含する、請求項1〜17のいずれか1項に記載の方法。
- 血管新生の増大が、前記ポリペプチドの投与後に生じたか否かを決定する工程をさらに包含する、請求項1〜18のいずれか1項に記載の方法。
- 前記ポリペプチドは、全身投与を介して前記哺乳動物に投与される、請求項1〜19のいずれか1項に記載の方法。
- 前記ポリペプチドは、皮下投与を介して前記哺乳動物に投与される、請求項1〜19のいずれか1項に記載の方法。
- 前記ポリペプチドは、局所投与を介して前記哺乳動物に投与される、請求項1〜19のいずれか1項に記載の方法。
- 前記アミノ酸配列は、配列番号1のアミノ酸15〜113に対して少なくとも90%同一である、請求項1〜22のいずれか1項に記載の方法。
- 前記アミノ酸配列は、配列番号1のアミノ酸15〜113に対して少なくとも95%同一である、請求項1〜22のいずれか1項に記載の方法。
- 前記アミノ酸配列は、配列番号1のアミノ酸15〜113に対して少なくとも98%同一である、請求項1〜22のいずれか1項に記載の方法。
- 前記ポリペプチドは、配列番号1のアミノ酸15〜113、配列番号2のアミノ酸15〜113、配列番号3のアミノ酸15〜113、配列番号4のアミノ酸15〜113、配列番号5のアミノ酸15〜113、配列番号8のアミノ酸15〜113、もしくは配列番号9のアミノ酸15〜113を含む、請求項1〜22のいずれか1項に記載の方法。
- 前記ポリペプチドは、配列番号1のアミノ酸配列、配列番号2のアミノ酸配列、配列番号3のアミノ酸配列、配列番号4のアミノ酸配列、配列番号5のアミノ酸配列、配列番号8のアミノ酸配列、もしくは配列番号9のアミノ酸配列を含む、請求項1〜22のいずれか1項に記載の方法。
- 前記ポリペプチドは、配列番号1のアミノ酸10〜113を含む、請求項1〜22のいずれか1項に記載の方法。
- 前記哺乳動物は、神経学的障害と診断されていない、請求項1〜28のいずれか1項に記載の方法。
- 前記哺乳動物は、眼の障害と診断されていない、請求項1〜29のいずれか1項に記載の方法。
- 前記哺乳動物はヒトである、請求項1〜30のいずれか1項に記載の方法。
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JP2013216689A (ja) | 2013-10-24 |
ES2476253T3 (es) | 2014-07-14 |
AU2008247637A1 (en) | 2008-11-13 |
EP2142205A1 (en) | 2010-01-13 |
TWI445544B (zh) | 2014-07-21 |
EP2142205A4 (en) | 2011-09-07 |
US9138461B2 (en) | 2015-09-22 |
US8329655B2 (en) | 2012-12-11 |
TW200914040A (en) | 2009-04-01 |
JP5583005B2 (ja) | 2014-09-03 |
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US20100261654A1 (en) | 2010-10-14 |
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