Compositions and methods for the treatment and prevention of fibrotic, inflammatory and neovascularization conditions

Abstract

The present invention relates to compositions and methods for prevention and treatment of diseases and conditions, including ocular diseases and conditions, characterized by aberrant fibrogenesis or scarring, inflammation and/or aberrant neovascularization or angiogenesis. The compositions and methods of the invention utilize immune-derived moieties that are specifically reactive against bioactive lipids and which are capable of decreasing the effective concentration of said bioactive lipid. In some embodiments, the immune-derived moiety is a monoclonal antibody that is reactive against sphingosine-1-phosphate (S1P) or lysophosphatidic acid (LPA).

1 . A method of decreasing or preventing aberrant fibrogenesis, fibrosis or scarring of the eye of an animal comprising administering to said animal an immune-derived moiety reactive against a bioactive lipid, wherein said immune-derived moiety is capable of decreasing the effective concentration of said bioactive lipid.  
     
     
         2 . The method of  claim 1  wherein said immune-derived moiety is a monoclonal antibody or a fragment, variant or a derivative thereof.  
     
     
         3 . The method of  claim 1  wherein the bioactive lipid is a lysolipid.  
     
     
         4 . The method of  claim 3  wherein the lysolipid is S1P or LPA or a variant thereof.  
     
     
         5 . The method of  claim 2  wherein said immune-derived moiety is a monoclonal antibody which is reactive against S1P or LPA or a variant thereof.  
     
     
         6 . The method of  claim 1  wherein the animal is a human.  
     
     
         7 . A method of modulating surgical and traumatic wound healing responses of the eye of an animal comprising administering to said animal an immune-derived moiety reactive against a bioactive lipid, wherein said immune-derived moiety is capable of decreasing the effective concentration of said bioactive lipid.  
     
     
         8 . The method of  claim 7  wherein said immune-derived moiety is a monoclonal antibody or a fragment, variant or a derivative thereof.  
     
     
         9 . The method of  claim 7  wherein the bioactive lipid is a lysolipid.  
     
     
         10 . The method of  claim 9  wherein the lysolipid is S1P or LPA or a variant thereof.  
     
     
         11 . The method of  claim 8  wherein said immune-derived moiety is a monoclonal antibody which is reactive against S1P or LPA or a variant thereof.  
     
     
         12 . The method of  claim 7  wherein the animal is a human.  
     
     
         13 . A method of decreasing or preventing inflammation of the eye of an animal comprising administering to said animal an immune-derived moiety reactive against a bioactive lipid, wherein said immune-derived moiety is capable of decreasing the effective concentration of said bioactive lipid.  
     
     
         14 . The method of  claim 13  wherein said immune-derived moiety is a monoclonal antibody or a fragment, variant or a derivative thereof.  
     
     
         15 . The method of  claim 13  wherein the bioactive lipid is a lysolipid.  
     
     
         16 . The method of  claim 15  wherein the lysolipid is S1P or LPA or a variant thereof.  
     
     
         17 . The method of  claim 14  wherein said immune-derived moiety is a monoclonal antibody which is reactive against S1P or LPA or a variant thereof.  
     
     
         18 . The method of  claim 13  wherein the animal is a human.  
     
     
         19 . A method of decreasing or preventing aberrant neovascularization of the eye of an animal comprising administering to said animal an immune-derived moiety reactive against a bioactive lipid, wherein said immune-derived moiety is capable of decreasing the effective concentration of said bioactive lipid.  
     
     
         20 . The method of  claim 19  wherein said immune-derived moiety is a monoclonal antibody or a fragment, variant or a derivative thereof.  
     
     
         21 . The method of  claim 19  wherein the bioactive lipid is a lysolipid.  
     
     
         22 . The method of  claim 21  wherein the lysolipid is S1P or LPA or a variant thereof.  
     
     
         23 . The method of  claim 20  wherein said immune-derived moiety is a monoclonal antibody which is reactive against S1P or LPA or a variant thereof.  
     
     
         24 . The method of  claim 19  wherein the animal is a human.  
     
     
         25 . A method for attenuating an ocular immune response in an animal comprising administering to said animal an immune-derived moiety reactive against a bioactive lipid, wherein said immune-derived moiety is capable of decreasing the effective concentration of said bioactive lipid.  
     
     
         26 . The method of  claim 25  wherein said immune-derived moiety is a monoclonal antibody or a fragment, variant or a derivative thereof.  
     
     
         27 . The method of  claim 25  wherein the bioactive lipid is a lysolipid.  
     
     
         28 . The method of  claim 27  wherein the lysolipid is S1P or LPA or a variant thereof.  
     
     
         29 . The method of  claim 26  wherein said immune-derived moiety is a monoclonal antibody which is reactive against S1P or LPA or a variant thereof.  
     
     
         30 . The method of  claim 25  wherein the animal is a human.  
     
     
         31 . A method for decreasing the effective ocular concentration or activity of bioactive lipid in an animal comprising administering to said animal an immune-derived moiety reactive against a bioactive lipid, wherein said immune-derived moiety is capable of decreasing the effective concentration of said bioactive lipid.  
     
     
         32 . The method of  claim 31  wherein said immune-derived moiety is a monoclonal antibody or a fragment, variant or a derivative thereof.  
     
     
         33 . The method of  claim 31  wherein the bioactive lipid is a lysolipid.  
     
     
         34 . The method of  claim 33  wherein the lysolipid is S1P or LPA or a variant thereof.  
     
     
         35 . The method of  claim 32  wherein said immune-derived moiety is a monoclonal antibody which is reactive against S1P or LPA or a variant thereof.  
     
     
         36 . The method of  claim 31  wherein the animal is a human.  
     
     
         37 . A method of treating an ocular disease or condition in a subject comprising administering to said subject a pharmaceutical composition comprising an immune-derived moiety reactive against a bioactive lipid, wherein said immune-derived moiety is capable of decreasing the effective concentration of said bioactive lipid.  
     
     
         38 . The method of  claim 37  wherein said immune-derived moiety is a monoclonal antibody or a fragment, variant or a derivative thereof.  
     
     
         39 . The method of  claim 37  wherein the bioactive lipid is a lysolipid.  
     
     
         40 . The method of  claim 39  wherein the lysolipid is S1P or LPA or a variant thereof.  
     
     
         41 . The method of  claim 38  wherein said immune-derived moiety is a monoclonal antibody which is reactive against S1P or LPA or a variant thereof.  
     
     
         42 . The method of  claim 37  wherein the subject is a human subject.  
     
     
         43 . The method of  claim 37  wherein the ocular disease or condition is characterized, at least in part, by aberrant fibrogenesis, fibrosis, or scarring.  
     
     
         44 . The method of  claim 43  wherein the ocular disease or condition characterized, at least in part, by aberrant fibrogenesis, fibrosis or scarring is selected from the group consisting of age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, sickle cell retinopathy, ischemic retinopathies, retinal venous occlusive disease, macular pucker, cellophane retinopathy, ERM formation, contact lens overwear, tractional retinal detachment, proliferative vitreoretinopathy, traumatic injury, ocular cicatricial pemphigoid, Stevens Johnson Syndrome, toxic epidermal necrolysis, pterygium, and consequences of ocular surgery, including refractive surgery, vitrectomy and glaucoma surgery.  
     
     
         45 . The method of  claim 37  wherein the ocular disease or condition is an inflammatory or immunologic condition.  
     
     
         46 . The method of  claim 45  wherein the inflammatory or immunologic condition is selected from the group consisting of age-related macular degeneration, uveitis, vitritis, infections, including herpes simplex infection, herpes zoster infection and protozoan infection; corneal graft rejection and ocular histoplasmosis.  
     
     
         47 . The method of  claim 37  wherein the ocular disease or condition is characterized, at least in part, by aberrant neovascularization.  
     
     
         48 . The method of  claim 47  wherein the ocular disease or condition characterized, at least in part, by aberrant neovascularization is selected from the group consisting of age-related macular degeneration, diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, neovascular glaucoma, contact lens overwear, infections of the cornea, including herpes simplex infection, herpes zoster infection and protozoan infection; pterygium, ischemic retinopathy, retinal venous occlusive disease, infectious uveitis, chronic retinal detachment, laser injury, sickle cell retinopathy, venous occlusive disease, choroidal neovascularization, retinal angiomatous proliferation, and idiopathic polypoidal choroidal vasculopathy.  
     
     
         49 . The method of  claim 37  wherein the immune-derived moiety is administered systemically, topically, by intravitreal or periocular injection, iontophoresis, spray or drops, or as part of an in situ gel, ocular insert, corneal shield or contact lens, liposome, niosome/discome, mucoadhesive system, lyophilized carrier system, particulate, submicron emulsion, dendrimer, microsphere, nanosphere, or collasome, or combination thereof.  
     
     
         50 . The method of  claim 37  wherein the immune-derived moiety is modified, unmodified, or provided as a prodrug, with or without enhancers and/or penetration enhancers.  
     
     
         51 . A pharmaceutical composition comprising an immune-derived moiety reactive against a bioactive lipid, in a pharmaceutically acceptable carrier.  
     
     
         52 . The pharmaceutical composition of  claim 51  which is suitable for use in and/or on the eye.  
     
     
         53 . The pharmaceutical composition of  claim 51  where the pharmaceutical composition comprises phosphate-buffered saline.  
     
     
         54 . A method of treating scleroderma in a subject comprising administering to said subject a pharmaceutical composition comprising an immune-derived moiety reactive against a bioactive lipid, wherein said immune-derived moiety is capable of decreasing the effective concentration of said bioactive lipid.  
     
     
         55 . The method of  claim 54  wherein the pharmaceutical composition is administered systemically, intradermally, subcutaneously, mucosally, by inhalation or topically.  
     
     
         56 . The method of  claim 54  wherein the subject is a human subject.