JP2006509730A - 合成ヘパリン結合成長因子類似体 - Google Patents
合成ヘパリン結合成長因子類似体 Download PDFInfo
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- JP2006509730A JP2006509730A JP2004529777A JP2004529777A JP2006509730A JP 2006509730 A JP2006509730 A JP 2006509730A JP 2004529777 A JP2004529777 A JP 2004529777A JP 2004529777 A JP2004529777 A JP 2004529777A JP 2006509730 A JP2006509730 A JP 2006509730A
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- heparin
- growth factor
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- binding growth
- fgf
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Abstract
Description
本出願は、2002年8月20日に提出された「合成ヘパリン結合成長因子類似体」と題される米国特許出願番号第10/224,268号の一部継続出願であり、そしてそれに対して優先権を主張し、そしてその明細書は、ここに参照して組み込まれる。
本発明は、米国エネルギー省により授与される契約番号DE−AC02−98CH10886号の下に米国連邦政府支援を伴い発明された。米国連邦政府が本発明のあらゆる権利を有する。
各Xは、(i)最小3個のアミノ酸残基を有し、(ii)最大約50個のアミノ酸残基を有し、そして(iii)ヘパリン結合成長因子レセプター(HBGFR)を結合するペプチド鎖である;R1は、アミノ酸残基であり、Xは、R1のN末端を通して、またはR1の側鎖を通して共有結合で結合されている;R2は、三官能性アルファアミノ酸残基であり、Xは、R2の側鎖を通して共有結合で結合されている;Yは、n=0の場合、R1およびZに、またはn=1の場合、R2およびZに共有結合で結合された0個から約50個の原子までの鎖を包含するリンカーである;Zは、ヘパリン結合ドメインを包含する非シグナル発生ペプチド鎖であり、そして(i)最小1個のヘパリン結合モチーフ、(ii)最大約10個のヘパリン結合モチーフ、および(iii)最大約30個のアミノ酸を包含するアミノ酸配列を包含する;そしてnは、0または1であり、n=1の場合、ペプチド鎖Xは同一である。
R3およびR5は、独立に、NH2;N末端NH2、NH3 +、またはNH基あるいは対応のアシル化誘導体を含む、線状または分岐C1からC17までのアルキル、アリール、ヘテロアリール、アルケン、アルケニルまたはアラルキル鎖を有するアシル基であるか、またはN末端NH2、NH3 +、NH基あるいは対応のアシル化誘導体を有するアミノ酸、ジペプチドまたはトリペプチドである;R4は、−OH、NH2、NH−R6であるか、またはC末端−OH、NH2、またはNH−R6を有するアミノ酸、ジペプチドまたはトリペプチドである;R6は、脂肪族C1からC17までの鎖である;各Xは、(i)最小3個のアミノ酸残基を有し、(ii)最大約50個のアミノ酸残基を有し、そして(iii)HBGFRを結合するペプチド鎖である;J1およびJ2は、各々独立に、各Xが、J1およびJ2の側鎖を通して共有結合で結合される三官能性アルファアミノ酸残基である;Yは、n=0である場合、J1およびZに、あるいはn=1である場合、J2およびZに共有結合で結合された0から約50個までの原子の鎖を包含するリンカーである;Zは、ヘパリン結合ドメインを包含する非シグナル発生ペプチドであり、そして(i)最小1個のヘパリン結合モチーフ、(ii)最大約10個のヘパリン結合モチーフ、および(iii)最大約30個のアミノ酸を包含するアミノ酸配列を包含する;そしてnは、0または1であり、n=1の場合、合成ペプチド鎖Xは同一である。
式IからIVまでのヘパリン結合成長因子
式IからIVまでの合成HBGF類似体の領域XおよびZは、アミノ酸残基を含み、そして都合により領域Yは、アミノ酸残基を含む。アミノ酸残基は、Rが水素またはあらゆる有機基でありうる−NHRCO−として定義される。アミノ酸は、D−アミノ酸またはL−アミノ酸でありうる。さらに、アミノ酸は、アミノ酸の炭素鎖の長さによって、α−アミノ酸、β−アミノ酸、γ−アミノ酸、またはδ−アミノ酸などでありうる。
FGF合成類似体
別の特定の態様では、本発明は、合成FGFペプチド類似体を提供する。Xが、FGF類似体である、式IからIVまでのいずれかによって表される合成FGF類似体は、23のFGF−1からFGF−23まですべてを含めた既知FGFのいずれかのようなすべてのFGFでありうるFGFの類似体である。
別の特定の態様では、本発明は、合成VEGFペプチド類似体を提供する。示される合成VEGF類似体は、1つの実施態様では、X領域のアミノ酸配列がAPMAEGGGQNHHEVVKFMDV(配列番号:12)であるVEGF類似体を含む。別の実施態様では、X領域のアミノ酸配列がGATWLPPNPTK(配列番号:13)である合成VEGFペプチド類似体を提供する。さらに別の実施態様では、X領域のアミノ酸配列がNFLLSWVHWSLALLLYLHHA(配列番号:14)である合成VEGFペプチド類似体を提供する。
別の特定の態様では、本発明は、合成BMPペプチド類似体を提供する。合成骨形成タンパク質類似体は、X領域がアミノ酸配列LYVDFSDVGWNDW(配列番号:15)、AISMLYLDENEKVVL(配列番号:16)、ISMLYLDENEKVVLKNY(配列番号:17)、EKVVLKNYQDMVVEG(配列番号:18)、LVVKENEDLYLMSIAC(配列番号:19)、AFYCHGECPFPLADHL(配列番号:20)、またはPFPLADHLNSTNHAIVQTLVNSV(配列番号:21)である実施態様を含む。
本発明の類似体の合成は、当業界で周知である多様な化学的方法のいずれかにより達成されうる。このような方法は、ベンチスケールの固相合成および市販で入手可能な多くのペプチド合成機のいずれか1つでの自動ペプチド合成を含む。好ましくは、合成機は、99パーセントより大きな周期当たりのカップリング効率を示す。
本発明のHBGF類似体は、例えば、種々の疾患の予防または治療のための溶解性薬剤としての投与のように、溶解性予防薬または治療用医薬製剤としてを含めて、例えば癌療法および放射線防御での使用を含めて、多くの点で有用である生物学的に活性な分子の費用効率の高い、そして潜在的に制限のない源を提供する。
繊維芽細胞成長因子FGFは、間葉、上皮、および神経外胚葉の細胞型の正常な成長および分化を制御する関連タンパク質のファミリーを構築する。相同体は、広範で多様な種で見られた。FGFは、ヘパリンに非常に高い親和性を示し、したがって、ヘパリン結合成長因子(HBGF)とも称される。ここで使用される場合、用語「HBGF」は、全てのFGFを含む。
<110> Brookhaven Science Associates
BioSurface Engineering Technologies, Inc.
Pena, Louis A.
Zamora, Paul
Lu, Xinhua
Glass, John D.
<120> Synthetic Heparin-Binding Growth Factor Analogs
<130> 30817-1008-CIP
<150> US 10/224,268
<151> 2002-08-20
<160> 22
<170> PatentIn version 3.2
<210> 1
<211> 6
<212> PRT
<213> Artificial
<220>
<223> Heparin-binding motif
<220>
<221> misc_feature
<222> (1)..(3)
<223> LYS or ARG
<220>
<221> misc_feature
<222> (4)..(5)
<223> any amino acid
<220>
<221> misc_feature
<222> (6)..(6)
<223> LYS or ARG
<400> 1
Xaa Xaa Xaa Xaa Xaa Xaa
1 5
<210> 2
<211> 10
<212> PRT
<213> Artificial
<220>
<223> Heparin-binding domain of Z region
<400> 2
Arg Lys Arg Lys Leu Glu Arg Ala Ile Arg
1 5 10
<210> 3
<211> 10
<212> PRT
<213> Artificial
<220>
<223> Heparin-binding domain of Z region
<400> 3
Arg Lys Arg Lys Leu Gly Arg Ile Ala Arg
1 5 10
<210> 4
<211> 10
<212> PRT
<213> Artificial
<220>
<223> Heparin-binding domain of Z region
<400> 4
Arg Lys Arg Lys Leu Trp Arg Ala Arg Ala
1 5 10
<210> 5
<211> 11
<212> PRT
<213> Artificial
<220>
<223> Heparin-binding domain of Z region
<400> 5
Arg Lys Arg Lys Leu Glu Arg Ile Ala Arg Cys
1 5 10
<210> 6
<211> 15
<212> PRT
<213> Artificial
<220>
<223> Synthetic FGF-2 analog
<400> 6
Tyr Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys Arg
1 5 10 15
<210> 7
<211> 28
<212> PRT
<213> Artificial
<220>
<223> Synthetic FGF-2 analog
<400> 7
Asn Arg Phe His Ser Trp Asp Cys Ile Lys Thr Trp Ala Ser Asp Thr
1 5 10 15
Phe Val Leu Val Cys Tyr Asp Asp Gly Ser Glu Ala
20 25
<210> 8
<211> 17
<212> PRT
<213> Artificial
<220>
<223> Synthetic FGF-1 analog
<400> 8
Tyr Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys
1 5 10 15
Lys
<210> 9
<211> 15
<212> PRT
<213> Artificial
<220>
<223> Synthetic FGF-1 analog
<400> 9
His Ile Gln Leu Gln Leu Ser Ala Ser Glu Val Gly Glu Val Tyr
1 5 10 15
<210> 10
<211> 20
<212> PRT
<213> Artificial
<220>
<223> Synthetic FGF-7 analog
<400> 10
Tyr Ala Ser Ala Lys Trp Thr His Asn Gly Gly Glu Met Phe Val Ala
1 5 10 15
Leu Asn Gln Lys
20
<210> 11
<211> 15
<212> PRT
<213> Artificial
<220>
<223> Synthetic FGF-7 analog
<400> 11
Tyr Asn Ile Met Glu Ile Arg Thr Val Ala Val Gly Ile Val Ala
1 5 10 15
<210> 12
<211> 20
<212> PRT
<213> Artificial
<220>
<223> Synthetic VEGF analog
<400> 12
Ala Pro Met Ala Glu Gly Gly Gly Gln Asn His His Glu Val Val Lys
1 5 10 15
Phe Met Asp Val
20
<210> 13
<211> 11
<212> PRT
<213> Artificial
<220>
<223> Synthetic VEGF analog
<400> 13
Gly Ala Thr Trp Leu Pro Pro Asn Pro Thr Lys
1 5 10
<210> 14
<211> 20
<212> PRT
<213> Artificial
<220>
<223> Synthetic VEGF analog
<400> 14
Asn Phe Leu Leu Ser Trp Val His Trp Ser Leu Ala Leu Leu Leu Tyr
1 5 10 15
Leu His His Ala
20
<210> 15
<211> 13
<212> PRT
<213> Artificial
<220>
<223> Synthetic BMP analog
<400> 15
Leu Tyr Val Asp Phe Ser Asp Val Gly Trp Asn Asp Trp
1 5 10
<210> 16
<211> 15
<212> PRT
<213> Artificial
<220>
<223> Synthetic BMP analog
<400> 16
Ala Ile Ser Met Leu Tyr Leu Asp Glu Asn Glu Lys Val Val Leu
1 5 10 15
<210> 17
<211> 17
<212> PRT
<213> Artificial
<220>
<223> Synthetic BMP analog
<400> 17
Ile Ser Met Leu Tyr Leu Asp Glu Asn Glu Lys Val Val Leu Lys Asn
1 5 10 15
Tyr
<210> 18
<211> 15
<212> PRT
<213> Artificial
<220>
<223> Synthetic BMP analog
<400> 18
Glu Lys Val Val Leu Lys Asn Tyr Gln Asp Met Val Val Glu Gly
1 5 10 15
<210> 19
<211> 16
<212> PRT
<213> Artificial
<220>
<223> Synthetic BMP analog
<400> 19
Leu Val Val Lys Glu Asn Glu Asp Leu Tyr Leu Met Ser Ile Ala Cys
1 5 10 15
<210> 20
<211> 16
<212> PRT
<213> Artificial
<220>
<223> Synthetic BMP analog
<400> 20
Ala Phe Tyr Cys His Gly Glu Cys Pro Phe Pro Leu Ala Asp His Leu
1 5 10 15
<210> 21
<211> 23
<212> PRT
<213> Artificial
<220>
<223> Synthetic BMP analog
<400> 21
Pro Phe Pro Leu Ala Asp His Leu Asn Ser Thr Asn His Ala Ile Val
1 5 10 15
Gln Thr Leu Val Asn Ser Val
20
<210> 22
<211> 29
<212> PRT
<213> Artificial
<220>
<223> Synthetic heparin-binding growth factor analog specific for FGF-2
with heparin-binding region
<220>
<221> MISC_FEATURE
<222> (17)..(19)
<223> 6-aminohexanoic acid
<400> 22
Tyr Arg Ser Arg Lys Tyr Ser Ser Trp Tyr Val Ala Leu Lys Arg Thr
1 5 10 15
Xaa Xaa Xaa Arg Lys Arg Lys Leu Glu Arg Ile Ala Arg
20 25
Claims (59)
-
各Xは、(i)最小3個のアミノ酸残基を有し、(ii)最大約50個のアミノ酸残基を有し、そして(iii)ヘパリン結合成長因子レセプター(HBGFR)を結合するペプチド鎖であり、
R1は、XがR1のN末端を通して、またはR1の側鎖を通して共有結合で結合されるものであるアミノ酸残基である;
R2は、XがR2の側鎖を通して共有結合で結合されるものである三官能性アルファアミノ酸残基である;
Yは、n=0の場合、R1およびZに、またはn=1の場合、R2およびZに、共有結合で結合した0から約50個までの原子の鎖を包含するリンカーである;
Zは、ヘパリン結合ドメインを包含する非シグナル発生ペプチド鎖であり、そして(i)最小1個のヘパリン結合モチーフ、(ii)最大約10個のヘパリン結合モチーフ、そして(iii)最大約30個のアミノ酸を包含するアミノ酸配列を含む;そして;
n=1の場合、ペプチド鎖Xは、同一である、nは、0または1である
式Iで表されるヘパリン結合成長因子(HBGF)類似体。 - XおよびZが、合成ペプチド鎖である請求項1のヘパリン結合成長因子類似体。
- Yが、さらに、(i)疎水性であり、(ii)最小約9個および最大約50個の原子の鎖を包含し、そして(iii)Xが結合するヘパリン結合成長因子レセプター(HBGFR)の天然のリガンドで見られないリンカーを包含する請求項1または2に記載のヘパリン結合成長因子類似体。
- R1は、Xが、R1の側鎖を通して共有結合で結合されている三官能性アミノ酸残基である請求項1または2に記載のヘパリン結合成長因子類似体。
- ヘパリン結合成長因子類似体は、合成ヘパリン結合成長因子類似体が、0.15M NaCl中でヘパリンを結合するが、しかし1M NaClによって溶出されるようにヘパリンについての結合活性を示す請求項1または2に記載のヘパリン結合成長因子類似体。
- 基本的に、式(I)の分子から構成される請求項1または2に記載のヘパリン結合成長因子類似体。
- 式(I)の分子から構成される請求項1または2に記載の合成ヘパリン結合成長因子類似体。
-
式II
R3およびR5は、各々独立に、NH2;N末端NH2、NH3 +、NH基あるいは対応するアシル化誘導体を含む、線状または分岐C1からC17までのアルキル、アリール、ヘテロアリール、アルケン、アルケニルまたはアラルキル鎖を有するアシル基であるか、またはN末端NH2、NH3 +、NH基あるいは対応するアシル化誘導体を有するアミノ酸、ジペプチドまたはトリペプチドである;
R4は、−OH、NH2、NH−R6であるか、またはC末端−OH、NH2、またはNH−R6を有するアミノ酸、ジペプチドまたはトリペプチドである;
R6は、脂肪族C1からC17までの鎖である;
各Xは、(i)最小3個のアミノ酸残基を有し、(ii)最大約50個のアミノ酸残基を有し、そして(iii)ヘパリン結合成長因子レセプター(HBGFR)を結合するペプチド鎖である;
J1およびJ2は、各々独立に、三官能性アルファアミノ酸残基であり、各Xは、J1およびJ2の側鎖を通して共有結合で結合される;
Yは、n=0である場合、J1およびZに、あるいはn=1である場合、J2およびZに共有結合で結合された0から約50個までの原子の鎖を包含するリンカーである;
Zは、ヘパリン結合ドメインを包含する非シグナル発生ペプチドであり、そして(i)最小1個のヘパリン結合モチーフ、(ii)最大約10個のヘパリン結合モチーフ、および(iii)最大約30個のアミノ酸を包含するアミノ酸配列を包含する;そして
nは、0または1であり、n=1の場合、合成ペプチド鎖Xは同一である、
式IIで表されるヘパリン結合成長因子(HBGF)類似体。 - XおよびZは、合成ペプチド鎖である請求項8に記載のヘパリン結合成長因子類似体。
- 合成ヘパリン結合成長因子類似体である請求項9に記載のヘパリン結合成長因子類似体。
- Yは、さらに、(i)疎水性であり、(ii)最小約9個および最大約50個の原子の鎖を包含し、そして(iii)Xが結合するヘパリン結合成長因子レセプター(HBGFR)の天然のリガンドには見られないリンカーを包含する、請求項8、9または10に記載のヘパリン結合成長因子類似体。
- ヘパリン結合成長因子類似体は、ヘパリン結合成長因子類似体が、0.15M NaCl中でヘパリンを結合するが、1M NaClによって溶出されるようにヘパリンについての結合活性を示す、請求項8、9または10に記載のヘパリン結合成長因子類似体。
- ヘパリン結合成長因子レセプターへのヘパリン結合成長因子類似体の結合が、ヘパリン結合成長因子レセプターによりシグナルを発生させる請求項8、9または10に記載のヘパリン結合成長因子類似体。
- ヘパリン結合成長因子レセプターへのヘパリン結合成長因子類似体の結合が、ヘパリン結合成長因子レセプターによりシグナル発生を阻止する請求項8、9または10に記載のヘパリン結合成長因子類似体。
- J1および、n=1の場合には、J2は、ジアミンアミノ酸残基である請求項8、9または10に記載のヘパリン結合成長因子類似体。
- ジアミンアミノ酸残基は、2,3ジアミノプロピオニルアミノ酸残基である請求項15に記載のヘパリン結合成長因子類似体。
- ジアミンアミノ酸残基は、リシンである請求項15に記載のヘパリン結合成長因子類似体。
- ジアミンアミノ酸残基は、オルニチンである請求項15に記載のヘパリン結合成長因子類似体。
- XとJ1または、n=1の場合には、J2との間の共有結合は、ペプチド、ジスルフィド、チオエーテル、シッフ塩基、還元シッフ塩基、イミド、二級アミン、カルボニル、尿素、ヒドラゾンまたはオキシム結合を包含する請求項8、9または10に記載のヘパリン結合成長因子類似体。
- J1および、n=1の場合には、J2の側鎖は、反応性カルボキシル基を含む請求項8、9または10に記載のヘパリン結合成長因子類似体。
- pは、5であり、qは、3であり、Zは、配列番号:2、配列番号:3、配列番号:4または配列番号:5であり、そしてXは、配列番号:6、配列番号:7、配列番号:8、配列番号:9、配列番号:10、配列番号:11、配列番号:12、配列番号:13、配列番号:14、配列番号:15、配列番号:16、配列番号:17、配列番号:18、配列番号:18、配列番号:19、配列番号:20または配列番号:21である請求項22に記載のヘパリン結合成長因子類似体。
- ペプチド鎖Xは、最小およそ5個のアミノ酸残基を有する請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体。
- ペプチド鎖Xは、最小およそ9個のアミノ酸残基を有する請求項24に記載のヘパリン結合成長因子類似体。
- ペプチド鎖Xは、最大およそ33個のアミノ酸残基を有する請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体。
- ペプチド鎖Xは、ヘパリン結合成長因子で見出されるアミノ酸配列を包含する請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体。
- ヘパリン結合成長因子は、ホルモン、サイトカイン、リンホカイン、キモカインまたはインターロイキンである請求項27に記載のヘパリン結合成長因子類似体。
- Xは、FGF−1、FGF−2、FGF−3、FGF−4、FGF−5、FGF−6、FGF−7、FGF−8、FGF−9、FGF−10、FGF−11、FGF−12、FGF−13、FGF−14、FGF−15、FGF−16、FGF−17、FGF−18、FGF−19、FGF−20、FGF−21、FGF−22、FGF−23、HBBM(ヘパリン結合脳分裂促進剤)、HB−GAF(ヘパリン結合成長関連因子)、HB−EGF(ヘパリン結合EGF様因子)、HB−GAM(ヘパリン結合成長関連分子;プレイオトロフィン、PTN、HARPとしても知られる)、TGF−α(形質転換成長因子−α)、TGF−β(形質転換成長因子−β)、VEGF(脈管内皮成長因子)、EGF(表皮成長因子)、IGF−1(インスリン様成長因子−1)、IGF−2(インスリン様成長因子−2)、PDGF(血小板由来成長因子)、RANTES、SDF−1、分泌フリーズルド関連タンパク質−1(SFRP−1)、小型誘導性サイトカインA3(SCYA3)、誘導性サイトカイン・サブファミリーAメンバー20(SCYA20)、誘導性サイトカイン・サブファミリーBメンバー14(SCYB14)、誘導性サイトカイン・サブファミリーDメンバー1(SCYD1)、支質細胞由来因子−1(SDF−1)、トロンボスポンジン1、2、3および4(THBS1−4)、血小板因子4(PF4)、水晶体上皮由来成長因子(LEDGF)、ミディカイン(MK)、マクロファージ炎症性タンパク質(MIP−1)、モエシン(MSN)、肝細胞成長因子(HGF;SFとも称される)、胎盤成長因子、IL−1(インターロイキン−1)、IL−2(インターロイキン−2)、IL−3(インターロイキン−3)、IL−6(インターロイキン−6)、IL−7(インターロイキン−7)、IL−10(インターロイキン−10)、IL−12(インターロイキン−12)、IFN−α(インターフェロン−α)、IFN−γ(インターフェロン−γ)、TNF−α(腫瘍壊死因子−α)、SDGF(神経鞘腫由来成長因子)、神経成長因子、軸索成長促進因子2(NEGF2)、ニュートロフィン、BMP−2(骨形態発生タンパク質2)、OP−1(骨形成タンパク質1;BMP−7とも称される)、ケラチノサイト成長因子(KGF)、インターフェロン−γ誘導性タンパク質−20、RANTES、およびHIV−tat−相互作用因子、アンフィレグリン(AREG)、脈管関連移行細胞タンパク質(AAMP)、アンギオスタチン、ベータセルリン(BTC)、結合組織成長因子(CTGF)、システイン富脈管形成インデューサー61(CYCR61)、エンドスタチン、フラクタルカイン/ニューロアクチン、神経膠由来神経栄養因子(GDNF)、GRO2、肝癌由来成長因子(HDGF)、および顆粒球マクロファージコロニー刺激因子(GMCSF)のいずれかに見られるアミノ酸配列を包含する請求項29に記載のヘパリン結合成長因子類似体。
- Xは、繊維芽細胞成長因子(FGF)で見られるアミノ酸配列を包含する請求項29に記載のヘパリン結合成長因子類似体。
- ペプチド鎖Xは、天然のヘパリン結合成長因子レセプターリガンドで見られないアミノ酸配列を包含する請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体。
- ヘパリン結合成長因子類似体が、FGFレセプターを結合する請求項31に記載のヘパリン結合成長因子類似体。
- ヘパリン結合成長因子類似体が、ヘパリン結合成長因子レセプターのアゴニストである請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体。
- ヘパリン結合成長因子類似体が、ヘパリン結合成長因子レセプターのアンタゴニストである請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体。
- ヘパリン結合成長因子類似体が、ヘパリン結合成長因子に対する生物学的反応の正の修飾因子である請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体。
- ヘパリン結合成長因子類似体が、ヘパリン結合成長因子に対する生物学的反応の負の修飾因子である請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体。
- ペプチド鎖Xが、架橋または環化されている請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体。
- ペプチド鎖Xが、少なくとも1つのジスルフィド、ペプチド、またはチオエーテル結合によって架橋または環化される請求項37に記載のヘパリン結合成長因子類似体。
- Yが、1個と約33個の間のエチレングリコール単位を包含する請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体。
- Yは、1個と約20個の間の炭素原子の分岐または未分岐、飽和または不飽和アルキル鎖を包含する請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体。
- Yは、pは、1から約10までであり、そしてqは、1から約20までである、[NH2−(CH2)pCO]qを包含する請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体。
- Yは、1から約16個のGly残基を包含するペプチド配列を含む請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体。
- Zの各ヘパリン結合モチーフは、各Bは、独立に、リシン、アルギニン、オルニチン、またはヒスチジンであり、そしてxは、天然に生じるアミノ酸である、BxBB、またはBBBxxBである請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体。
- Zは、少なくとも2個のヘパリン結合モチーフを含む請求項43に記載のヘパリン結合成長因子類似体。
- Zは、少なくとも5個のヘパリン結合モチーフを含む請求項43に記載のヘパリン結合成長因子類似体。
- 請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体、またはその医薬上許容しうる塩、および医薬上の担体を包含する医薬組成物。
- 哺乳類に、有効用量の請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体を投与することを包含する、有害用量の照射または化学療法剤にさらされる哺乳類を処置する方法。
- 哺乳類に、有効用量の請求項1、2、3、8、9、10、21または22に記載のXは、FGFレセプターを結合する、ヘパリン結合成長因子類似体を投与することを包含する、有害用量の照射または化学療法剤にさらされる哺乳類を処置する方法。
- 照射または化学療法剤の投与量が、粘膜炎、胃腸症候群、または放射線壊死を引起すのに十分である請求項47または48に記載の方法。
- FGFレセプターが、FGF−7レセプターである請求項48に記載の方法。
- 細胞を、有効用量の請求項1、2、3、8、9、10、21または22に記載のヘパリン結合成長因子類似体に接触させることを包含する、細胞中で成長因子レセプターシグナル発生を刺激する方法。
- シグナル発生が、細胞の増殖を刺激する請求項51に記載の方法。
- 細胞が、哺乳類の一部である請求項52に記載の方法。
- 非共有結合を介して、請求項1、2、3、8、9、10、21または22に記載の合成ヘパリン結合成長因子類似体をその表面に、被覆した医療用デバイスを供し、そして
哺乳類の表面上に医療用デバイスを乗せるか、またはその中に医療用デバイスを移植することを包含する、活性ヘパリン結合成長因子類似体を哺乳類に送出する方法。 - 医療用デバイスは、縫合糸、移植片材料、外傷被覆材、神経ガイド、骨ワックス、動脈瘤コイル、塞栓形成粒子、微細ビーズ、ステント、歯科移植片、または骨プロテーゼ、組織足場、または徐放性薬剤送出デバイスである請求項54に記載の方法。
- 非共有結合は、合成ヘパリン結合成長因子類似体のヘパリン結合ドメインと、医療用デバイスの表面に結合したヘパリン含有化合物の間の結合である請求項54に記載の方法。
- ヘパリン含有化合物は、ベンジル−ビス(ジメチルシリルメチル)オキシカルバモイル−ヘパリンである請求項56に記載の方法。
- 医療用デバイスの表面は、ステンレス鋼、チタン、プラチナ、タングステン、セラミックス、ポリウレタン、ポリテトラフルオロエチレン、伸縮ポリテトラフルオロエチレン、ポリカーボネート、ポリエステル、ポリプロピレン、ポリエチレン、ポリスチレン、ポリ塩化ビニル、ポリアミド、ポリアクリレート、ポリウレタン、ポリビニルアルコール、ポリカプロラクトン、ポリラクチド、ポリグリコライド、ポリシロキサン、天然ゴム、人工ゴム、ブロック重合体またはブロック重合体の共重合体である請求項54に記載の方法。
- ポリシロキサンが、2,4,6,8−テトラメチルシクロテトラシロキサンである請求項58に記載の方法。
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JP4895826B2 (ja) * | 2004-02-20 | 2012-03-14 | バイオサーフェス エンジニアリング テクノロジーズ,インク. | 骨形成蛋白−2の正のモジュレーター |
JP2008531505A (ja) * | 2005-02-22 | 2008-08-14 | バイオサーフェス エンジニアリング テクノロジーズ,インク. | 単一分岐ヘパリン結合増殖因子類似体 |
JP4897708B2 (ja) * | 2005-02-22 | 2012-03-14 | バイオサーフェス エンジニアリング テクノロジーズ,インク. | 単一分岐ヘパリン結合増殖因子類似体 |
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US7700563B2 (en) | 2010-04-20 |
JP4712383B2 (ja) | 2011-06-29 |
JP5346911B2 (ja) | 2013-11-20 |
US20040038348A1 (en) | 2004-02-26 |
US20040087505A1 (en) | 2004-05-06 |
JP2011078806A (ja) | 2011-04-21 |
US7166574B2 (en) | 2007-01-23 |
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