JP2011032286A - ペプチドを含むインテグリン結合モチーフと骨疾患の治療法 - Google Patents
ペプチドを含むインテグリン結合モチーフと骨疾患の治療法 Download PDFInfo
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Abstract
【解決手段】10〜50 アミノ酸を含むペプチド配列を開示する。この配列は、RGD配列などのインテグリン結合モチーフ、グリコサミノグリカン結合モチーフ、およびカルシウム結合モチーフの少なくとも一つを含み、基質細胞外リン糖タンパク質のRGD配列に隣接する残りのアミノ酸を含むことを特徴とする。これらの配列は、注射用に製剤化することができるほか、練り歯磨きもしくは口内洗浄剤、または歯肉パッチ中に分散させることが可能であり、これを投与することで骨/歯の成長を促したり、および/または体内から尿中へのリン酸塩の過剰な喪失を抑えたりすることができる。
【選択図】図6
Description
本発明は、一般に、骨格系疾患の治療に有用なペプチドの分野、またより具体的にはペプチドおよびその製剤に関する。
骨格組織および無機質代謝の障害が、数多くの健康上の大きな問題を世界的に生じていることは諸文献に詳しく記載されている。
本発明のペプチド、類似体、製剤、および方法を記載するにあたり、本発明が、記載された特定の態様を限定しないことは明らかである。これらが変化するのは言うまでもない。また、本明細書で使用される用語が、特定の態様のみの説明を目的とし、添付の特許請求の範囲でのみ制限される本発明の範囲を限定する意図がないことは明らかである。
「ペプチド」および「ペプチド化合物」という用語は、コードされたアミノ酸、またはコードされていないアミノ酸、化学的もしくは生化学的に修飾されたアミノ酸、または誘導体化されたアミノ酸、L型もしくはD型のアミノ酸、修飾型ペプチドバックボーンを含むペプチド、およびアミノ酸類似体を含むペプチドを含む場合がある、約10〜約50アミノ酸のアミノ酸重合体を意味する用語として本明細書で互換的に用いられる。ペプチド化合物は以下の重合体の場合がある:(a)天然のアミノ酸残基;(b)非天然のアミノ酸残基、例えばN-置換グリシン、アミノ酸置換基など;または(c)天然および非天然のアミノ酸残基/置換基の両方。言い換えると、対象となるペプチド化合物はペプチドまたはペプトイドの場合がある。ペプトイド化合物およびその調製法は、参照として本明細書に組み入れられる国際公開公報第91/19735号に記載されている。
(a)対象疾患に罹患しやすい傾向があるが対象疾患であると未だ診断されていない被験体における疾患の発生を予防する段階;
(b)疾患を抑制する段階、すなわち疾患の進行を止める段階;または
(c)疾患を緩和する段階、すなわち疾患の改善を誘導する段階。
本発明のペプチド化合物は10〜50アミノ酸を含むペプチドである。アミノ酸は好ましくは、20種の天然のL型アミノ酸の一種である。しかし、アミノ酸類似体のようにD型アミノ酸が存在する場合がある。本発明のペプチドは、一つまたは複数の以下のアミノ酸配列モチーフを含む:RGD配列などのインテグリン結合モチーフ;グリコサミノグリカン結合モチーフ;およびカルシウム結合モチーフ。個々のアミノ酸は、L型またはD型のいずれかの状態で、しかし好ましくはL型の状態でペプチド中に存在する場合がある。本発明のペプチドは、そのC末端がアミド化される場合もされない場合もあるほか、N末端がカルボキシル化される場合もあればされない場合もある。本発明のペプチドは、SGDG配列(配列番号:41)などのグリコサミノグリカン結合モチーフをLイソ型またはDイソ型の状態で含む場合もあれば含まない場合もある。本発明の化合物は生物学的活性を特徴とする、すなわち骨格成長を促進すること、ならびに骨格成長の表面における骨芽細胞または象牙芽細胞の成長または動員を促進することをさらに特徴とする。
を有する。また「カルシウム結合モチーフ」という表現は、配列番号:42と1残基、2残基、3残基、4残基、5残基、6残基、7残基、または8残基のアミノ酸が異なるアミノ酸配列である。多くの態様で特に対象となるのは、配列番号:42のアミノ酸1位、3位、5位、7位、9位、および12位が保存されたモチーフである。したがっていくつかの態様では、本発明のペプチドはカルシウム結合モチーフとして配列
(Xは任意のアミノ酸またはアミノ酸類似体)を含む。
X1は任意のアミノ酸;
X2はD、N、もしくはS;
X3はI、L、V、F、Y、もしくはW;
X4はD、E、N、S、T、もしくはG;
X5はD、N、Q、G、H、R、もしくはK;
X6はG、もしくはP;
X7はL、I、V、M、C;
X8はD、E、N、Q、S、T、A、G、またはC;
X9およびX10はそれぞれ独立に任意のアミノ酸;
X11はD、もしくはE;また
X12はL、I、V、M、F、Y、もしくはWである。
X2、X5、X6、X7、X9、X10、X11、X12、およびX14はそれぞれ独立に任意のアミノ酸であり;
nは3〜14であり;
mは3〜7であり;
X8はD、もしくはNであり;また
X13はF、もしくはYである。
X3、X4、X6、X7、X8、X10、X11、X12、X15、X18、およびX19は独立に任意のアミノ酸であり;
X5はL、またはKであり;
X9はD、またはNであり;
X13はD、N、S、またはGであり;
X14はF、またはYであり;
X16はE、またはSであり;
X17はF、Y、V、またはCであり;
X20はL、I、V、M、F、またはSであり;
またX21はL、I、V、M、またはFである。
X2およびX9はそれぞれ独立にL、またはIである。
を有するペプチドは相互に重複する3種すべてのモチーフを含む。
本発明は、本発明のペプチド化合物を投与する段階を含む、骨格の骨喪失を抑える方法、腎でのリン酸塩漏出を抑える方法、骨量を増加させる方法、骨強度を高める方法、およびPi排泄を抑える方法を提供する。典型的には、本発明のペプチド化合物は、処置を必要とする個体へ輸送するための薬学的に許容される賦形剤とともに製剤化される。
本発明のペプチドは、インビボ法、エキソビボ法、ならびに全身投与経路、および局所投与経路を含む、任意の利用可能な方法、および薬剤輸送に適した経路で個体に投与される。
用量は、達成すべき臨床上の目標に応じて変動するが、適切な用量範囲は、最大約1 μg、最大約1,000 μg、最大約10,000 μg、最大約25,000 μg、または約50,000 μgの本発明のペプチドを提供する範囲である。本発明のペプチドは、単回投与が可能であるほか、経時的に少量を複数回投与することもできる。あるいはペプチドの標的用量は、対象ペプチド投与直後の24〜48時間以内に採取した宿主血液試料中に約0.1〜1000 μM、約1〜500 μM、または約5〜250 μMとすることができる。
一般にペプチドは、宿主輸送用の薬学的に許容される組成物中に調製される。本発明のペプチドとの使用に好ましい薬学的に許容される担体には、無菌性の水溶液または非水溶液、懸濁液、および乳濁液などがある。非水性溶媒の例には、プロピレングリコール、ポリエチレングリコール、オリーブオイルなどの植物油、およびオレイン酸エチルなどの注射用有機エステルがある。水性担体には、水、アルコール/水溶液、乳濁液、または懸濁液(生理食塩水および緩衝用溶媒を含む)がある。非経口的な溶媒には、塩化ナトリウム溶液、リンゲルデキストロース液、デキストロースおよび塩化ナトリウム、乳酸加リンゲル液、または不揮発性油などがある。静脈注射用の溶媒には、溶液、および栄養補充液、電解質補充液(例えばリンゲルデキストロース液を元にした溶液)などがある。本発明のペプチドを含む組成物は、当技術分野で周知の手段で凍結乾燥した後に、再構成して本発明に使用することもできる。また、リポソームを用いた輸送用の製剤、およびマイクロカプセル化されたペプチドを含む製剤も対象となる。
胎児マウスの頭蓋冠アッセイ法
試薬
FGF-1はペプロテック(Peprotech Inc.)(Rocky Hill、NJ)から購入した。RGD-1、2、3、4、5、および6(本明細書ではD-00001、D-00002、D-00003、D-00004、D-00005、およびD-00006と呼ぶ)は、ノミズ(Nomizu)博士(北海道大学、日本)から供与された。
妊娠状態のICRマウスを日本エスエルシー株式会社(SLC Japan Co. Ltd.)(静岡、日本)から購入した。
マウス頭蓋冠の器官培養は、マンディ(Mundy G)ら、Science 286:1946〜1949、1999、およびトライアネデス(Traianedes K)ら、Endocrinology 139:3178〜3184、1998に記載された手順で実施した。4日齢のマウスの頭蓋冠を切除し、矢状縫合に沿って半分に切断した。頭蓋冠のそれぞれ半分を、12ウェル組織培養皿中のステンレス製グリッド(Asahi Glass Techno Corp.、船橋市、日本)上に置いた。各ウェルには、0.1% ウシ血清アルブミン(Sigma)および各化合物を添加した1.5 mlのBGj培地(Sigma、St. Louis、MO)を含むようにした。マンディらの記載にしたがってFGF-1を正の対照として使用した。培地は1日目と4日目に交換し、アッセイは7日目に終了した。
頭蓋冠を10% 中性緩衝ホルマリンで固定し、4.13% EDTAで脱灰し、パラフィンに包埋した。4 mm厚の切片を作製し、ヘマトキシリンおよびエオシンで染色した。新しい骨領域をイメージ・プロ プラス(Image-Pro Plus)(Media Cybernetics、Silver Spring、MD)で測定した。
インビボにおける骨形成試験
試薬
FGF-1はペプロテック(Peprotech Inc.)(Rocky Hill、NJ)から購入した。RGD-6(本明細書ではD-00006と呼ぶ)はCSバイオ(CS Bio)(San Carlos、CA)により、発明者の指示にしたがって合成した。
4週齢のマウスを日本エスエルシー株式会社(SLC Japan Co. Ltd.)(静岡、日本)から購入し、3群に無作為に割り付けた(n=5)。
D-00006(20 μg/kg/日)、FGF-1(12.5 μg/kg/日)、または溶媒(生理食塩水)を、試験動物の皮下から、頭蓋冠に隣接する軟組織内に注射した。試料の1日量をそれぞれ2つに分け、1日2回、5日間にわたって注射を行った。最終投与から15日後に頭蓋冠を切除し、矢状縫合に沿って半分に切断し、組織形態学的分析に使用した。
頭蓋冠を10% 中性緩衝ホルマリンで固定し、4.13% EDTAで脱灰し、パラフィンに包埋した。4 mm厚の断片を作製し、ヘマトキシリンおよびエオシンで染色した。新しい骨領域をイメージ・プロ プラス(Image-Pro Plus)(Media Cybernetics、Silver Spring、MD)で測定した。
FGF-1を投与した動物に由来する頭蓋冠切片では、溶媒投与群と比較して骨領域が有意な拡大が認められた。D-00006を投与した動物に由来する切片でも、溶媒投与群と比較して骨領域の有意な拡大が認められ、効率はFGF-1と同等であった。これらの結果から得られたデータを図5に図示する。
D-00006が腎でのリン酸塩排泄に及ぼす影響
実験デザインおよび投与
40匹の3か月齢の処女雌SDラット(Harlan Sprague Dawley, Inc.)を1週間にわたって順化した後に実験を開始した。順化期間に続き、ラットを表1で概説された投与群に初期体重で無作為化した。Ovx:卵巣摘出;LD:低用量;HD:高用量;Est:エストラジオール;
総血清カルシウム濃度およびクレアチニン濃度は、血清カルシウムの若干の上昇を示したエストラジオール投与Ovx動物を除く全投与群で同じであった。D-00006投与群の血清中のリンには用量依存性の上昇が認められた。18時間かけて採取した総尿容量は全群で同じであった。得られた尿パラメータを図6に示す。
Claims (13)
- 配列に約10〜約50アミノ酸を含むペプチド化合物であって、ペプチド化合物が骨成長を促し、各アミノ酸がD型またはL型構造をとることが可能であり、配列がインテグリン結合モチーフ、グリコサミノグリカン結合モチーフ、およびカルシウム結合モチーフからなる群より選択されるモチーフを含むペプチド化合物。
- インテグリン結合モチーフがRGD配列である、請求項1記載のペプチド化合物。
- グリコサミノグリカンモチーフが配列SGDGを有する、請求項1記載のペプチド化合物。
- 請求項1記載のペプチドの多量体。
- 担体;および請求項1記載の治療的有効量のペプチドを含む製剤。
- 担体が生理食塩水であり、製剤が注射用である、請求項7記載の製剤。
- 担体がペーストであり、製剤が練り歯磨きである、請求項7記載の製剤。
- 担体が風味のついた水溶液であり、製剤が口内洗浄剤である、請求項7記載の製剤。
- 請求項7記載の製剤を含む、化合物の経口投与用のパッチ。
- 請求項1記載の有効量のペプチド化合物を個体に投与する段階を含む、骨喪失を抑える方法。
- 請求項1記載の有効量のペプチド化合物を個体に投与する段階を含む、個体における腎でのリン酸塩排泄を抑える方法。
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EP1086225B1 (en) * | 1998-05-18 | 2007-02-21 | University College London | Human tumour-derived polypeptide hormone phosphatonin |
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CA2418716A1 (en) | 2002-02-21 |
US7160862B2 (en) | 2007-01-09 |
US6911425B2 (en) | 2005-06-28 |
US20090062201A1 (en) | 2009-03-05 |
WO2002014360A1 (en) | 2002-02-21 |
EP1309616B1 (en) | 2009-04-29 |
AU8649101A (en) | 2002-02-25 |
ES2324153T3 (es) | 2009-07-31 |
US20020197267A1 (en) | 2002-12-26 |
EP1309616A4 (en) | 2004-12-08 |
US20050163728A1 (en) | 2005-07-28 |
EP1309616A1 (en) | 2003-05-14 |
CN100488980C (zh) | 2009-05-20 |
JP2004506654A (ja) | 2004-03-04 |
MXPA03001394A (es) | 2004-12-13 |
US20090042791A1 (en) | 2009-02-12 |
JP2007302673A (ja) | 2007-11-22 |
DE60138552D1 (de) | 2009-06-10 |
AU2001286491B2 (en) | 2006-04-27 |
ATE430165T1 (de) | 2009-05-15 |
JP4318246B2 (ja) | 2009-08-19 |
US20070014742A1 (en) | 2007-01-18 |
CN1458935A (zh) | 2003-11-26 |
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