WO1998022130A1 - UTILISATION LOCALE DE IL-1ra POUR LE TRAITEMENT DES REJETS DE GREFFONS CORNEENS ET D'AUTRES TROUBLES DE L'OEIL - Google Patents

UTILISATION LOCALE DE IL-1ra POUR LE TRAITEMENT DES REJETS DE GREFFONS CORNEENS ET D'AUTRES TROUBLES DE L'OEIL Download PDF

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Publication number
WO1998022130A1
WO1998022130A1 PCT/US1997/021393 US9721393W WO9822130A1 WO 1998022130 A1 WO1998022130 A1 WO 1998022130A1 US 9721393 W US9721393 W US 9721393W WO 9822130 A1 WO9822130 A1 WO 9822130A1
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therapeutic composition
interleukin
corneal
treatment
therapeutically effective
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PCT/US1997/021393
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English (en)
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WO1998022130A9 (fr
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M. Reza Dana
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The Schepens Eye Research Institute, Inc.
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Priority to JP52393498A priority Critical patent/JP2002514194A/ja
Priority to AU54527/98A priority patent/AU5452798A/en
Priority to CA002272073A priority patent/CA2272073A1/fr
Priority to EP97948458A priority patent/EP0944395A1/fr
Publication of WO1998022130A1 publication Critical patent/WO1998022130A1/fr
Publication of WO1998022130A9 publication Critical patent/WO1998022130A9/fr

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    • 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
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/20—Interleukins [IL]
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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

Definitions

  • This invention relates to the prophylaxis and treatment of corneal transplant rejection and other immune and inflammatory disorders of the eye and more particularly to a topical treatment therefor.
  • Corneal transplantation has emerged as the most common and successful form of solid tissue transplantation with over 40,000 cases performed in the United States alone (1) .
  • the 2 -year survival rate is over 90% (2) .
  • the extraordinary success of penetrating keratoplasty can be attributed to various features of the normal cornea and anterior segment that in the aggregate account for their "immune-privileged" state (3) including: (a) the avascularity of the stroma, (b) the absence of corneal lymphatics, (c) the rarity of indigenous professional antigen-presenting Langerhans cells (LC) or macrophages in the normal graft bed, (d) a unique spectrum of locally produced immunomodulatory cytokines that suppress immunogenic inflammation and complement activation (to which the cornea itself contributes) , and (e) expression of Fas ligand by these ocular tissues that can directly suppress immunogenic inflammation (4) .
  • corticosteroids and their use in the prophylaxis and treatment of corneal transplant rejections has represented the most significant contribution to the prolongation of corneal transplant survival over the last several decades (11,12) .
  • corticosteroids or alternative general immunosuppressants, is associated with significant complications such as infection, cataracts, glaucoma and corneal thinning
  • Interleukin-1 is a potent proinflammatory cytokine that has a wide range of activities including the critical mediation of the acute-phase response, chemotaxis and activation of inflammatory and antigen-presenting cells, upregulation of adhesion molecules/ costimulatory factors on cells, and stimulation of neovascularization (17,18,19,20) .
  • IL-1 has been implicated as an important cytokine in host immunologic reactions to a variety of non-ocular allografts (21,22,23).
  • IL-1 activity has been correlated with corneal neovascularization (24) , endotoxin-mediated uveitis (25) , corneal collagenase and metalloprotease expression (26,27), corneal injury in vitamin-A deficiency (28) , and herpetic stromal keratitis (29) .
  • Endotoxin-mediated uveitis (25)
  • corneal collagenase and metalloprotease expression 26,27
  • corneal injury in vitamin-A deficiency 8
  • herpetic stromal keratitis 219
  • IL-1 mediated Langerhans cell migration can play a critical role in host allosensitization in the setting of corneal transplantation (17,30). For all these reasons, IL-1 is an attractive target for therapeutic intervention in immunogenic inflammatory diseases.
  • Interleukin-1 receptor antagonist is a naturally occurring IL-1 isoform with high-affinity binding to both IL-1 receptor subtypes. IL-lra functions as an active IL-1 inhibitor, having no agonist activity (31,32) . There is a 77% homology between the predominant human and murine isoforms of IL-lra, and systemic administration of recombinant human IL-lra has been shown to have a profound downregulatory effect on the acute phase cytokine cascade in both man and mouse (33,34) .
  • IL-lra administration has a significant positive effect in promoting corneal allograft survival, i.e., in increasing survival rates, of both normal- and high-risk transplant recipients.
  • both normal- and high-risk IL-lra treated graft sites had significantly less inflammation and Langerhans cell infiltration compared to untreated controls. Therefore, the invention is directed to a method for treating allografts and preventing allograft rejection, or for generally treating an immune or inflammatory response of the eye.
  • the method of the invention includes direct, local application of a therapeutic composition to an affected area of a patient.
  • the therapeutic composition useful in the method of the invention comprises a therapeutically effective amount of an interleukin-1 antagonist in association with a pharmaceutically acceptable carrier vehicle for local application.
  • the therapeutic composition can be packaged as an article of manufacture of the invention that includes a label indicating the use of the composition in the method of the invention.
  • the interleukin- 1 antagonist is an interleukin-1 receptor antagonist and, most preferably, the naturally occurring (or recombinant) human IL-1 isoform IL-lra. Alternatively, other interleukin- 1 antagonists may be utilized for the same effect.
  • the carrier vehicle in the composition of the invention is preferably a viscous formulation, and most preferably, sodium hyaluronate for application to the corneal surface, to promote a longer residence time for the therapeutic agent at the affected site of the patient.
  • sodium hyaluronate (or any other appropriate hyaluronate salt) can be used as a pharmaceutical carrier vehicle for the delivery of other therapeutic agents to the ocular surface of a patient.
  • the method of the invention is used to prolong transplant survival in corneal allograft recipients.
  • the method of the invention would also be useful for therapeutic intervention in immunogenic inflammatory diseases of the cornea and ocular surface, such as keratoconjunctivitis sicca and other dry eye states including Sj ⁇ gren's syndrome, allergic conjunctivitis and other atopic conditions of the ocular surface, corneal neovascularization, and immune or infectious keratitis states.
  • the method of the invention upon local injection or irrigation, would be useful for suppressing diseases such as uveitis and post-surgical inflammation in intraocular compartments (e.g. , anterior chamber or vitreous cavity) .
  • Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof and from the claims.
  • Fig. 1 shows a conceptual relationship among corneal neovascularization, IL-lra treatment, and graft outcome based on degree of preoperative risk
  • Fig. 2 shows Kaplan-Meier survival curves for normal -risk and high-risk corneal allograft recipients
  • Figs. 3A and 3B show association between corneal allograft survival and neovascularization score in normal - risk recipients based on IL-lra treatment; and Fig. 4A and 4B show association between corneal allograft survival and neovascularization score in high-risk recipients based on IL-lra treatment.
  • corticosteroids The currently available pharmaceutic armamentarium for corneal transplant survival is primarily composed of corticosteroids. Their introduction into ophthalmology is arguably the single most significant factor in the last four decades' advances in corneal transplant surgery (13) . Nevertheless, beyond their well-known serious complications, corticosteroids show widely variable efficacy in preventing ultimate immunogenic graft failure, and this is particularly the case in high-risk keratoplasty (1,7) .
  • IL-lra treatment was determined to be associated with a blunted postkeratoplasty neovascularization response.
  • Laboratory results show that IL-lra can significantly blunt the early, but not late, phase corneal neovascularization development m response to standard angiogenic stimuli, suggesting that there are non-IL-1 mediated factors that can overshadow IL-1 suppression m corneal angiogenesis .
  • IL-lra The failure of IL-lra to lead to significant neovascularization regression m the high-risk beds, as opposed to its capacity for angiostas s m the normal-risk beds as demonstrated here, is apparently due to the dominance of non-IL-1 driven angiogenic factors m the former. However, IL-lra appears to play an important role, possibly m combination with other agent (s) m suppressing the neovascular response.
  • corneal neovascularization causes sufficient perturbation of the ocular microenvironment to lead to a loss of "immune privilege" as measured by the ability to m ⁇ uce anterior chamber-associated immune deviation (ACAID) (35) .
  • ACAID m ⁇ uce anterior chamber-associated immune deviation
  • m contrast to the expectation that the efficacy with which IL-lra could blunt rejection m the high-risk corneas would be paralleled by an equal degree of suppression m corneal neovascularization
  • treatment with IL-lra promotes allograft survival m recipients regardless of their neovascularization status. This effect could mirror what has been described previously m neovascularized corneas where therapeutic measures that have been shown to restore immune privilege/ACAID are associated with highly variable degrees of angiostasis (35) .
  • IL-lra treatment 20 in the neovascularized cornea 18, the effect of IL-lra treatment 20 on corneal transplantation 16 appears to be independent of the degree of corneal neovascularization, which remains at the significant (+++NV) level 22. Specifically, IL-lra treatment of high-risk beds (with antecedent neovascularization) does not appear to significantly suppress neovascularization; however, this same treatment leads to significant prolongation of graft survival compared to untreated controls .
  • IL-1 has been shown to be a critical regulator of LC migration m the cornea (17) , and the activity of epidermal LC is known to be at least partially controlled by IL-1 (30,49).
  • IL-1 (30,49).
  • the demonstrated constitutive expression by normal corneal cells of IL-lra (50) likely plays an important immune regulatory role m the avascular/non-traumatized cornea by keeping the microenvironment in an inhospitable site for sensitization.
  • Topical preparations of the therapeutic agent were applied to the recipient mice three times daily for the 56 days (8 weeks) duration of the study.
  • the study medication was composed of 20 mg/ml of human recombinant IL-lra in 0.2% sodium hyaluronate in PBS (supplied by Amgen, Boulder, CO) .
  • Placebo-treated animals received the vehicle 0.2% sodium hyaluronate only. Graft success or failure was established based on opacity scores, as detailed in Materials and Methods below.
  • Corneal transplant rejection rates stratified by IL-la therapy and degree of risk.
  • Corneal Neovascularization In addition to graft survival/opacification criteria detailed in Materials and Methods, transplants were also followed biomicroscopically for the degree of corneal neovascularization. All high-risk beds had been specially prepared for two weeks to develop two or more quadrants of stromal neovascularization as described previously (36) , and all normal-risk corneal beds were avascular.
  • the corneas were also examined to see if treatment with IL-lra had an appreciable effect on this parameter, and an angiostatic effect with IL-lra treatment m the normal -risk, but not high-risk, transplants was observed.
  • Figs. 3A and 3B among the normal-risk grafts, 38% of the untreated corneas (Fig. 3A) had a neovascularization score of >3 at 4 weeks compared to none of the IL-lra treated cases (Fig. 3B) . Respective rates at 8 weeks were 31% for untreated controls and 18% for treated cases.
  • Figs. 4A and 4B no significant association of angiostatic effect with IL-lra treatment was apparent m high-risk eyes that had been induced to have corneal neovascularization two weeks previously.
  • the proportions of corneas with a neovascularization score of ⁇ 3 at 4 and 8 weeks follow-up was very comparable between untreated controls (Fig. 4A) (91% at both time points) and treated cases (Fig. 4B) (100% and 86% at respective time points) .
  • LC Langerhans Cell Population.
  • BALB/c corneas and allografts were excised at the completion of the follow-up period to assay their LC populations with fluorescence microscopy, as described m Materials and Methods .
  • the decreased corneal inflammation in the IL-lra-treated allografts was reflected by a generally lower opacity score (irrespective of final rejection status) m the IL-lra-treated transplants.
  • opacity score irrespective of final rejection status
  • mice Materials and Methods Mice and anesthesia. Six to ten-week old BALB/c (H-2 d ) and C57BL/6 (H-2 b ) mice were purchased (Taconic, New York) or obtained from the Schepens Eye Research Institute animal colony. All animals were treated according to the Association for Research m Vision and Ophthalmology Statement for the Use of Animals m Ophthalmic and Vision
  • Corneal transplantation All 55 transplants involved combined MHC- and minor alloantigen disparate corneas that were grafted from C57BL/6 donors into BALB/c eyes as follows. On day 0, m each case, the central 2 -mm of the donor cornea was marked with a microcurrette and the donor button excised by Vannas scissors and placed m phosphate-buffered saline
  • the recipient graft bed was prepared by excising the central 2 -mm of the cornea.
  • the donor button was then secured m place with 8 interrupted 11-0 nylon sutures
  • Intrastromal sutures induce robust neovascularization growth into the normally avascular corneal stroma from the limbus that can be appreciated as early as three days following suture placement (35) , and untreated allografts into these high-risk beds are rejected swiftly (36).
  • Two parallel protocols were devised to study normal- and high-risk corneal transplantation. In the former case, animals were left unmanipulated until the day of surgery. High-risk beds were developed as described previously (36) . Briefly, three interrupted 11-0 sutures were placed in the central cornea of one eye of a normal BALB/c mouse on day -14 under aseptic microsurgical technique using an operating microscope. The neovascularized beds then served as high-risk graft beds for orthotopic corneal transplants on day 0 as described above (neovascularization-inducing sutures were removed at the time of transplantation) . Neovascularization was graded between
  • grafts with an opacity score of 2+ or greater at any time point after two weeks were considered to have a rejection reaction (RR) , regardless of the opacity score at eight weeks (37) .
  • LC Langerhans cell
  • the LC were assessed by an immunofluorescence assay performed on whole corneal epithelial mounts as previously described (38) . Briefly, each eye was enucleated and the anterior segment dissected under the operating microscope. The cornea was placed in 20mM ethylenediaminetetraacetic acid (EDTA) buffer and incubated for 30 minutes at 37°C, followed by removal of the epithelium in toto and washed in PBS at room temperature . The cornea was then fixed with 95% ethanol prior to washing and incubation with 1:20 diluted primary anti-murine Ia d antibody for 45 minutes at 37°C.
  • EDTA ethylenediaminetetraacetic acid
  • the tissue was then washed in PBS and incubated with a FITC-labeled goat anti-mouse secondary antibody for 30 minutes at 37°C. Negative controls either bypassed this step or were incubated with antibody specific for an unrelated MHC epitope. Sections were then mounted on slides and examined under the fluorescent microscope with a square ocular grid where LC were enumerated. Corneal specimens that were not processed for LC enumeration were fixed, sectioned, and stained with hematoxylin-eosin for light microscopic evaluation. Statistical techniques. The proportional rates of rejected allografts in the IL-lra and vehicle-only treated groups were compared using two methods.
  • the Mantel - Haenszel summary chi-square statistic was obtained, stratified by (adjusted for) degree of preoperative risk (i.e., normal vs. vascularized stromal bed) to compare the proportion of rejected transplants in the two groups.
  • Second, Kaplan-Meier survival curves were constructed in order to compare the probability of graft survival over the follow-up period, both overall and separately for normal- and high-risk eyes, in the IL-lra treated and untreated controls. This method accounted for the variability in the time-to- graft rejection in addition to the variation in follow-up time (4 mice in the normal -risk group had follow-up terminated prior to the end of the 8-week period) . Comparison of Langerhans cell population means among IL-lra treated eyes and untreated controls was made by the Student's t-test .
  • IL-lra is a very promising agent for use in corneal transplantation, both because of its efficacy as demonstrated in these experimental results and its putative value over existing therapy, which has well-known side-effects and complications.
  • the very significant dampening of the inflammatory response observed suggests that treatment with IL-lra and other antagonists of IL-1 and its receptors can be applied to a wide variety of ocular immune and inflammatory disorders.
  • IL-1 antagonism e.g., via use of IL-lra, can suppress immunogenic inflammation, as demonstrated in the corneal transplant model herein, in both virgin and previously inflamed/neovascularized eyes.
  • the topical administration of IL-lra can include non-transplant therapeutic uses such as treatment of allergic and hypersensitivity disorders of the ocular surface, burns, infections, dry eye disorders, and chronic inflammatory states that may lead to neovascularization and/or scarring or fibrosis of the cornea and ocular surface.
  • non-transplant therapeutic uses such as treatment of allergic and hypersensitivity disorders of the ocular surface, burns, infections, dry eye disorders, and chronic inflammatory states that may lead to neovascularization and/or scarring or fibrosis of the cornea and ocular surface.
  • other vehicles e.g., cyclodextrms may be used to increase drug deliver to the surface epithelium.
  • IL-lra is not limited to topical administration to the cornea and ocular surface.
  • Intraocular administration e.g., by intraocular injection into the anterior chamber or irrigation at the time of surgery, is appropriate for treatment (or prophylaxis of recurrence) of intraocular inflammatory disorders such as autoimmune or infectious uveitis, post-traumatic or post-surgical inflammation, or ldiopathic uveitides.
  • Sustained release formulations e.g., with use of biodegradable or non- degradable biocompatible polymers, or simple irrigation of these agent (s) at the time of surgery, can be used for intraocular delivery of IL-lra to subjects.
  • mterleukm-1 antagonists that might be useful m the methods of the invention, as described earlier, can be tested for effectiveness using one of the assays described herein (e.g., measuring the extent of corneal inflammation, neovascularization, graft survival or Langerhans cell migration) and the results compared to those obtained with IL-lra.
  • IL-lra used m the experiments described herein was relatively high m order to determine the maximum positive effect of treatment. However, IL-lra appears to be able to exert its suppressive effect over a wide dose range (56) .
  • Optimal dosage and appropriate modes of administration for each of the conditions delineated above can be determined by conventional protocols. For example, m the case of corneal transplantation, other doses ranging between 20ng/ml
  • 2mg/ml will additionally be tested and the endpomts described above (e.g., effect on corneal inflammation, neovascularization, graft longevity or Langerhans cell migration) for the tested dosage will be compared to those obtained using the current dose herein of 20mg/ml. It is to be expected that an appropriate concentration of an IL-1 receptor antagonist in a vehicle for local administration to a human patient will be in the range of 20ng/ml to 20 mg/ml .

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Abstract

Cette invention concerne l'utilisation topique d'un antagoniste du récepteur de l'interleukine 1 (IL-1Ra) qui s'avère utile pour prolonger la vie d'un greffon cornéen dans un modèle murin d'allogreffe orthotopique, et notamment pour prolonger de manière significative la vie d'un greffon à la fois dans des stromas cornéens à haut risque et des stromas cornéens normaux (à risque faible). L'allongement de la durée de vie du greffon est par ailleurs associée à une diminution importante de l'inflammation de la cornée. Il est par conséquent possible d'utiliser IL-1ra, ainsi que les antagonistes de l'interleukine-1 associés, dans une composition thérapeutique destinée à la prophylaxie et au traitement topique du rejet des allogreffons et au traitement local d'une large gamme de troubles inflammatoires immunogéniques de l'oeil. Ladite composition contient une quantité thérapeutiquement efficace de IL-1ra associée à un excipient pharmaceutiquement acceptable pour l'application topique.
PCT/US1997/021393 1996-11-19 1997-11-19 UTILISATION LOCALE DE IL-1ra POUR LE TRAITEMENT DES REJETS DE GREFFONS CORNEENS ET D'AUTRES TROUBLES DE L'OEIL WO1998022130A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP52393498A JP2002514194A (ja) 1996-11-19 1997-11-19 角膜移植拒否又は眼疾におけるｉｌ―１ｒａの局所使用
AU54527/98A AU5452798A (en) 1996-11-19 1997-11-19 Local use of il-1ra in corneal transplant rejection or disorders of the eye
CA002272073A CA2272073A1 (fr) 1996-11-19 1997-11-19 Utilisation locale de il-1ra pour le traitement des rejets de greffons corneens et d'autres troubles de l'oeil
EP97948458A EP0944395A1 (fr) 1996-11-19 1997-11-19 UTILISATION LOCALE DE IL-1ra POUR LE TRAITEMENT DES REJETS DE GREFFONS CORNEENS ET D'AUTRES TROUBLES DE L'OEIL

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US7718696P 1996-11-19 1996-11-19
US75207596A 1996-11-19 1996-11-19
US08/752,075 1996-11-19
US60/077,186 1996-11-19

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WO1998022130A1 true WO1998022130A1 (fr) 1998-05-28
WO1998022130A9 WO1998022130A9 (fr) 1998-08-27

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WO1999030730A1 (fr) * 1997-12-15 1999-06-24 Universite Laval Procedes et compositions permettant d'ameliorer la reussite de la transplantation cellulaire chez un receveur
JP2002520355A (ja) * 1998-07-14 2002-07-09 アルコン ラボラトリーズ， インコーポレイテッド 非アレルギー性眼炎症障害を処置および眼新生血管形成を予防する医薬製造のための、１１−（３−ジメチルアミノプロピリデン）−６，１１−ジヒドロジベンズ［ｂ，ｅ］オキセピン−２−酢酸の使用
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US6699493B2 (en) 2000-11-29 2004-03-02 Oculex Pharmaceuticals, Inc. Method for reducing or preventing transplant rejection in the eye and intraocular implants for use therefor
US6733753B2 (en) 1997-02-10 2004-05-11 Amgen Inc. Composition and method for treating inflammatory diseases
EP2021026A1 (fr) * 2006-04-14 2009-02-11 Novartis AG Utilisation d'anticorps anti-il-1 pour le traitement de troubles ophtalmiques
WO2009025763A3 (fr) * 2007-08-16 2009-04-23 Schepens Eye Res Inst Composition thérapeutique pour le traitement de l'inflammation des annexes et des tissus oculaires
WO2010081091A3 (fr) * 2009-01-09 2010-11-18 The Schepens Eye Research Institute, Inc. Compositions thérapeutiques pour le traitement de troubles de la cornée
US8263581B2 (en) 2009-07-03 2012-09-11 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US8513259B2 (en) 2009-07-03 2013-08-20 Jdp Therapeutics, Inc. Non-sedating antihistamine injection formulations and methods of use thereof
US8853150B2 (en) 2010-07-29 2014-10-07 Eleven Biotherapeutics, Inc. Chimeric IL-1 receptor type I antagonists
US8911768B2 (en) 2004-04-30 2014-12-16 Allergan, Inc. Methods for treating retinopathy with extended therapeutic effect
US9012437B2 (en) 2000-07-05 2015-04-21 Allergan, Inc. Implants and methods for treating inflammation-mediated conditions of the eye
US9192511B2 (en) 2003-01-09 2015-11-24 Allergan, Inc. Ocular implant made by a double extrusion process
US9309313B2 (en) 2008-01-09 2016-04-12 The Schepens Eye Research Institute, Inc. Therapeutic compositions for treatment of ocular inflammatory disorders
US10799589B2 (en) 2013-03-13 2020-10-13 Buzzard Pharmaceuticals AB Chimeric cytokine formulations for ocular delivery

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Cited By (36)

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