JP2008543345A - トロンボスポンジン−1由来ペプチド及び治療方法 - Google Patents
トロンボスポンジン−1由来ペプチド及び治療方法 Download PDFInfo
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Abstract
Description
Libby, P., Atheroma: more than mush. Lancet, 1996. 348 Suppl 1: p. s4-7. Ross, R., Atherosclerosis~an inflammatory disease. N Engl J Med, 1999. 340(2): p. 115- 26. Bornstein, P., Thrombospondins as matricellular modulators of cell function. J Clin Invest, 2001. 107(8): p. 929-34. Sage, E.H., Regulation of interactions between cells and extracellular matrix: a command performance on several stages. J Clin Invest, 2001. 107(7): p. 781-3. Murphy-Ullrich, J.E., The de-adhesive activity of matricellular proteins: is intermediate cell adhesion an adaptive state? J Clin Invest, 2001. 107(7): p. 785- 90. Elzie, CA. and J.E. Murphy-Ullrich, The N-terminus of thrombospondin: the domain stands apart, lht J Biochem Cell Biol, 2004. 36(6): p. 1090-101. Li, D.Y., G. Faury, D.G. Taylor, E.G. Davis, W.A. Boyle, R.P. Mecham, P. Stenzel, B. Bo ak, and M.T. Keating, Novel arterial pathology in mice and humans hemizygous for elastin. J Clin Invest, 1998. 102(10): p. 1783-7. Aszodi, A., D. Chan, E. Hunziker, J.F. Bateman, and R. Fassler, Collagen π is essential for the removal of the notochord and the formation of intervertebral discs. J Cell Biol, 1998. 143(5): p. 1399-412. Forsberg, E., E. Hirsch, L. Frohlich, M. Meyer, P. Ekblom, A. Aszodi, S. Werner, and R. Fassler, Skin wounds and severed nerves heal normally in mice lacking tenascin-C. Proc Natl Acad Sci U S A, 1996. 93(13): p. 6594-9. Lawler, J., M. Sunday, V. Thibert, M. Duquette, E.L. George, H. Rayburn, and R.O. Hynes, Thrombospondin- 1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest, 1998. 101(5): p. 982-92. Kyriakides, T.R., J. W. Tarn, and P. Bornstein, Accelerated wound healing in mice with a disruption of the thrombospondin 2 gene. J Invest Dermatol, 1999. 113(5): p. 782-7. Adams, J.C. and J. Lawler, The thrombospondins. Lit J Biochem Cell Biol, 2004. 36(6): p. 961-8. Crawford, S.E., V. Stellmach, J.E. Murphy-Ullrich, S.M. Ribeiro, J. Lawler, R.O. Hynes, G.P. Boivin, and N. Bouck, Thrombospondin- 1 is a major activator of TGF-betal in vivo. Cell, 1998. 93(7): p. 1159-70. Agah, A., T.R. Kyriakides, J. Lawler, and P. Bornstein, The lack of thrombospondin- 1 (TSPl) dictates the course of wound healing in double- TSPl/TSP2-null mice. Am J Pathol, 2002. 161(3): p. 831-9. Yee, K.O., M. Streit, T. Hawighorst, M. Detmar, and J. Lawler, Expression of the type-1 repeats of thrombospondin- 1 inhibits tumor growth through activation of transforming growth factor-beta. Am J Pathol, 2004. 165(2): p. 541-52. Miao, W.M., W.L. Seng, M. Duquette, P. Lawler, C. Laus, and J. Lawle r, Thrombospondin- 1 type 1 repeat recombinant proteins inhibit tumor growth through transforming growth factor-beta-dependent and -independent mechanisms. Cancer Res, 2001. 61(21): p. 7830-9. Yano, K., H. Oura, and M. Detmar, Targeted overexpression of the angiogenesis inhibitor thrombospondin- 1 in the epidermis of transgenic mice prevents ultraviolet-B-induced angiogenesis and cutaneous photo-damage. J Invest Dermatol, 2002. 118(5): p. 800-5. Simantov, R., M. Febbraio, R. Crombie, A.S. Asch, R.L. Nachman, and R.L. Silverstein, Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin- 1. J Clin Invest, 2001. 107(1): p. 45-52. Bornstein, P., A. Agah, and T.R. Kyriakides, The role of thrombospondins 1 and 2 in the regulation of cell-matrix interactions, collagen fibril formation, and the response to injury. Int J Biochem Cell Biol, 2004. 36(6): p. 1115-25. Lawler, J. and M. Detmar, Tumor progression: the effects of thrombospondin- 1 and -2. Int J Biochem Cell Biol, 2004. 36(6): p. 1038-45. Topol, EJ., J. McCarthy, S. Gabriel, DJ. Moliterno, WJ. Rogers, L.K. Newby, M. Freedman, J. Metivier, R. Cannata, CJ. O'Donnell, K. Kottke-Marchant, G. Murugesan, E.F. Plow, O. Stenina, and G.Q. Daley, Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction. Circulation, 2001. 104(22): p. 2641-4. Stenina, O.I., T.V. Byzova, J.C. Adams, JJ. McCarthy, EJ. Topol, and E.F. Plow, Coronary artery disease and the thrombospondin single nucleotide polymorphisms. Int J Biochem Cell Biol, 2004. 36(6): p. 1013-30. Raines, E.W., The extracellular matrix can regulate vascular cell migration, proliferation, and survival: relationships to vascular disease. Int J Exp Pathol, 2000. 81(3): p. 173-82. Roth, JJ., V. Gahtan, J.L. Brown, C. Gerhard, V.K. Swami, V.L. Rothman, T.N. Tulenko, and G.P. Tuszynski, Thrombospondin- 1 is elevated with both intimal hyperplasia and hypercholesterolemia. J Surg Res, 1998. 74(1): p. 11-6. Lawler, J., The functions of thrombospondin- 1 and-2. Curr Opin Cell Biol, 2000. 12(5): p. 634-40. Chen, H., M.E. Herndon, and J. Lawler, The cell biology of thrombospondin- 1. Matrix Biol, 2000. 19(7): p. 597-614. Majack, R.A., S.C. Cook, and P. Bornstein, Control of smooth muscle cell growth by components of the extracellular matrix: autocrine role for thrombospondin. Proc Natl Acad Sci U S A, 1986. 83(23): p. 9050-4. Schultz-Cherry, S., S. Ribeiro, L. Gentry, and J.E. Murphy-Ullrich, Thrombospondin binds and activates the small and large forms of latent transforming growth factor-beta in a chemically defined system. J Biol Chem, 1994. 269(43): p. 26775-82. Fischer, J.W., M. Stoll, A. W. Hahn, and T. Unger, Differential regulation of thrombospondin- 1 and fibronectin by angiotensin JI receptor subtypes in cultured endothelial cells. Cardiovasc Res, 2001. 51(4): p. 784-91. Lymn, J.S., M.K. Patel, G.F. Clunn, SJ. Rao, KX. Gallagher, and A.D. Hughes, Thrombospondin-1 differentially induces chemotaxis and DNA synthesis of human venous smooth muscle cells at the receptor-binding level. J Cell Sci, 2002. 115(Pt 22): p. 4353-60. Patel, M.K., J.S. Lymn, G.F. Clunn, and A.D. Hughes, Thrombospondin-1 is a potent mitogen and chemoattractant for human vascular smooth muscle cells. Arterioscler Thromb Vase Biol, 1997. 17(10): p. 2107-14. Rodriguez-Manzaneque, J.C., T.F. Lane, M.A. Ortega, R.O. Hynes, J. Lawler, and M.L. Iruela-Arispe, Thrombospondin-1 suppresses spontaneous tumor growth and inhibits activation of matrix metalloproteinase-9 and mobilization of vascular endothelial growth factor. Proc Natl Acad Sci U S A, 2001. 98(22): p. 12485-90. Bein, K. and M. Simons, Thrombospondin type 1 repeats interact with matrix metalloproteinase 2. Regulation of metalloproteinase activity. J Biol Chem, 2000. 275(41): p. 32167-73. Lutgens, E., M. Gijbels, M. Smook, P. Heeringa, P. Gotwals, V.E. Koteliansky, and MJ. Daemen, Transforming growth factor-beta mediates balance between inflammation and fibrosis during plaque progression. Arterioscler Thromb Vase Biol, 2002. 22(6): p. 975-82. Mallat, Z., A. Gojova, C. Marchiol-Fournigault, B. Esposito, C. Kamate, R. Merval, D. Fradelizi, and A. Tedgui, Inhibition of transforming growth factorbeta signaling accelerates atherosclerosis and induces an unstable plaque phenotype in mice. Circ Res, 2001. 89(10): p. 930-4. Luttun, A., E. Lutgens, A. Manderveld, K. Maris, D. Collen, P. Carmeliet, and L. Moons, Loss of matrix metalloproteinase-9 or matrix metalloproteinase- 12 protects apolipoprotein E- deficient mice against atherosclerotic media destruction but differentially affects plaque growth. Circulation, 2004. 109(11): p. 1408-14. Stefanidakis, M., M. Bjorklund, E. Hianus, CG. Gahmberg, and E. Koivunen, Identification of a negatively charged peptide motif within the catalytic domain of progelatinases that mediates binding to leukocyte beta 2 integrins. J Biol Chem, 2003. 278(36): p. 34674-84. Stefanidakis, M., T. Ruohtula, N. Borregaard, CG. Gahniberg, and E. Koivunen, Intracellular and cell surface localization of a complex between alphaMbeta2 integrin and promatrix metalloproteinase-9 progelatinase in neutrophils. J Immunol, 2004. 172(11): p. 7060-8. Wrana, J.L., L. Attisano, J. Carcamo, A. Zentella, J. Doody, M. Laiho, X.F. Wang, and J. Massague, TGF beta signals through a heteromeric protein kinase receptor complex. Cell, 1992. 71(6): p. 1003-14. Stefanidakis, M., M. Bjorklund, E. Hianus, CG. Gahmberg, and E. Koivunen, Identification of a negatively charged peptide motif within the catalytic domain of progelatinases that mediates binding to leukocyte beta 2 integrins. J Biol Chem, 2003. 278(36): p. 34674-84. Libby, P., Atheroma: more than mush. Lancet, 1996. 348 Suppl 1: p. s4-7. Ross, R., Atherosclerosis an inflammatory disease. N Engl J Med, 1999. 340(2): p. 115- 26. FaIk, E., P.K. Shah, and V. Fuster, Coronary plaque disruption. Circulation, 1995. 92(3): p. 657-71.
1及びMMP-9活性を調節するためのTSP-1の活性部位に関連する1つ以上の配列を含む。
各種の感染症の治療方法は、「予防上の」処置又は「治療上の」処置を含む意味を有する。「予防上の」処置は、疾患に関連する病理を発症するリスクを低減するために疾患の兆候を示していないか又は疾患の初期の兆候を示す対象に施す処置である。
TSP-1は、150kDaの分子量の鎖を有する三量体である。TSP-1の各サブユニットは、幾つかの構造ドメインからなる(12)。これらのドメインは、アミノ末端ドメイン、プロコラーゲンドメイン、タイプ1、タイプ2、及びタイプ3反復配列、並びにカルボキシル末端ドメインとして広範に定義されている(25,26)。各ドメインは、図1に示すように多数の細胞機能の調節において重要である事が示されている。さらに、特異的なリガンド結合部位が、TSP-1について定義されている(図1)。これらは、リポタンパク質受容体関連タンパク質(LRP)、CD36、β3インテグリン、及びインテグリン関連タンパク質(IAP)、並びにTGF-β1及びPDGFを含むサイトカインを含む(3,12,27,28)。その多数の結合部位を介して、TSP-1は膜タンパク質及びサイトカインを有する細胞表面で機能しているようである。この様に、TSP-1は、シグナル伝達及び転写を含む細胞のフェノタイプに影響を与える。各細胞が異なる種類の受容体を発現するため、TSP-1によって形成される複合体の組成及び個々の細胞応答は、各細胞種によって変化する。例えば、TSP-1は、平滑筋細胞移動を促進するが、内皮細胞移動を阻害する(29-31)。
本発明者は、TSP-1マトリックス細胞タンパク質がプラーク安定化効果を有することを示すことができた。本発明者は、TSP-/-ApoE-/-ダブルノックアウトマウスを作製して、病変の形成及び組成に対するTSP-1欠失の役割を試験した。食事(3%脂肪)の24週後に、TSP-/-ApoE-/-マウス及びApoE-/-対照マウスを屠殺した。TSPノックアウトマウスと対象マウスとの間には、体重、総コレステロール、HDLコレステロール、及びトリグリセリドに優位な差はなかった。
上述のように、in vivoの組織創傷におけるTSP-1の他の研究において、大部分のフェノタイプの発見は、創傷部位において局所的にTGF-β1を活性化するTSP-1の機能に帰する。さらに、TGF-β1活性の中和は、TSP-/-ApoE-/-マウスにおける上述の本発明者による発見と同様に、炎症を増大し、アテローム性動脈硬化症の病変内のマトリックスを低減させることが示されている(34,35)。そのため、本発明者は、TSP-/-ApoE-/-動物由来の組織における全TGF-β1及び活性型TGF-β1の双方のレベルを測定した。本発明者は、アテローム性動脈硬化症が形成される傾向がある既知の領域である大動脈弓由来のサンプルを均質化して、ELISAアッセイにおいて、その可溶化液を使用した。これらのマウスにおける総(潜在型及び活性型)TGF-β1レベルには変化が無かったが、TSP-/-ApoE-/-マウスにおいて活性型TGF-β1レベルにおける低減が存在した(図4)。アテローム性動脈硬化症の病変の可溶化物を用いた結果と比較すると、Tsp-/-ApoE-/-マウスとApoE-/-マウスとの間の活性型TGF-β1の全身(血清)レベルにおいて差は無かった(225±87pg/mlに対して186±138pg/ml)。これらのデータは、TSP-1の欠損が、血管壁内で局所的にTGF-β1の活性化の低減を引き起こすことを示す。
免疫沈降実験によって、ゼラチナーゼ-B(MMP-9)はTSP-1に結合することが示されている(33)。さらに、TSP-1は、プロMMP-9の活性型への変換を調節し得る(32)。しかしながら、MMP-9の修飾語翻訳のTSP-1による制御についての機構は未知である。TSP-/-ApoE-/-マウスの病変内にマトリックスの顕著な損失が存在したため(図3e)、本発明者は、ウエスタンブロットにおいて大動脈弓均質化物由来の組織可溶化物を用いてMMP-9レベルを試験した。図5に示すように、これらのマウスのアテローム性動脈硬化症の病変において、総MMP-9及び活性型MMP-9のレベルの双方の増大が存在した。
TSP-1は、CD44、LAP、及びCD36を含むマクロファージに結合するための多数の潜在的な結合部位を有する(図1)。しかしながら、TSP-1には過去に確立されているβ2-インテグリン結合モチーフが存在しない。ファージ配列アッセイを用いた過去の研究は、ペプチドモチーフD(D/E)(G/L)Wが、β2インテグリンに結合するプロ-MMP-9と競合することを報告している(40)。完全なTSP-1ペプチド配列の配列探索によって、本発明者は、図2に示すように、TSP-1は2つのその様な推定のβ2インテグリン結合部位を有することを決定した:1つがTSR-1(DDGW、完全に一致)であり、他方がTSR-2(DGGW、2位の置換を有し、ほぼ一致している)。本発明者は、TSP-1のマクロファージへの結合を評価するための細胞接着アッセイを使用した(図6)。このアッセイを使用して、本発明者はマクロファージへのTSP-1の接着におけるD-Xaa-G-Wの作用を示すことができた。具体的には、本発明者は、DDGWが、TSP-1への細胞接着を十分に阻害することを示すことができた。この競合の特異性が、ペプチド配列DDGAによるTSP-1に結合するマクロファージの緩衝の損失、及び配列ADGWによる部分的な干渉によって示された。
TSP-1によるMMP-9の制御の機構は、ほとんど分かっていない。しかしながら、プロMMP-9は、そのD(D/E)(L/G)Wモチーフによって細胞表面aMβ2及びaLβ2インテグリンに結合し、その活性化を引き起こすことが示されている(37,38)。
TSP-1におけるWSxWモチーフは、TGF-β1活性化に重要である事が過去に示されている。この仮説を評価するために、本発明者は、組織培養実験を実施して、TSP-1が実際に、活性化マクロファージの存在下において、TGR-β1を活性化することを実証した。さらに、本発明者は変異体を使用して、TSR-2のWSPWモチーフが、TSP-1によるTGF-β1の活性化に主要な役割を担っていることを観察した。
ペプチド配列
本発明は、各種の新規なペプチドを提供する。これらは、各種の結合ドメイン及び活性化配列、並びにそれらのホモログの1つ以上を含んで良い。
上述のように、本発明の実施態様は、TSP-1、その一部、又は関連するペプチド、例えば、上述のように同定したものを用いる治療方法に関連する。一般的には、TSP-1及び本発明のペプチドを投与して、動脈壁上のプラークを安定化する。かくして、それらは、疾患を有する動物においてプラークを安定化する方法で利用されて良い。これは、アテローム性動脈硬化症の治療方法とは区別されるべきである。
上述の記載は説明を意図するものであって、これに制限するもので無いことが理解されるべきである。各種の実施態様及び変形が、本発明の範囲及び精神を逸脱すること無く、本願に開示されている発明に為されて良いことが当業者には明らかであるはずである。したがって、本発明の範囲は、上述の記載に表わされる具体的な実施態様を参照するのではなく、その様な実施態様と均等の全範囲を参照して決定されるべきである。本明細書に挙げた全ての文献は、本発明との関係において使用され得る生物学的機構、治療、方法論、及び概念を説明するために参照される。これらの参照文献が本明細書に記載の発明との関係において従来技術であると認められるべきではない。他に示さない限り、本明細書に挙げた各参照文献は、参照することによって、全ての目的のためにその全体を本明細書に組み込む。
1. Libby, P., Atheroma: more than mush. Lancet, 1996. 348 Suppl 1: p. s4-7.
2. Ross, R., Atherosclerosis~an inflammatory disease. N Engl J Med, 1999. 340(2): p. 115- 26.
3. Bornstein, P., Thrombospondins as matricellular modulators of cell function. J Clin Invest, 2001. 107(8): p. 929-34.
4. Sage, E.H., Regulation of interactions between cells and extracellular matrix: a command performance on several stages. J Clin Invest, 2001. 107(7): p. 781-3.
5. Murphy-Ullrich, J.E., The de-adhesive activity of matricellular proteins: is intermediate cell adhesion an adaptive state? J Clin Invest, 2001. 107(7): p. 785- 90.
6. Elzie, CA. and J.E. Murphy-Ullrich, The N-terminus of thrombospondin: the domain stands apart, lht J Biochem Cell Biol, 2004. 36(6): p. 1090-101.
7. Li, D.Y., G. Faury, D.G. Taylor, E.G. Davis, W.A. Boyle, R.P. Mecham, P. Stenzel, B. Bo ak, and M.T. Keating, Novel arterial pathology in mice and humans hemizygous for elastin. J Clin Invest, 1998. 102(10): p. 1783-7.
8. Aszodi, A., D. Chan, E. Hunziker, J.F. Bateman, and R. Fassler, Collagen π is essential for the removal of the notochord and the formation of intervertebral discs. J Cell Biol, 1998. 143(5): p. 1399-412.
9. Forsberg, E., E. Hirsch, L. Frohlich, M. Meyer, P. Ekblom, A. Aszodi, S. Werner, and R. Fassler, Skin wounds and severed nerves heal normally in mice lacking tenascin-C. Proc Natl Acad Sci U S A, 1996. 93(13): p. 6594-9.
10. Lawler, J., M. Sunday, V. Thibert, M. Duquette, E.L. George, H. Rayburn, and R.O. Hynes, Thrombospondin- 1 is required for normal murine pulmonary homeostasis and its absence causes pneumonia. J Clin Invest, 1998. 101(5): p. 982-92.
11. Kyriakides, T.R., J. W. Tarn, and P. Bornstein, Accelerated wound healing in mice with a disruption of the thrombospondin 2 gene. J Invest Dermatol, 1999. 113(5): p. 782-7.
12. Adams, J.C. and J. Lawler, The thrombospondins. Lit J Biochem Cell Biol, 2004. 36(6): p. 961-8.
13. Crawford, S.E., V. Stellmach, J.E. Murphy-Ullrich, S.M. Ribeiro, J. Lawler, R.O. Hynes, G.P. Boivin, and N. Bouck, Thrombospondin- 1 is a major activator of TGF-betal in vivo. Cell, 1998. 93(7): p. 1159-70.
14. Agah, A., T.R. Kyriakides, J. Lawler, and P. Bornstein, The lack of thrombospondin- 1 (TSPl) dictates the course of wound healing in double- TSPl/TSP2-null mice. Am J Pathol, 2002. 161(3): p. 831-9.
15. Yee, K.O., M. Streit, T. Hawighorst, M. Detmar, and J. Lawler, Expression of the type-1 repeats of thrombospondin- 1 inhibits tumor growth through activation of transforming growth factor-beta. Am J Pathol, 2004. 165(2): p. 541-52.
16. Miao, W.M., W.L. Seng, M. Duquette, P. Lawler, C. Laus, and J. Lawle r, Thrombospondin- 1 type 1 repeat recombinant proteins inhibit tumor growth through transforming growth factor-beta-dependent and -independent mechanisms. Cancer Res, 2001. 61(21): p. 7830-9.
17. Yano, K., H. Oura, and M. Detmar, Targeted overexpression of the angiogenesis inhibitor thrombospondin- 1 in the epidermis of transgenic mice prevents ultraviolet-B-induced angiogenesis and cutaneous photo-damage. J Invest Dermatol, 2002. 118(5): p. 800-5.
18. Simantov, R., M. Febbraio, R. Crombie, A.S. Asch, R.L. Nachman, and R.L. Silverstein, Histidine-rich glycoprotein inhibits the antiangiogenic effect of thrombospondin- 1. J Clin Invest, 2001. 107(1): p. 45-52.
19. Bornstein, P., A. Agah, and T.R. Kyriakides, The role of thrombospondins 1 and 2 in the regulation of cell-matrix interactions, collagen fibril formation, and the response to injury. Int J Biochem Cell Biol, 2004. 36(6): p. 1115-25.
20. Lawler, J. and M. Detmar, Tumor progression: the effects of thrombospondin- 1 and -2. Int J Biochem Cell Biol, 2004. 36(6): p. 1038-45.
21. Topol, EJ., J. McCarthy, S. Gabriel, DJ. Moliterno, WJ. Rogers, L.K. Newby, M. Freedman, J. Metivier, R. Cannata, CJ. O'Donnell, K. Kottke-Marchant, G. Murugesan, E.F. Plow, O. Stenina, and G.Q. Daley, Single nucleotide polymorphisms in multiple novel thrombospondin genes may be associated with familial premature myocardial infarction. Circulation, 2001. 104(22): p. 2641-4.
22. Stenina, O.I., T.V. Byzova, J.C. Adams, JJ. McCarthy, EJ. Topol, and E.F. Plow, Coronary artery disease and the thrombospondin single nucleotide polymorphisms. Int J Biochem Cell Biol, 2004. 36(6): p. 1013-30.
23. Raines, E.W., The extracellular matrix can regulate vascular cell migration, proliferation, and survival: relationships to vascular disease. Int J Exp Pathol, 2000. 81(3): p. 173-82.
24. Roth, JJ., V. Gahtan, J.L. Brown, C. Gerhard, V.K. Swami, V.L. Rothman, T.N. Tulenko, and G.P. Tuszynski, Thrombospondin- 1 is elevated with both intimal hyperplasia and hypercholesterolemia. J Surg Res, 1998. 74(1): p. 11-6.
25. Lawler, J., The functions of thrombospondin- 1 and-2. Curr Opin Cell Biol, 2000. 12(5): p. 634-40.
26. Chen, H., M.E. Herndon, and J. Lawler, The cell biology of thrombospondin- 1. Matrix Biol, 2000. 19(7): p. 597-614.
27. Majack, R.A., S.C. Cook, and P. Bornstein, Control of smooth muscle cell growth by components of the extracellular matrix: autocrine role for thrombospondin. Proc Natl Acad Sci U S A, 1986. 83(23): p. 9050-4.
28. Schultz-Cherry, S., S. Ribeiro, L. Gentry, and J.E. Murphy-Ullrich, Thrombospondin binds and activates the small and large forms of latent transforming growth factor-beta in a chemically defined system. J Biol Chem, 1994. 269(43): p. 26775-82.
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Claims (61)
- 配列Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-Xaa12-Xaa13-Xaa14-Xaa15を含むペプチドであって、Xaa1、Xaa2、及びXaa4が、Arg及びLysを含む塩基性の非環式アミノ酸からなる群から選択され;Xaa3、Xaa9、Xaa11、Xaa12、及びXaa15が、Phe、Trp、及びProを含む中性で大きな非極性環式アミノ酸からなる群から選択され;Xaa5が、Thr、Asn、及びGlnを含む中性で大きな極性非環式アミノ酸からなる群から選択され;Xaa6、Xaa7、及びXaa14が、Asp及びGlnを含む酸性アミノ酸からなる群から選択され;並びにXaa8、Xaa10、及びXaa13が、Gly、Ser、及びCysを含む中性で小さな極性アミノ酸からなる群から選択されるペプチド、又は7から14のアミノ酸を有する前記配列の切断型のセグメント。
- 前記ペプチドが15から25アミノ酸からなる、請求項1に記載のペプチド。
- 前記ペプチドが15から20アミノ酸からなる、請求項1に記載のペプチド。
- Xaa2がArgである、請求項1に記載のペプチド。
- Xaa6がAspである、請求項1に記載のペプチド。
- Xaa7がAspである、請求項1に記載のペプチド。
- Xaa9がTrpである、請求項1に記載のペプチド。
- Xaa12がTrpである、請求項1に記載のペプチド。
- Xaa15がTrpである、請求項1に記載のペプチド。
- Xaa2がArgであり、Xaa7がAspであり、Xaa9がTrpである、請求項1に記載のペプチド。
- 配列Lys-Arg-Phe-Lys-Gln-Asp-Asp-Gly-Trp-Ser-Pro-Trp-Ser-Glu-Trpを含む、15から25のアミノ酸からなるペプチド。
- 配列Lys-Arg-Phe-Lys-Gln-Asp-Asp-Gly-Trp-Ser-Pro-Trp-Ser-Glu-Trpからなる、請求項11に記載のペプチド。
- 8から14のアミノ酸残基からなる、請求項12に記載のペプチドのアミノ及び/又はカルボキシル切断型のセグメント。
- 配列Asp-Xaa-Gly-Trp-Ser-Pro/His-Trp-Ser-Glu/Pro-Trpを含み、Xaaが任意のアミノ酸である、10から20のアミノ酸からなるペプチド。
- 配列Asp-Asp-Gly-Trp-Ser-Pro-Trp-Ser-Glu-Trpを含む、10から20のアミノ酸からなるペプチド。
- 配列Asp-Xaa-Gly/Leu-Trp又はAsp/Glu-Asp/Glu-Gly/Leu-Trp又はAsp-Asp/Glu-Gly/Leu-Trpを含み、Xaaが任意のアミノ酸である、7から20のアミノ酸からなるペプチド。
- 配列Lys-Arg-Phe-Lys-Gln-Asp/Glu-Xaa-Gly/Leu-Trpを含み、Xaaが任意のアミノ酸である、9から20のアミノ酸からなるペプチド。
- 配列Lys-Arg-Phe-Lys-Asp/Glu-Xaa-Gly/Leu-Trpを含み、Xaaが任意のアミノ酸である、8から20のアミノ酸からなるペプチド。
- 配列Asp/Glu-Xaa1-Gly/Leu-Trp-Ser-Xaa2-Trp-Ser-Xaa3-Trpを含み、Xaa1、Xaa2、及びXaa3が任意のアミノ酸である、10から20のアミノ酸をからなるペプチド。
- Xaa1がAsp又はGluであり、Xaa2がPro又はHisであり、Xaa3がGlu又はProである、請求項19に記載のペプチド。
- 配列Asp-Asp-Gly-Trp-Ser-Pro-Trp-Ser-Glu-Trpを含む10から20のアミノ酸からなるペプチド。
- アテローム性動脈硬化症のプラークを安定化する活性がある、請求項1、11、14から19、及び21のいずれか一項に記載のペプチド。
- 1つ以上の保存的アミノ酸置換を含む、請求項1、11、14から19、及び21のいずれか一項に記載のペプチド。
- 請求項1、11、14から19、及び21のいずれか一項に記載のペプチドと95%の相同性を有するペプチド。
- 請求項1、11、14から19、及び21のいずれか一項に記載のペプチドをコードするヌクレオチド配列。
- 請求項1、11、14から19、及び21のいずれか一項に記載のペプチドをコードするヌクレオチド配列を含む発現ベクター。
- 請求項26に記載の発現ベクターを含む宿主細胞。
- タンパク質-タンパク質相互作用によってTGF-β1及び/又はMMP-9活性を調節する、請求項1、11、14から19、及び21のいずれか一項に記載のペプチド。
- 非天然アミノ酸、D-異性体又はD,L-ラセミ混合異性体の形態、ジスルフィド結合、カルボキシ又はアミノ末端修飾、脂肪酸及びPEGを含む生体適合性分子への接合、並びにアミノ酸の化学的置換からなる群から選択される1つ以上の修飾を含む、請求項1、11、14から19、及び21のいずれか一項に記載のペプチド。
- ホモポリマー化又はヘテロポリマー化されている、請求項1、11、14から19、及び21のいずれか一項に記載のペプチド。
- C末端、N末端、又はそれらの側鎖に結合している請求項1、11、14から19、及び21のいずれか一項に記載のペプチドを含む融合タンパク質。
- 請求項1、11,14から19、及び21のいずれか一項に記載のペプチドを含む、純粋な医薬製剤。
- 動物に投与するため、又はヒトに投与するための医薬製剤として調製される、請求項1、11、14から19、及び21のいずれか一項に記載のペプチドを含む組成物。
- 液体として製剤化されている、請求項33に記載の組成物。
- 輸液又は注射に適切なものである、請求項34に記載の液体。
- 請求項1、11、14から19、又は21のいずれか一項に記載のペプチドを含む組成物又は医薬製剤を動物に投与する工程を含む、アテローム性動脈硬化症のプラークを安定化し、プラークが破裂する事象の発生を低減するための方法。
- 前記組成物又は医薬製剤が液体である、請求項36に記載の方法。
- 前記組成物又は医薬製剤が、輸液又は注射に適切な液体である、請求項36に記載の方法。
- 前記動物が、アテローム性動脈硬化症のプラークの存在によって、少なくとも部分的に特徴付けられる疾患を有する、請求項36に記載の方法。
- 前記疾患が、以下の特徴:心筋梗塞、脳卒中、及び急性肢虚血、又はその様な疾患に対する素因の1つ以上を含む、請求項36に記載の方法。
- 前記動物への投与が、輸液又は注射による投与を含む、請求項36に記載の方法。
- 請求項1、11、14から19、又は21のいずれか一項に記載のペプチドを含む組成物又は医薬製剤を動物に投与する工程を含む、内膜病変内の炎症及び脂質沈着を低減し、且つ、コラーゲン及びエラスチン沈着を増大させるための方法。
- 前記組成物又は医薬製剤が液体である、請求項42に記載の方法。
- 前記組成物又は医薬製剤が、輸液又は注射に適切な液体である、請求項42に記載の方法。
- 前記動物が、内膜病変内の炎症、脂質沈着、又はコラーゲン及びエラスチン沈着の減少の存在によって、少なくとも部分的に特徴付けられる疾患を有する、請求項42に記載の方法。
- 前記疾患が、心筋梗塞、脳卒中、及び急性肢虚血、又はその様な疾患に対する素因を含む、請求項45に記載の方法。
- 前記動物への投与が、輸液又は注射によるものである、請求項42に記載の方法。
- 請求項1、11、14から19、及び21のいずれか一項に記載のペプチドを含む組成物又は医薬製剤を動物に投与する工程を含む、大動脈壁でTGF-β1を活性化し、且つ、MMP-9を不活性化するための方法。
- 前記組成物又は医薬製剤が液体である、請求項48に記載の方法。
- 前記組成物又は医薬製剤が、輸液又は注射に適切な液体である、請求項48に記載の方法。
- 前記動物への投与が、輸液又は注射によるものである、請求項48に記載の方法。
- 前記動物が、大動脈壁におけるTGF-β1の不活性化及び/又はMMP-9の活性化の存在によって、少なくとも部分的に特徴付けられる疾患を有する、請求項48に記載の方法。
- 請求項1、11、14から19、及び21のいずれか一項に記載のペプチドを含む組成物または医薬製剤を動物に投与する工程を含む、TGF-β1の活性化及び/又はMMP-9の不活性化のための方法。
- 前記組成物又は医薬製剤が液体である、請求項53に記載の方法。
- 前記組成物又は医薬製剤が、輸液又は注射に適切な液体である、請求項53に記載の方法。
- 前記動物への投与が、輸液又は注射によるものである、請求項53に記載の方法。
- 動物が、癌及び/又は血管新生、あるいはその様な疾患に対する素因の存在によって、少なくとも部分的に特徴付けられる疾患を有する、請求項53に記載の方法。
- 請求項1、11、14から19、及び21のいずれか一項に記載のペプチドを含む組成物又は医薬製剤と動物を接触させる工程を含む、TGF-β1及び/又はMMP-9活性を調節するための方法。
- 前記動物が、癌及び/又は血管新生、あるいはその様な疾患に対する素因の存在によって、少なくとも部分的に特徴付けられる疾患を有する、請求項58に記載の方法。
- 前記動物が、内膜病変内の炎症、脂質沈着、又はコラーゲン及びエラスチン沈着の減少の存在によって、少なくとも部分的に特徴付けられる疾患を有する、請求項58に記載の方法。
- 前記疾患が、心筋梗塞、脳卒中、及び急性肢虚血、あるいはその様な疾患に対する素因の1つ以上を含む、請求項60に記載の方法。
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JP2012512842A (ja) * | 2008-12-18 | 2012-06-07 | アポサイエンス アクチエンゲゼルシャフト | 血単核球の培養物の上清を包含する薬剤 |
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KR20080039878A (ko) | 2008-05-07 |
EP1901761A2 (en) | 2008-03-26 |
UA94046C2 (ru) | 2011-04-11 |
US20090131314A1 (en) | 2009-05-21 |
BRPI0613357A2 (pt) | 2017-02-21 |
EP1901761A4 (en) | 2009-08-12 |
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