WO1997011718A1 - Inhibitors of integrin receptors and their therapeutical uses - Google Patents

Inhibitors of integrin receptors and their therapeutical uses Download PDF

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Publication number
WO1997011718A1
WO1997011718A1 PCT/GB1996/002366 GB9602366W WO9711718A1 WO 1997011718 A1 WO1997011718 A1 WO 1997011718A1 GB 9602366 W GB9602366 W GB 9602366W WO 9711718 A1 WO9711718 A1 WO 9711718A1
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Prior art keywords
inhibitor
activation
integrin receptor
healing
receptor
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Application number
PCT/GB1996/002366
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French (fr)
Inventor
Mark William James Ferguson
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The Victoria University Of Manchester
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Publication date
Application filed by The Victoria University Of Manchester filed Critical The Victoria University Of Manchester
Priority to AU70901/96A priority Critical patent/AU7090196A/en
Priority to JP9513215A priority patent/JPH11511478A/en
Priority to EP96931895A priority patent/EP0852504A1/en
Publication of WO1997011718A1 publication Critical patent/WO1997011718A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/06—Tripeptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/39—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin, cold insoluble globulin [CIG]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/02—Drugs for dermatological disorders for treating wounds, ulcers, burns, scars, keloids, or the like
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/04—Drugs for skeletal disorders for non-specific disorders of the connective tissue
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2839—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily
    • C07K16/2848—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the integrin superfamily against integrin beta3-subunit-containing molecules, e.g. CD41, CD51, CD61

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Immunology (AREA)
  • Veterinary Medicine (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Genetics & Genomics (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Dermatology (AREA)
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  • Physical Education & Sports Medicine (AREA)
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Abstract

The present invention concerns inhibitors of activation of at least one integrin receptor for use in promoting the healing of wounds or fibrotic disorders with reduced scarring. Also provided are methods for promoting the healing of wounds or fibrotic disorders with reduced scarring, comprising inhibiting the activation of at least one integrin receptor.

Description

INHIBITORS OF INTEGRIN RECEPTORS AND THEIR THERAPEUTICAL USES
The present invention concerns inhibitors of at least one integrin receptor for use in promoting the healing of wounds or fibrotic disorders, in particular for promoting the healing of wounds or fibrotic disorders with reduced scarring, and for use in promoting the healing of chronic wounds.
By "wounds or fibrotic disorders" is meant any condition which may result in the formation of scar tissue. In particular, this includes the healing of skin wounds, the repair of tendon damage, the healing of crush injuries, the healing of wounds to the eye, including wounds to the cornea, the healing of central nervous system (CNS) injuries, conditions which result in the formation of scar tissue in the CNS, scar tissue formation resulting from strokes, and tissue adhesion, for example, as a result of injury or surgery (this may apply to e.g. tendon healing and abdominal strictures and adhesions). Examples of fibrotic disorders include pulmonary fibrosis, glomerulonephritis, cirrhosis of the liver, systemic sclerosis, scleroderma and proliferative vitreoretinopathy.
In particular, there is a lack of compositions for promoting the healing of wounds or fibrotic disorders with reduced scarring. Scar tissue formation, although providing mechanical strength to a healed wound, can be unsightly and may impair the function ofthe tissue.
This is particularly the case in wounds which result in scar tissue formation in the CNS, the scar tissue inhibiting the reconnection of severed or re-growing nerve ends, so significantly affecting their function.
There is also a lack of compositions for use in the treatment of chronic wounds, for example venous ulcers, diabetic ulcers and bed sores (decubitus ulcers), especially in the elderly and wheel chair bound patients. Such compositions may be extremely useful in patients where wound healing is either slow or in whom the wound healing process has not yet started. Such compositions may be used to "kick-start" wound healing and may then be used in combination with compositions (e.g. those of PCT/GB92/00570 and PCT/GB93/00586) which promote the healing of wounds or fibrotic disorders with reduced scarring. Hence not only may a chronic wound be healed, but it may be healed with reduced scarring.
According to the present invention there is provided an inhibitor of activation of at least one integrin receptor for use in promoting the healing of wounds or fibrotic disorders with reduced scarring
Integrins perform various roles at a site of wounding or fibrotic disorder (a "site"). They are involved in the binding of growth factors at the site to e.g. platelets embedded in fibrin clots and are also used by fibroblasts to migrate to the site of the wound. Integrins affect both fibrotic and non-fibrotic growth factors and so it would be supposed that by affecting integrins in general there would not be a beneficial effect upon healing.
The profile of growth factors at a site during the healing process varies over time. Initially, fibrotic growth factors predominate, in paricular fibrotic TGF-β, as it is released upon platelet degranulation at initial wounding.
The various members ofthe TGF-β family are present at the site in various forms - free-TGF-β (which is in its active form), the TGF-β-LAP (TGF-β-latency associated peptide) complex, which is endocytosed by cells (via the M-6-P receptor) and which also binds via the RGD site in the LAP to the integrin receptor gpIIb/IIIa on the active platelet surface, and the TGF-β-LAP-LTBP (TGF-β-LAP-latent TGF-β binding protein) complex which masks the RGD-peptide binding site on the LAP and so circulates in the serum but also binds to extracellular matrix molecules. This mechanism provides for a slow release of TGF-β, from the fibrin clot to promote wound healing.
Over time, the profile of TGF-β changes in favour of the non- fibrotic TGF-β3 as fibroblasts migrate into the provisional wound matrix using integrin receptors which bind to ECM (extracellular matrix) molecules and release TGF-β3.
By inhibiting the activation of integin receptors, the present inventor has found that, surprisingly, inhibitors of integrin receptor activation may be used to promote healing with reduced scarring.
The inhibitor may bind to at least one receptor but not activate it.
The inhibitor may comprise an antibody. It may comprise a neutralising antibody. The antibody may bind specifically to at least one integrin receptor. It may bind specifically to the RGD recognition peptide or an analogue thereof.
The inhibitor may comprise at least the RGD peptide or an analogue thereof.
The inhibitor may be any form of inhibitor which inhibits the activation of at least one integrin receptor. It may, for example, be a neutralising antibody specific to the RGD recognition site of integrins, it may be a neutralising antibody specific to the integrin receptor, or it may contain the RGD peptide or an analogue (e.g. a RGDS peptide or a mimotope of RGD - see for example Geysen, H.M. et al, 1987, Journal of Immunological Methods, \QZ: 259-274) thereof which will bind to the integrin receptor and prevent the natural ligand from binding to it. A receptor may be the GpIIb/IIIa platelet receptor. Hence an inhibitor may be any form ofa GpIIb/IIIa platelet receptor inhibitor including existing pharmaceutical compounds. The inhibitor may also comprise an RGD peptide or an analogue thereof. Hence a double effect may be achieved by the present invention using a Gp Ilb/IIIa inhibitor containing an RGD peptide or an analogue thereof which binds to integrin receptors (e.g. on platelets) and prevents RGD-containing LAP-TGF-β, complexes from binding to them, and also prevents the platelet release reaction, thereby reducing the quantity of fibrotic TGF-β! at the wound site.
The inhibitor may inhibit the binding of TGF-β, and/or platelets or leucocytes to fibrin and/or fibrinogen and/or fibronectin. It may for example be a fibrinogen receptor antagonist.
The inhibitor of activation of at least one integrin receptor may be used in a quantity sufficient to inhibit, or to substantially inhibit, the activation of the integrin receptor, i.e. an activity inhibiting amount ofthe inhibitor may be used.
The inhibitor of activation of at least one integrin receptor may be used in conjunction with an inhibitor of platelet activation and/or degranulation.
The inhibitor of activation of at least one integrin receptor may be used in conjunction with a pharmaceutically acceptable carrier, diluent or excipient.
The inhibitor of activation of at least one integrin receptor may be used in conjunction with a composition for promoting the healing of wounds or fibrotic disorders with reduced scarring.
The inhibitor of activation of at least one integrin receptor may be used in conjunction with a composition for promoting the healing of chronic wounds. Also provided according to the present invention is a method for promoting the healing of wounds and fibrotic disorders comprising inhibiting the activation of at least one integrin receptor.
The inhibition may be achieved by administering to a site an inhibitor of the activation of at least one integrin receptor. The inhibitor may be an inhibitor of activation of at least one integrin receptor according to the present invention.
The integrin may be inhibited immediately prior to wounding/onset (by "onset" is meant the onset of a fibrotic disorder). It may be inhibited immediately after wounding onset, although it may also be inhibited later, for example within 12, 24, 48, 72, 96 or 120 hours of wounding/onset.
The efficacy of the present invention is significantly enhanced by the inhibition of integrins either immediately before or just after wounding/onset. As described above, the profile of TGF-β at the wound site changes over time, initially favouring fibrotic TGF-βs upon platelet degranulation and the release of TGF-β ,, and later favouring non-fibrotic TGF-β as fibroblasts migrate to the site and release TGF-β3. By inhibiting integrins primarily at the time when they are being used by predominantly fibrotic TGF-β-LAP to bind to platelets in the fibrin clots, the subsequent release of fibrotic TGF-β may be significantly reduced and hence even more reduced scarring may be achieved.
The method may be used in conjunction with a method for promoting the healing of wounds or fibrotic disorders with reduced scarring.
The method may be used in conjunction with a method for promoting the healing of chronic wounds. The invention will be further apparent from the following examples which show, by way of example only, forms of promotion of healing of wounds or fibrotic disorders with reduced scarring.
Example 1
An activity-inhibiting amount of neutralising anti-RGD antibody is applied to a site of wounding immediately prior to an incisional wound being made.
Example 2
An acitivity-inhibiting amount of an RGD peptide is applied to a site of wounding immediately after wounding has occurred.
Example 3
An activity-inhibiting amount of neutralising antibody specific to the GpIIa/III platelet receptor is applied to a site of wounding immediately before and after wounding has occurred.
Example 4
An acivity-inhibiting amount of an anti-RGD antibody is applied to a site of fibrosis.

Claims

1. An inhibitor of activation of at least one integrin receptor for use in promoting the healing of wounds or fibrotic disorders with reduced scarring.
2. An inhibitor of activation of at least one integrin receptor according to claim 1 wherein it binds to at least one receptor but does not activate it.
3. An inhibitor of activation of at least one integrin receptor according to either one of claims 1 or 2, comprising an antibody.
4. An inhibitor of activation of at least one integrin receptor according to claim 3, comprising a neutralising antibody.
5. An inhibitor of activation of at least one integrin receptor according to either one of claims 3 or 4 wherein the antibody binds specifically to at least one integrin receptor.
6. An inhibitor of activation of at least one integrin receptor according to either one of claims 3 or 4 wherein it binds specifically to the RGD peptide or an analogue thereof.
7. An inhibitor of activation of at least one integrin receptor according to either one of claims 1 or 2 wherein it comprises at least the RGD peptide or an analogue thereof.
8. An inhibitor of activation of at least one integrin receptor according to any one ofthe preceding claims wherein a receptor is the GpIIb/IIIa platelet receptor.
9. An inhibitor of activation of at least one integrin receptor according to claim 8 wherein it comprises a GpIIb/IIIa platelet receptor inhibitor.
10. An inhibitor of activation of at least one integrin receptor according to claim 9 wherein the GpIIb/IIIa platelet receptor inhibitor also comprises an RGD peptide or an analogue thereof.
11. An inhibitor of activation of at least one integrin receptor according to any one of the preceding claims wherein a receptor is the fibrinogen receptor.
12. An inhibitor of activation of at least one integrin receptor according to any one ofthe preceding claims wherein it inhibits the binding of TGF-β, and/or platelets or leucocytes to fibrin and/or fibrinogen and/or fibronectin.
13. An inhibitor of activation of at least one integrin receptor according to any one ofthe preceding claims wherein it is an inhibitor of platelet activation and/or degranulation.
14. An inhibitor of activation of at least one integrin receptor according to any one ofthe preceding claims for use in conjunction with a pharmaceutically acceptable carrier, diluent or excipient.
15. An inhibitor of activation of at least one integrin receptor according to any one of the preceding claims for use in conjunction with a composition for promoting the healing of wounds or fibrotic disorders with reduced scarring.
16. An inhibitor of activation of at least one integrin receptor according to any one ofthe preceding claims for use in conjunction with a composition for promoting the healing of chronic wounds.
17. A method for promoting the healing of wounds or fibroic disorders with reduced scarring comprising inhibiting the activation of at least one integrin receptor.
18. A method according to claim 17 comprising administering to a site an inhibitor ofthe activation of at least one integrin receptor.
19. A method according to claim 18 wherein it comprises administering an inhibitor of activation of at least one integrin receptor according to any one of claims 1-15.
20. A method according to any one of claims 17-19 wherein the activation ofthe integrin receptor is inhibited either immediately prior to or immediately after onset.
21. A method according to any one of claims 17-20 for use in conjunction with a method for promoting the healing of wounds or fibrotic disorders with reduced scarring.
22. A method according to any one of claims 17-21 for use in conjunction with a method or composition for promoting the healing of chronic wounds.
PCT/GB1996/002366 1995-09-27 1996-09-25 Inhibitors of integrin receptors and their therapeutical uses WO1997011718A1 (en)

Priority Applications (3)

Application Number Priority Date Filing Date Title
AU70901/96A AU7090196A (en) 1995-09-27 1996-09-25 Inhibitors of integrin receptors and their therapeutical uses
JP9513215A JPH11511478A (en) 1995-09-27 1996-09-25 Integrin receptor inhibitors and their therapeutic use
EP96931895A EP0852504A1 (en) 1995-09-27 1996-09-25 Inhibitors of integrin receptors and their therapeutical uses

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GBGB9519667.1A GB9519667D0 (en) 1995-09-27 1995-09-27 Pharmaceutical composition
GB9519667.1 1995-09-27

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JP (1) JPH11511478A (en)
AU (1) AU7090196A (en)
CA (1) CA2233138A1 (en)
GB (1) GB9519667D0 (en)
WO (1) WO1997011718A1 (en)
ZA (1) ZA968081B (en)

Cited By (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999061040A2 (en) * 1998-05-22 1999-12-02 Boys Town National Research Hospital USE OF α1β1 INTEGRIN RECEPTOR INHIBITORS AND TGF-β1 INHIBITORS IN THE TREATMENT OF KIDNEY DISEASE
WO2000064474A1 (en) * 1999-04-22 2000-11-02 Biogen, Inc. Method for the treatment of fibrosis using an antagonist of the integrin alpha-4 subunit
US6486174B2 (en) 2000-08-07 2002-11-26 3-Dimensional Pharmaceuticals, Inc. Tetrahydroisoquinoline-3-carboxylic acid alkoxyguanidines as integrin antagonists
US6492325B1 (en) 1998-05-22 2002-12-10 Boys Town National Research Hospital Use of α1β1 integrin receptor inhibitors and TGF-β1 inhibitors in the treatment of kidney disease
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
EP2075258A1 (en) * 2006-10-26 2009-07-01 Gene Techno Science Co., Ltd. Antibody against rgd in amino acid sequence of extracellular matrix protein and production method and use of the same
US8084031B2 (en) 1999-06-01 2011-12-27 Biogen Idec Ma Inc. Method for the treatment of inflammatory disorders
US8084028B2 (en) 2001-04-13 2011-12-27 Biogen Idec Ma Inc. Antibodies to VLA-1
US8563690B2 (en) 2008-11-03 2013-10-22 The Board Of Trustees Of The University Of Illinois Modulation of platelet aggregation
US8614296B2 (en) 2008-04-24 2013-12-24 Gene Techno Science Co., Ltd. Humanized antibodies specific for amino acid sequence RGD of an extracellular matrix protein and the uses thereof
US8617829B2 (en) 2009-09-24 2013-12-31 Gene Techno Science Co., Ltd. Humanized antibodies specific for amino acid sequence RGD of an extracellular matrix protein and the uses thereof
US20140134192A1 (en) * 2010-12-21 2014-05-15 Leidos, Inc. Methods and Compositions For Wound Treatment
WO2015039020A1 (en) * 2013-09-15 2015-03-19 The Johns Hopkins University Integrin-modulating therapies for treating fibrotic disease
US10119979B2 (en) 2006-05-25 2018-11-06 Biogen Ma Inc. Methods of treating stroke and traumatic brain injury using humanized AQC2 anti-VLA-1 antibodies
US10160808B2 (en) 2012-02-16 2018-12-25 Santarus, Inc. Anti-VLA1 (CD49A) antibody pharmaceutical compositions

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Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999061040A2 (en) * 1998-05-22 1999-12-02 Boys Town National Research Hospital USE OF α1β1 INTEGRIN RECEPTOR INHIBITORS AND TGF-β1 INHIBITORS IN THE TREATMENT OF KIDNEY DISEASE
WO1999061040A3 (en) * 1998-05-22 2000-01-27 Boys Town National Research Ho USE OF α1β1 INTEGRIN RECEPTOR INHIBITORS AND TGF-β1 INHIBITORS IN THE TREATMENT OF KIDNEY DISEASE
JP2002516287A (en) * 1998-05-22 2002-06-04 ボーイズ タウン ナショナル リサーチ ホスピタル Use of α1β1 integrin receptor inhibitor and IGF-β1 inhibitor in the treatment of kidney disease
US6492325B1 (en) 1998-05-22 2002-12-10 Boys Town National Research Hospital Use of α1β1 integrin receptor inhibitors and TGF-β1 inhibitors in the treatment of kidney disease
AU761928B2 (en) * 1998-05-22 2003-06-12 Boys Town National Research Hospital Use of alpha1beta1 integrin receptor inhibitors and TGF-beta1 inhibitors in the treatment of kidney disease
SG117434A1 (en) * 1998-05-22 2005-12-29 Boys Town Nat Res Hospital Use of alpha1beta1 integrin receptor inhibitors and tgf-beta1 inhibitors in the treatment of kidney disease
US6833373B1 (en) 1998-12-23 2004-12-21 G.D. Searle & Co. Method of using an integrin antagonist and one or more antineoplastic agents as a combination therapy in the treatment of neoplasia
WO2000064474A1 (en) * 1999-04-22 2000-11-02 Biogen, Inc. Method for the treatment of fibrosis using an antagonist of the integrin alpha-4 subunit
CZ301636B6 (en) * 1999-04-22 2010-05-12 Biogen Idec Ma Inc. Pharmaceutical composition for treating fibrosis containing composition comprising antibody homologue antagonizing interaction of integrin alpha-4 subunit with said integrin ligand
US6652856B2 (en) 1999-04-22 2003-11-25 Biogen, Inc. Method for the treatment of fibrosis
AU783054B2 (en) * 1999-04-22 2005-09-22 Biogen Ma Inc. Method for the treatment of fibrosis using an antagonist of the integrin alpha-4 subunit
CN1332714C (en) * 1999-04-22 2007-08-22 比奥根艾迪克Ma公司 Method for treating fibrosis by utilizing integrin alpha 4 subunit antagonist
US9902774B2 (en) 1999-06-01 2018-02-27 Biogen Ma Inc. Method for the treatment of inflammatory disorders
US8557240B2 (en) 1999-06-01 2013-10-15 Biogen Idec Ma Inc. Method for the treatment of inflammatory disorders
US8084031B2 (en) 1999-06-01 2011-12-27 Biogen Idec Ma Inc. Method for the treatment of inflammatory disorders
US6486174B2 (en) 2000-08-07 2002-11-26 3-Dimensional Pharmaceuticals, Inc. Tetrahydroisoquinoline-3-carboxylic acid alkoxyguanidines as integrin antagonists
US8084028B2 (en) 2001-04-13 2011-12-27 Biogen Idec Ma Inc. Antibodies to VLA-1
US9644030B2 (en) 2001-04-13 2017-05-09 Biogen Ma Inc. Antibodies to VLA-1
US10119979B2 (en) 2006-05-25 2018-11-06 Biogen Ma Inc. Methods of treating stroke and traumatic brain injury using humanized AQC2 anti-VLA-1 antibodies
EP2075258A4 (en) * 2006-10-26 2010-08-04 Gene Techno Science Co Ltd Antibody against rgd in amino acid sequence of extracellular matrix protein and production method and use of the same
US8901280B2 (en) 2006-10-26 2014-12-02 Gene Techno Science Co., Ltd. Antibody against RGD in amino acid sequence of extracellular matrix protein and production method and use of the same
EP2075258A1 (en) * 2006-10-26 2009-07-01 Gene Techno Science Co., Ltd. Antibody against rgd in amino acid sequence of extracellular matrix protein and production method and use of the same
US8614296B2 (en) 2008-04-24 2013-12-24 Gene Techno Science Co., Ltd. Humanized antibodies specific for amino acid sequence RGD of an extracellular matrix protein and the uses thereof
US8563690B2 (en) 2008-11-03 2013-10-22 The Board Of Trustees Of The University Of Illinois Modulation of platelet aggregation
US8617829B2 (en) 2009-09-24 2013-12-31 Gene Techno Science Co., Ltd. Humanized antibodies specific for amino acid sequence RGD of an extracellular matrix protein and the uses thereof
US9387253B2 (en) 2010-12-21 2016-07-12 Leidos, Inc. Methods and compositions for wound treatment
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JPH11511478A (en) 1999-10-05
AU7090196A (en) 1997-04-17
EP0852504A1 (en) 1998-07-15
ZA968081B (en) 1998-03-26
GB9519667D0 (en) 1995-11-29
CA2233138A1 (en) 1997-04-03

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