WO1999013909A1 - Inhibiteurs de neovascularisation corneenne - Google Patents

Inhibiteurs de neovascularisation corneenne Download PDF

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Publication number
WO1999013909A1
WO1999013909A1 PCT/JP1998/004114 JP9804114W WO9913909A1 WO 1999013909 A1 WO1999013909 A1 WO 1999013909A1 JP 9804114 W JP9804114 W JP 9804114W WO 9913909 A1 WO9913909 A1 WO 9913909A1
Authority
WO
WIPO (PCT)
Prior art keywords
vegf
vpf
corneal
antibody
edema
Prior art date
Application number
PCT/JP1998/004114
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English (en)
Japanese (ja)
Inventor
Shigeru Yatoh
Yasushi Kawakami
Yukichi Okuda
Tadahiko Kozawa
Toshiaki Segawa
Original Assignee
Toagosei Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Toagosei Co., Ltd. filed Critical Toagosei Co., Ltd.
Publication of WO1999013909A1 publication Critical patent/WO1999013909A1/fr

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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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to vascular permeability factor (VPF) [also referred to as vascular endothelial cell growth factor (VEGF), and collectively referred to as “VEGF / VPF” in the present specification].
  • VPF vascular permeability factor
  • VEGF vascular endothelial cell growth factor
  • the present invention relates to an inhibitor, particularly to an agent that suppresses vascularization and corneal opacity and / or edema during corneal transplantation.
  • steroid and non-steroid anti-inflammatory drugs are used to prevent rejection during corneal transplantation.
  • both steroid and non-steroid anti-inflammatory drugs have significant problems.
  • steroid eye drops have a strong anti-inflammatory effect, but have serious side effects.
  • These side effects include exacerbation of infections, induction of infections, delayed wound healing, cataracts, glaucoma, and suppression of adrenal gland system function. When medication is stopped, rebound phenomena may cause exacerbation of inflammation.
  • Non-steroid anti-inflammatory drugs do not have as severe side effects as steroids, but have the disadvantage of being less effective.
  • immunosuppressive drugs that can be used to prevent rejection during corneal transplantation, and at present, corneal transplants have weak efficacy even for drugs that can be used for other organ transplants.
  • T lymphocyte function such as cyclosporin A and FK506
  • an anti-VEGF VPF antibody may prevent excessive angiogenesis in transplantation of cornea and other tissues (Japanese Patent Application Laid-Open No. Hei 8-520254).
  • Japanese Patent Application Laid-Open No. Hei 8-520254 Japanese Patent Application Laid-Open No. Hei 8-520254.
  • drugs must always be used with the visual function in mind, and it is necessary to confirm that not only vascularization during corneal transplantation is suppressed, but also opacity and edema of the transplanted cornea do not occur. Without it, usefulness or practicality cannot be recognized.
  • the present inventors have developed a practical corneal neovascularization inhibitor that not only suppresses keratitis and vascularization during corneal transplantation but also does not cause corneal opacity or edema.
  • the present invention was completed. Disclosure of the invention
  • the present invention relates to a corneal angiogenesis inhibitor comprising VEGF / VPF angulinist as an active ingredient.
  • the present inventors conducted a rat corneal transplantation experiment (Invest. Ophthalmol. Visual Sci., 26, 23 (1985)) using an anti-VEGFVPF antibody capable of neutralizing the activity of VEGFVPF, and As a result of finding that not only suppression of angiogenesis but also significant improvement in blood vessel size, edema, clarity, etc. as compared with the control group, the present invention was completed.
  • the VEGF / VPF antagonist is a substance having a function of inhibiting the function of VEGF / VPF having a specific cell growth promoting activity or a vascular permeability promoting activity on vascular endothelial cells, It may be in any form as long as it has the function, most commonly, an antibody acting on VEGF / VPF, or a part thereof, but is not limited thereto, for example, VEGF Inactive VEGF / VPF that inhibits the action of VGF / VPF, or a part thereof, impairs the function of VEGF / VPF receptor, such as vascular endothelial cell growth factor / vascular permeability factor receptor (eg, FLT or KDR And a part thereof, and an agent that suppresses VEGF / VPF production itself.
  • vascular endothelial cell growth factor / vascular permeability factor receptor eg, FLT or KDR And a part thereof, and an agent that suppresses VEGF / VPF
  • VEGF / VPF contains 121, 165, 189 or 206 amino acid residues There are four subtypes (see Masashi Shibuya, Clinical Immunity, 28 (6) 758-764 (1996)), but the antibody may be an antibody against any subgroup. Examples of the antibody include a mouse antibody and the like. However, it is desirable to use an antibody which has been treated to reduce side effects in administration to humans. For example, a mouse monoclonal antibody which has been chemically modified with a substance such as polyethylene glycol to reduce its antigenicity, a mouse-human chimeric antibody or a humanized antibody can be used. Furthermore, antibodies that have been degraded by enzymatic cleavage can also be used.
  • Examples of the chimeric antibody or humanized antibody include IgG type and IgA type, and examples of the IgG isotype include IgGl, IgG2, IgG3 and IgG4.
  • the chimeric antibody or humanized antibody is, for example, an anti-VEGFVPF mouse monoclonal antibody MV833 (neutralizing antibody) that neutralizes the proliferation of human umbilical cord vascular endothelial cells (HUVEC) by VEGFAHPF with the same neutralizing activity as an anti-VEGFVPF ⁇ sagi polyclonal antibody.
  • anti-VEGF / VPF monoclonal antibodies are commercially available from various companies, and any of them can be used in the present invention. Examples of commercially available products include R & D Systems, INC. And Austral Biologicals (USA). Mouse monoclonal antibody sold on the market.
  • the corneal angiogenesis inhibitor of the present invention is preferably parenterally, for example, instillation, It can be administered systemically or locally by vitreous injection, subcutaneous injection, intravenous injection, intramuscular injection, intraperitoneal injection, etc.
  • the pharmaceutical composition can be in the form of a kit together with at least one pharmaceutical carrier or diluent.
  • the dose of the corneal angiogenesis inhibitor of the present invention to humans varies depending on the disease state, age and administration method of the patient, but it is necessary to select an appropriate amount as appropriate.
  • 1 ⁇ : L 0 can be administered in the range of mg / kg, per body weight, administered as lg ⁇ lm g / patient in the topical administration, such as eye drops.
  • the corneal angiogenesis inhibitor of the present invention is not limited to these doses.
  • the corneal angiogenesis inhibitor of the present invention can be formulated according to a conventional method.
  • injectable preparations are prepared by dissolving purified VEGF / VPF antagonists in a solvent such as physiological saline or buffer, and adding an anti-adsorption agent such as Tween80, gelatin, or human serum albumin (HSA). ) Or lyophilized for reconstitution before use.
  • an excipient for freeze-drying for example, sugar alcohols such as mannitol and glucose and sugars can be used.
  • it can be used in the form of an ophthalmic solution, an ointment ointment, an emulsifier, or the like, or can be used as a lipo-microsphere to prolong the retention.
  • the angiogenesis accompanying corneal transplantation is suppressed, and the occurrence of opacity and edema of the transplanted cornea is suppressed. It is considered to suppress the activity and promote engraftment without causing rejection of the transplanted cornea, maintain transparency, and contribute to the healing of the transplanted cornea.
  • the animal experiment model in the following examples is considered to be a keratitis model, the VEGF / VPF angel It is contemplated that it could also be used to treat angiogenesis due to meningitis.
  • keratitis Diseases that cause such keratitis include Stevens-Johnson syndrome, diseases related to Stevens-Johnson syndrome, pemphigus ophthalmopathy, diseases related to ocular pemphigus, corneal erosion (alkali, acid, surfactant, These include various solvents, volatile gases, and various other cytotoxic agents), long-term contact lens wear, keratitis due to viral, bacterial, or fungal infections, keratitis due to foreign substances, keratitis due to allergies, etc. No. BRIEF DESCRIPTION OF THE FIGURES
  • FIG. 1 is a graph showing the clarity of the graft when an anti-VEGF / VPF antibody was instilled into a corneal transplant model rat.
  • FIG. 2 is a graph showing a range of new blood vessels when an anti-VEGF / VPF antibody was applied to a corneal transplant model rat.
  • FIG. 3 is a graph showing the size of new blood vessels when an anti-VEGF / VPF antibody was instilled into a corneal transplant model rat.
  • FIG. 4 is a graph showing the occurrence of edema in a graft when an anti-VEGF / VPF antibody was instilled into a corneal transplant model mouse.
  • FIG. 1 is a graph showing the clarity of the graft when an anti-VEGF / VPF antibody was instilled into a corneal transplant model rat.
  • FIG. 2 is a graph showing a range of new blood vessels when an anti-VEGF / VPF antibody was applied to a corneal transplant model rat.
  • FIG. 5 is a graph showing the determination of the range of neovascularization by an ophthalmologist on day 14 after instilling an anti-VEGF / VPF antibody into a corneal transplant model mouse.
  • FIG. 6 is a graph showing the determination of neovascular size by an ophthalmologist on day 14 after instilling anti-VEGF / VPF antibody into a horn transplant model rat.
  • FIG. 7 is a graph showing the determination of the occurrence of edema by an ophthalmologist on the 14th day after instilling an anti-VEGF / VPF antibody into a corneal transplant model rat.
  • FIG. 8 is a photomicrograph showing the state of the transplanted cornea on day 19 after instilling the egret immunoglobulin fraction into a corneal transplant model rat.
  • FIG. 9 is a microscopic photograph showing the condition of the transplanted cornea on day 19 when an anti-VEGF VPF antibody was applied to a corneal transplant model rat.
  • Reference Example 1 Preparation of GST-VEGF / VPF and preparation of anti-VEGF / VPF ⁇ Sagi polyclonal antibody
  • VEGF / VPF cDNA isolated from cultured cells of human origin was purified by glutathione-S-transferase (GST).
  • GST glutathione-S-transferase
  • Escherichia coli expressed as a fusion protein (GST-VEGF / VPF)
  • the IgG fraction was fractionated from the serum with increased antibody titer by DEAE chromatography.
  • the corneal transplanted rats were divided into three groups A to C by 10 rats.
  • group C the anti-VEGF / VPF ⁇ sagi polyclonal antibody prepared using the VEGF 121-GST (glutathione-S-transferase) fusion protein as the antigen in Reference Example 1 was used 5 times a day (5, 9, 13, and 17). , 22 o'clock) I instilled 10 1 for 10 days.
  • This antibody was used after diluting the immunoglobulin (IgG) fraction obtained in Reference Example 1 with a protein concentration of 14 mg / ml to 10-fold with physiological saline.
  • Group B was prepared by diluting the egret immunoglobulin fraction (DAKO Japan, 20 mg / ml) 10-fold with physiological saline, and then, as with the anti-VEGF VPF antibody, 10 ⁇ 1 / time, 5 times a day, It was instilled for 10 days.
  • Group A was performed using physiological saline in the same manner as the anti-VEGF / VPF antibody. '
  • the evaluation was based on the clarity of the transplanted cornea, the extent of angiogenesis and the size of the blood vessel, and the degree of edema.On the day of the transplant operation, 1, 2, 4, 6, 8, 11, 1, 12, 14, and 19 The eyes were photographed with a stereomicroscope and examined. Furthermore, on the 14th day of surgery, without informing the treatment group, the ophthalmologist was asked to randomly evaluate the extent of neovascularization, blood vessel size, and the degree of edema under a stereoscopic microscope.
  • the evaluation criteria for each evaluation are as follows: • Graft clarity
  • the area of neovessels on the cornea under a microscope was evaluated by percentage.
  • FIG. 2 Severe edema protruding at the edge From Figure 1, the clarity of group C (anti-VEGFVPF antibody-administered group) is more significant than that of group B ( ⁇ egan IgG-administered group) from day 4 to day 14. 4 to 12, it was shown to be significantly better than Group A (saline administration group). FIG. 2 shows that the range of angiogenesis in group C was significantly smaller than groups B and A on days 6-19.
  • FIG. 4 shows that the edema of the group C was significantly suppressed on the 6th to 19th days compared to the groups B and A.
  • Fig. 5 shows that the range of neovascularization in group C was 14 days, and that the range of neovascularization in group C was significantly narrower in group B and group A, as determined by the ophthalmologist. .
  • the ophthalmologist determined the size of the new blood vessel, and as a result, the thickness of the new blood vessel in the group C was significantly smaller than that in the groups ⁇ ⁇ ⁇ and ⁇ in 14 words.
  • the ophthalmologist determined that edema was present. The edema in group C was significantly more suppressed on day 14 than in groups B and A.
  • the rat was sacrificed, and the cornea-transplanted eyes were removed. After fixing the extracted eyeball, a section was prepared and subjected to pass staining. The results are shown in the photographs of FIGS.
  • the photograph in Fig. 8 shows the Egret immunoglobulin fraction.
  • the instillation and the photograph in Fig. 9 show the instillation of the anti-VEGF ⁇ sagi polyclonal antibody. It can be seen in Fig. 9 that the swelling of the transplanted cornea is clearly suppressed.
  • the anti-VEGF / VPF antibody has a function of neutralizing the action of VEGF / VPF, and during administration, it significantly suppresses angiogenesis occurring in the transplanted corneal slices, and at the same time, It was shown that corneal transplant rejection was suppressed by keeping the clarity of the sera good and preventing the occurrence of edema.
  • the administration of VEGF / VPF antagonists suppresses angiogenesis of a transplanted corneal piece, maintains the clarity of the graft well, and prevents the occurrence of edema. It can prevent corn transplantation rejection, and can also be used as a therapeutic agent for keratitis, and as a turbidity preventer or edema preventer for transplants.
  • the agent of the present invention can be used in combination with an immunosuppressant, an anti-inflammatory agent, an anti-cytokine agent and the like in order to further improve the angiogenesis inhibitory effect.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Ophthalmology & Optometry (AREA)
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Abstract

L'invention se rapporte à des inhibiteurs utiles de néovascularisation cornéenne qui sont capables non seulement d'inhiber la néovascularisation associée à une kératite ou à une greffe cornéenne mais également d'empêcher l'opacification de la cornée ou la formation d'oedème qui les accompagne. Ces inhibiteurs contiennent en tant qu'ingrédient actif des antagonistes de VEGF/VPF. Ces antagonistes de VEGF/VPF sont de préférence constitués d'un anticorps dirigé contre VEGF/VPF. Ces inhibiteurs peuvent également servir d'inhibiteurs d'opacification de la cornée ou de formation d'oedème et ils favorisent la prise des greffes.
PCT/JP1998/004114 1997-09-12 1998-09-11 Inhibiteurs de neovascularisation corneenne WO1999013909A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP9/267843 1997-09-12
JP9267843A JPH1180024A (ja) 1997-09-12 1997-09-12 角膜血管新生阻害剤

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Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001068053A3 (fr) * 2000-03-10 2002-08-29 Insite Vision Inc Procedes et compositions pour traiter et prevenir des affections ophtalmiques de la partie posterieure de l'oeil
WO2004106378A2 (fr) * 2003-05-28 2004-12-09 Regeneron Pharmaceuticals, Inc. Methode de traitement du rejet de greffon corneen
WO2006088650A2 (fr) * 2005-02-02 2006-08-24 Regeneron Pharmaceuticals, Inc. Methode de traitement de lesion oculaire par l'administration locale d'un inhibiteur de vegf
US7141607B1 (en) 2000-03-10 2006-11-28 Insite Vision Incorporated Methods and compositions for treating and inhibiting retinal neovascularization
WO2007038453A3 (fr) * 2005-09-26 2007-11-29 Advanced Ocular Systems Ltd Administration d'un agent pour l'amelioration de l'inflammation
US8404638B2 (en) 2005-03-25 2013-03-26 Regeneron Pharmaceuticals, Inc. Dimer VEGF antagonist formulations
US10501523B2 (en) 2014-07-18 2019-12-10 Sanofi IL-8 level based method of predicting the outcome of colon cancer treatment
US11033606B2 (en) 2011-04-26 2021-06-15 Sanofi Composition comprising aflibercept, folinic acid, 5-fluorouracil (5-FU) and irinotecan (FOLFIRI)
US11732024B2 (en) 2006-06-16 2023-08-22 Regeneron Pharmaceuticals, Inc. VEGF antagonist formulations suitable for intravitreal administration

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000040262A1 (fr) * 1999-01-05 2000-07-13 The Flinders University Of South Australia Nouveaux agents et methodes pour le traitement et le diagnostic de troubles oculaires
CN100591359C (zh) * 2000-12-19 2010-02-24 研究发展基金会 慢病毒载体介导的基因转移及其用途

Citations (1)

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WO1994010202A1 (fr) * 1992-10-28 1994-05-11 Genentech, Inc. Antagonistes du facteur de croissance des cellules endotheliales vasculaires

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WO1994010202A1 (fr) * 1992-10-28 1994-05-11 Genentech, Inc. Antagonistes du facteur de croissance des cellules endotheliales vasculaires

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YAMAGAMI S., SUZUKI Y., TSURU T.: "MULTIVARIATE ANALYSIS OF RISK FACTORS OF ALLOGRAFT REJECTION IN PENETRATING KERATOPLASTY.", JAPANESE JOURNAL OF OPHTHALMOLOGY., MARUZEN CO., LTD., TOKYO., JP, vol. 38., 1 January 1994 (1994-01-01), JP, pages 311 - 316., XP002917605, ISSN: 0021-5155 *
YOSHIDA S., ET AL.: "INVOLVEMENT OF INTERLEUKIN-8, VASCULAR ENDOTHELIAL GROWTH FACTOR, AND BASIC FIBROBLAST GROWTH FACTOR IN TUMOR NECROSIS FACTOR ALPHA-DEPENDENT ANGIOGENESIS.", MOLECULAR AND CELLULAR BIOLOGY., AMERICAN SOCIETY FOR MICROBIOLOGY, WASHINGTON., US, vol. 17., no. 07., 1 July 1997 (1997-07-01), US, pages 4015 - 4023., XP002917604, ISSN: 0270-7306 *

Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7141607B1 (en) 2000-03-10 2006-11-28 Insite Vision Incorporated Methods and compositions for treating and inhibiting retinal neovascularization
WO2001068053A3 (fr) * 2000-03-10 2002-08-29 Insite Vision Inc Procedes et compositions pour traiter et prevenir des affections ophtalmiques de la partie posterieure de l'oeil
AU2004242586C1 (en) * 2003-05-28 2011-02-24 Regeneron Pharmaceuticals, Inc. Method of treating corneal transplant rejection by using VEGF antagonists
WO2004106378A2 (fr) * 2003-05-28 2004-12-09 Regeneron Pharmaceuticals, Inc. Methode de traitement du rejet de greffon corneen
WO2004106378A3 (fr) * 2003-05-28 2005-05-19 Regeneron Pharma Methode de traitement du rejet de greffon corneen
US7300653B2 (en) 2003-05-28 2007-11-27 Regeneron Pharmaceuticals, Inc. Method of treating corneal transplant rejection
AU2004242586B2 (en) * 2003-05-28 2010-10-21 Regeneron Pharmaceuticals, Inc. Method of treating corneal transplant rejection by using VEGF antagonists
WO2006088650A2 (fr) * 2005-02-02 2006-08-24 Regeneron Pharmaceuticals, Inc. Methode de traitement de lesion oculaire par l'administration locale d'un inhibiteur de vegf
WO2006088650A3 (fr) * 2005-02-02 2006-11-30 Regeneron Pharma Methode de traitement de lesion oculaire par l'administration locale d'un inhibiteur de vegf
US7303748B2 (en) 2005-02-02 2007-12-04 Regeneron Pharmaceuticals, Inc. Method of treating eye injury with local administration of a VEGF inhibitor
US7531173B2 (en) 2005-02-02 2009-05-12 Regeneron Pharmaceuticals, Inc. Ophthalmic composition of a VEGF antagonist
US8404638B2 (en) 2005-03-25 2013-03-26 Regeneron Pharmaceuticals, Inc. Dimer VEGF antagonist formulations
US10406226B2 (en) 2005-03-25 2019-09-10 Regeneron Pharmaceuticals, Inc. Method of manufacturing VEGF antagonist fusion proteins
US8710004B2 (en) 2005-03-25 2014-04-29 Regeneron Pharmaceuticals, Inc. Stable liquid VEGF antagonist formulations
US8921316B2 (en) 2005-03-25 2014-12-30 Regeneron Pharmaceuticals, Inc. Stable liquid VEGF antagonist formulations
US9416167B2 (en) 2005-03-25 2016-08-16 Regeneron Pharmaceuticals, Inc. Stable liquid formulations of dimer VEGF antagonists
US9511140B2 (en) 2005-03-25 2016-12-06 Regeneron Pharmaceuticals, Inc. Stable VEGF antagonist formulations
US9636400B2 (en) 2005-03-25 2017-05-02 Regeneron Pharmaceuticals, Inc. VEGF specific fusion protein antagonist formulations
US11806398B2 (en) 2005-03-25 2023-11-07 Regeneron Pharmaceuticals, Inc. Citrate buffered VEGF antagonist formulations
US10857231B2 (en) 2005-03-25 2020-12-08 Regeneron Pharmaceuticals, Inc. Formulations of VEG antagonist fusion proteins and method of manufacturing them
WO2007038453A3 (fr) * 2005-09-26 2007-11-29 Advanced Ocular Systems Ltd Administration d'un agent pour l'amelioration de l'inflammation
US11732024B2 (en) 2006-06-16 2023-08-22 Regeneron Pharmaceuticals, Inc. VEGF antagonist formulations suitable for intravitreal administration
US11033606B2 (en) 2011-04-26 2021-06-15 Sanofi Composition comprising aflibercept, folinic acid, 5-fluorouracil (5-FU) and irinotecan (FOLFIRI)
US10501523B2 (en) 2014-07-18 2019-12-10 Sanofi IL-8 level based method of predicting the outcome of colon cancer treatment
US11208461B2 (en) 2014-07-18 2021-12-28 Sanofi Method for predicting the outcome of a treatment with aflibercept of a patient suspected to suffer from a cancer

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