Fgf21 compositions for treatment or prevention of neovascularization of the eye and methods therefor

Abstract

The instant disclosure provides methods and compositions related to discovery of a long-acting FGF21 as a therapeutic target for treatment or prevention of neovascular eye diseases or disorders that are characterized by angiogenesis, or of vascular diseases of the eye. Therapeutic and/or prophylactic uses and compositions of long-acting FGF21 are described.

1 . A method for treating or preventing neovascularization and/or angiogenesis in the eye of a subject, the method comprising:
 (a) identifying a subject having or at risk of neovascularization and/or angiogenesis in the eye; and   (b) administering a pharmaceutical composition comprising a stabilized fibroblast growth factor 21 (FGF21) agent to the subject in the eye of a subject   
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the subject has or is at risk of developing a condition selected from the group consisting of neovascular retinopathy, diabetic retinopathy in type I diabetes, retinopathy of prematurity (ROP), retinitis pigmentosa (RP) and macular telangiectasia (MacTel). 
     
     
         4 . The method of  claim 1 , wherein neovascularization and/or angiogenesis in the choroid or retinal cells of the eye is treated or prevented. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 1 , wherein the stabilized FGF21 agent comprises an FGF21 polypeptide or a modified FGF21 polypeptide conjugated to an antibody scaffold. 
     
     
         7 . (canceled) 
     
     
         8 . The method of  claim 6 , wherein the modified FGF21 is dHis/Ala129Cys, or wherein the modified FGF21 is conjugated at Cys 129 to the antibody scaffold. 
     
     
         9 . The method of  claim 6 , wherein two or more FGF21 polypeptide molecules are conjugated to one antibody scaffold. 
     
     
         10 . The method of  claim 6 , wherein the antibody scaffold is a CovX-2000 scaffold. 
     
     
         11 . The method of  claim 1 , wherein the stabilized FGF21 agent is a long acting FGF21 analog, comprising PF-05231023. 
     
     
         12 . The method of  claim 1 , wherein the stabilized FGF21 agent possesses a half-life of at least 1.5× the half-life of a native FGF21 peptide when assayed for stability under identical conditions. 
     
     
         13 . The method of  claim 1 , wherein the stabilized FGF21 agent possesses a half-life of at least 0.8 h in the circulation of a mammal, wherein the mammal is human. 
     
     
         14 . The method of  claim 1 , wherein the pharmaceutical composition is administered to the eye of the subject. 
     
     
         15 . (canceled) 
     
     
         16 . A pharmaceutical composition for use in treating or preventing neovascularization, and/or angiogenesis in the eye of a subject comprising fibroblast growth factor 21 (FGF21), a stabilized FGF21 agent, a modified FGF21 molecule, or combinations thereof, and a pharmaceutically acceptable carrier. 
     
     
         17 . The pharmaceutical composition of  claim 16 , wherein the stabilized FGF21 agent comprises an FGF21 polypeptide or modified FGF21 polypeptide conjugated to an antibody scaffold. 
     
     
         18 . (canceled) 
     
     
         19 . The pharmaceutical composition of  claim 17 , wherein the modified FGF21 is dHis/Ala129Cys, or wherein the modified FGF21 is conjugated at Cys 129 to the antibody scaffold. 
     
     
         20 . The pharmaceutical composition of  claim 17 , wherein two or more FGF21 polypeptide molecules are conjugated to one antibody scaffold. 
     
     
         21 . (canceled) 
     
     
         22 . The pharmaceutical composition of  claim 17 , wherein the stabilized FGF21 agent is a long acting FGF21 analog, comprising PF-05231023. 
     
     
         23 . (canceled) 
     
     
         24 . A method for treating or preventing hyperglycemic retinopathy of prematurity (ROP) in a subject, the method comprising:
 (a) identifying a subject having or at risk of hyperglycemic ROP; and   (b) administering a pharmaceutical composition comprising a fibroblast growth factor 21 (FGF21) agent to a subject,   
       thereby treating or preventing hyperglycemic ROP in the subject. 
     
     
         25 . (canceled) 
     
     
         26 - 30 . (canceled) 
     
     
         31 . A method of treating or preventing against photoreceptor dysfunction, inflammation and/or morphology in a subject in need thereof, comprising administering to the subject a composition comprising a therapeutically effective amount of fibroblast growth factor 21 (FGF21) or a long-acting FGF21 analog. 
     
     
         32 - 40 . (canceled) 
     
     
         41 . A pharmaceutical composition comprising one or more fibroblast growth factor 21 (FGF21) molecules, comprising: pegylated FGF21, modified FGF21 proteins, Fc-FGF21 fusion constructs, long acting FGF21 or combinations thereof. 
     
     
         42 . The pharmaceutical composition of  claim 41 , wherein a pegylated FGF21 comprises an FGFR21 with a R131AcF modification, coupled to PEG. 
     
     
         43 - 46 . (canceled)