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TARGETING AGENT FOR NEOVASCULARIZATION

Foreign code F200010108
File No. 2570
Posted date May 18, 2020
Country WIPO
International application number 2010JP059917
International publication number WO 2010143708
Date of international filing Jun 11, 2010
Date of international publication Dec 16, 2010
Priority data
  • P2009-140757 (Jun 12, 2009) JP
Title TARGETING AGENT FOR NEOVASCULARIZATION
Abstract Disclosed is a targeting agent which enables the drug delivery to a part where neovascularization occurs or the imaging of the part utilizing the effect of accumulation of the targeting agent in the part. Specifically disclosed is a targeting agent for a part where neovascularization occurs, which comprises a gelatin-like protein.
Outline of related art and contending technology BACKGROUND ART
Angiogenesis is, mainly, to form new blood vessels from existing blood vessels represents a phenomenon. As the normal physiological angiogenesis, and angiogenesis in embryonic stage, the endometrium and corpus luteum formation, wound healing such as angiogenesis is involved in present. On the other hand, the pathogenic angiogenesis is, the growth of solid tumors and metastasis, diabetic retinopathy, chronic inflammation such as rheumatoid arthritis and the like are deeply involved is known. Research on tumor angiogenesis in particular, the treatment, diagnosis are actively researched and from both sides. 1-2 mm tumor tumor diameter existing oxygen and nutrients diffusion from blood vessels is considered to be obtained, more proliferation of angiogenesis is required. In adult healthy subjects, an event that an angiogenesis a limited location, since there are only in limited cases, that target tumor angiogenesis therapeutic drugs or imaging agents, tumor-specific and universal drug, diagnostic agents which can be expected.
Current, in the diagnosis of tumor, tumor site FDG (fluorodeoxyglucose) using PET(positron emission tomography) but the diagnosis is performed, and the cells metabolic activity glucose FDG, targeted tissue site only, is not sufficient for tumor specificity. By integrated physiological FDG, brain, heart, that indicate the high integration also such as the liver, it may be difficult to diagnosis of tumors in question. Also, kidney, ureter, the urinary system is bladder, urine discharged into the background by a large amount of FDG is increased, it is difficult to diagnosis. Therefore, by targeting mechanism separate from the glucose metabolism by targeting, mainly targeting agent targeting angiogenesis (targeting agent) which has been developed.
On the other hand, in the treatment of angiogenesis event can be used, are implemented as angiogenesis therapy. Wound healing, as therapy for ischemic diseases, in addition, the organ regeneration or cell transplantation, such as enhancement of the effect of the natural healing, widely referred to as regenerative medicine in the treatment, the importance of angiogenesis been demonstrated. Angiogenesis itself exhibits a therapeutic effect, or to enhance the therapeutic effects of angiogenesis. Therefore, targeted angiogenesis targeting agent or therapeutic agent, imaging agents, a variety of therapeutic, agent in the regenerative medicine, diagnostic agent, therapeutic effect evaluation means are anticipated.
Particularly of a reproduction in the medical field, an operator of a detailed study its therapeutic effect is poor, the authenticity for its therapeutic effect, the presence of a combination of conventional diagnostic methods, in order to evaluate the direct non-stationary. In particular as described above, angiogenesis is an important role in regenerative medicine has a, distinct from the existing blood vessel and a technique for evaluating blood vessels is poor. Especially vascularized imaging means allows visualization of only the blood vessel and thus, the lack of specificity of neovascularization of the imaging agent, such as lack of sustained or, by various problems and does not lead to provide a result sufficiently yet.
As a means for targeting angiogenesis, endothelial cells during angiogenesis in (and in some tumor cells) have been reported highly expressed αV β3 targeted integrin targeting agent, the development of imaging agents are implemented. Α v β3 integrins are, arginine - glycine - aspartic acid (RGD) peptide having the sequence from recognize. Therefore, RGD sequence as a base and, in particular the various cyclic RGD and cyclic RGD-containing peptides is similar compounds have been developed and are, for example Munich Institute Kessler et al. developed by a cyclic pentapeptide c-RGDfV cyclo-RGDfK and lead compounds, cyclo-RGDyV, cyclo-RGDfY, a number of compounds such as cyclo-RGDyK (non-patent document 1) present.
However, the above-described compound is a cyclic RGD, mainly by renal excretion and so the emitted to the outside quickly after administration, short dwell time in vivo. Therefore, drug delivery agent or imaging agent is used as the targeting agent such as, its targeting ability can be utilized as a shorter period of time, before reaching to the target site, most being emitted to the outside is a problem. On the other hand, imaging of blood vessels, in the diagnosis or imaging, a fluorescent dye to the targeting agent or a radioactive isotope for labeling the probe, from the viewpoint of safety, the detection of the site, as soon as possible after the diagnosis is not signal, that is after the diagnosis is, from the corresponding parts required may be lost at an early stage. However, cyclic RGD peptide, even if the head reaches to a target site, neovascularity Integrin expressed from the strong bonding to, the loss of signal from a site of angiogenic blood vessels in case there is prolonged, in question. From these, 'long in vivo residence time of the loss of signal from the site of new blood vessels' and' rapid ' imaging material is demanded.
On the other hand, biological macromolecules including gelatin is widely known heretofore have been used as medical materials, can be utilized to image blood vessels has not been known until now. In addition, in recent years due to advances in genetic engineering techniques, to introduce the gene of E. coli or yeast is performed by protein synthesis. By the procedure, a variety of genes into the recombinant collagen-like protein (for example Patent Document 1 and 2) combined and compared to natural gelatin, noninfectious is excellent, uniform and, since the sequence is determined intensity, can be biodegradable to accurately design the advantages and can be used. However, these applications have been proposed alternative beyond the natural gelatin is not, of course also find application as imaging agents for neovascularization has not been known.
Scope of claims (In Japanese)[請求項1]
ゼラチン様タンパク質を含む、新生血管部位に対する標的化剤。

[請求項2]
新生血管部位を標的としたイメージング剤である、請求項1に記載の標的化剤。

[請求項3]
新生血管部位を標的としたドラッグデリバリー剤である、請求項1に記載の標的化剤。

[請求項4]
ゼラチン様タンパク質が、ゼラチン、コラーゲン、フィブロネクチン、プロネクチン、ビトロネクチン、又はそれらの組み合わせである、請求項1から3のいずれかに記載の標的化剤。

[請求項5]
ゼラチン様タンパク質が、コラーゲンの部分アミノ酸配列に由来するアミノ酸配列を有する遺伝子組み換えゼラチンである、請求項1から4のいずれかに記載の標的化剤。

[請求項6]
遺伝子組み換えゼラチンが、コラーゲンに特徴的なGly-X-Yで示される配列(X及びYはそれぞれ独立にアミノ酸の何れかを示す)の繰り返しを有し(複数個のGly-X-Yはそれぞれ同一でも異なっていてもよい)、分子量が2 KDa以上100 KDa以下である、請求項5に記載の標的化剤。

[請求項7]
遺伝子組み換えゼラチンが、コラーゲンに特徴的なGly-X-Yで示される配列(X及びYはそれぞれ独立にアミノ酸の何れかを示す)の繰り返しを有し(複数個のGly-X-Yはそれぞれ同一でも異なっていてもよい)、分子量が10 KDa以上90 KDa以下である、請求項5又は6に記載の標的化剤。

[請求項8]
遺伝子組み換えゼラチンが、コラーゲンに特徴的なGly-X-Yで示される配列(X及びYはそれぞれ独立にアミノ酸の何れかを示す)の繰り返しを有し(複数個のGly-X-Yはそれぞれ同一でも異なっていてもよい)、細胞接着シグナルを一分子中に2配列以上含む、請求項5から7の何れかに記載の標的化剤。

[請求項9]
細胞接着シグナルがArg-Gly-Aspで示されるアミノ酸配列である、請求項8に記載の標的化剤。

[請求項10]
遺伝子組み換えゼラチンのアミノ酸配列が、セリン及びスレオニンを含まない、請求項5から9の何れかに記載の標的化剤。

[請求項11]
遺伝子組み換えゼラチンのアミノ酸配列が、セリン、スレオニン、アスパラギン、チロシン、及びシステインを含まない、請求項5から10の何れかに記載の標的化剤。

[請求項12]
遺伝子組み換えゼラチンのアミノ酸配列が、Asp-Arg-Gly-Aspで示されるアミノ酸配列を含まない、請求項5から11の何れかに記載の標的化剤。

[請求項13]
遺伝子組み換えゼラチンが、
式:A-[(Gly-X-Y) nm-B
(式中、Aは任意のアミノ酸又はアミノ酸配列を示し、Bは任意のアミノ酸又はアミノ酸配列を示し、n個のXはそれぞれ独立にアミノ酸の何れかを示し、n個のYはそれぞれ独立にアミノ酸の何れかを示し、nは3~100の整数を示し、mは2~10の整数を示す。なお、n個のGly-X-Yはそれぞれ同一でも異なっていてもよい。)で示される、請求項5から12の何れかに記載の標的化剤。

[請求項14]
遺伝子組み換えゼラチンが、
式:Gly-Ala-Pro-[(Gly-X-Y) 633-Gly
(式中、63個のXはそれぞれ独立にアミノ酸の何れかを示し、63個のYはそれぞれ独立にアミノ酸の何れかを示す。なお、n個のGly-X-Yはそれぞれ同一でも異なっていてもよい。)
で示される、請求項5から13の何れかに記載の標的化剤。

[請求項15]
遺伝子組み換えゼラチンが、(1)配列番号1に記載のアミノ酸配列、又は(2)配列番号1に記載のアミノ酸配列と80%以上の相同性を有し、新生血管に集積する作用を有するアミノ酸配列を有する、請求項5から14の何れかに記載の標的化剤。

[請求項16]
遺伝子組み換えゼラチンが架橋されている、請求項5から15の何れかに記載の標的化剤。

[請求項17]
架橋がアルデヒド類、縮合剤、又は酵素により施される、請求項16に記載の標的化剤。

[請求項18]
さらに標識プローブまたは薬剤を含有する、請求項1から17の何れかに記載の標的化剤。

[請求項19]
標識プローブが、蛍光色素、放射性同位体、PET用核種、SPECT用核種、MRI造影剤、CT造影剤、又は磁性体である請求項18に記載の標的化剤。

[請求項20]
蛍光色素が、量子ドット、インドシアニングリーン又は近赤外蛍光色素であり、放射性同位体、PET用核種及びSPECT用核種が、 11C、 13N、 15O、 18F、 66Ga、 67Ga、 68Ga、 60Cu、 61Cu、 62Cu、 67Cu、 64Cu、 48V、Tc-99m、 241Am、 55Co、 57Co、 153Gd、 111In、 133Ba、 82Rb、 139Ce、Te-123m、 137Cs、 86Y、 90Y、 185/187Re、 186/188Re、 125I、又はそれらの錯体、あるいはそれらの組み合わせであり、MRI造影剤、CT造影剤及び磁性体が、ガドリニウム、Gd-DTPA、Gd-DTPA-BMA、Gd-HP-DO3A、ヨード、鉄、酸化鉄、クロム、マンガン、又はその錯体・キレート錯体、あるいは又はそれらの組み合せである、請求項19に記載の標的化剤。

[請求項21]
ゼラチン様タンパク質と標識プローブとが、直接又はリンカーを介すことにより物理的又は化学的に結合されている、請求項18から20の何れかに記載の標的化剤。

[請求項22]
該結合が、配位結合、共有結合、水素結合、疎水性相互作用、又は物理吸着である、請求項21に記載の標的化剤。

[請求項23]
ゼラチン様タンパク質を対象者に投与することを含む、新生血管部位に対して物質を標的化する方法。

[請求項24]
新生血管部位に対する標的化剤の製造のための、ゼラチン様タンパク質の使用。
  • Applicant
  • ※All designated countries except for US in the data before July 2012
  • FUJIFILM CORPORATION
  • KYOTO UNIVERSITY
  • Inventor
  • NAKAMURA Kentaro
  • TABATA Yasuhiko
IPC(International Patent Classification)
Specified countries National States: AE AG AL AM AO AT AU AZ BA BB BG BH BR BW BY BZ CA CH CL CN CO CR CU CZ DE DK DM DO DZ EC EE EG ES FI GB GD GE GH GM GT HN HR HU ID IL IN IS JP KE KG KM KN KP KR KZ LA LC LK LR LS LT LU LY MA MD ME MG MK MN MW MX MY MZ NA NG NI NO NZ OM PE PG PH PL PT RO RS RU SC SD SE SG SK SL SM ST SV SY TH TJ TM TN TR TT TZ UA UG US UZ VC VN ZA ZM ZW
ARIPO: BW GH GM KE LR LS MW MZ NA SD SL SZ TZ UG ZM ZW
EAPO: AM AZ BY KG KZ MD RU TJ TM
EPO: AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR
OAPI: BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG
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