Method of treating amd in patients refractory to anti-vegf therapy

Abstract

Disclosed herein are methods for the treatment of a patient having an ocular conditions such as age-related macular degeneration or diabetic macular edema through administration of a recombinant binding protein comprising an ankyrin repeat domain. In some embodiments, the composition may be administered every 8 weeks to every 16 weeks. In some embodiments, the patient being treated may be refractory to existing anti-VEGF therapies.

1 . A method of inhibiting binding between VEGF-Axxx and VEGFR-2, the method comprising the step of administering to a patient in need of such inhibition, at a frequency between 8 weeks and 16 weeks, a dose of about 1 mg to about 4 mg of a recombinant binding protein comprising an ankyrin repeat domain, wherein the ankyrin domain binds VEGF-Axxx with a Kd below 109M. 
     
     
         2 . The method of  claim 1 , wherein the binding protein further comprises a polyethylene glycol moiety of at least 5 kDa molecular weight. 
     
     
         3 . The method of  claim 2 , wherein the N-terminal capping module of the ankyrin repeat domain comprises an Asp residue at position 5. 
     
     
         4 . The method of  claim 3 , wherein the ankyrin repeat domain competes for binding to VEGF-Axxx with the ankyrin repeat domains of SEQ ID NO:1 or 3. 
     
     
         5 . The method of  claim 3 , wherein the ankyrin repeat domain is selected from the group consisting of the ankyrin repeat domains of SEQ ID NOS: 1 to 7. 
     
     
         6 . The method of  claim 5 , wherein the binding protein inhibits VEGF-Axxx binding to VEGFR-1. 
     
     
         7 . The method of  claim 6  wherein the ankyrin repeat domain is conjugated at its C-terminus via a peptide bond to a polypeptide linker and a C-terminal Cys residue, wherein the thiol of the C-terminal Cys is further conjugated to a maleimide-coupled polyethylene glycol. 
     
     
         8 . The method of  claim 7 , wherein the maleimide-coupled polyethylene glycol is α-[3-(3-maleimido-1-oxopropyl)amino]propyl-ω-methoxy-polyoxyethylene. 
     
     
         9 . The method of  claim 1 , wherein the binding protein is an ankyrin repeat protein selected from the group consisting of the ankyrin repeat proteins of SEQ ID NOS: 2, 3, 5, 6 or 7. 
     
     
         10 . The method of  claim 8 , wherein the polyethylene glycol moiety has a molecular weight of around 20 kDa. 
     
     
         11 . The method of  claim 1 , wherein the binding protein comprises the ankyrin repeat protein of SEQ ID NO:3 wherein the thiol of the C-terminal Cys of the ankyrin repeat protein is further conjugated to a maleimide-coupled polyethylene glycol. 
     
     
         12 . The method of  claim 11 , wherein the maleimide-coupled polyethylene glycol is α-[3-(3-maleimido-1-oxopropyl)amino]propyl-ω-methoxy-polyoxyethylene, and wherein the polyethylene glycol moiety has a molecular weight of at least 10 kDa. 
     
     
         13 . The method of  claim 12 , wherein the binding protein is administered with a pharmaceutically acceptable carrier and/or diluent. 
     
     
         14 . The method of  claim 13 , wherein the carrier is PBS. 
     
     
         15 . The method of  claim 14 , wherein the binding protein is administered by intravitreal injection. 
     
     
         16 . The method of  claim 15 , wherein the binding protein is administered every 4, 8, 9, 10, 11, 12, 13, 14, 15, or 16 weeks. 
     
     
         17 . The method of  claim 16 , wherein the binding protein is administered at a dose of 1 mg, 2 mg, 3 mg, or 4 mg, or at a dose of about 1.0 mg, 2.0 mg, about 3.0 mg, or about 4.0 mg. 
     
     
         18 . The method of  claim 17 , wherein the method is used to treat age-related macular degeneration, diabetic macular edema, pathological myopia, branch retinal vein occlusion, or central retinal vein occlusion in a patient having that condition. 
     
     
         19 . The method of  claim 18 , wherein the patient is refractory to ranibizumab, bevacizumab, aflibercept, or pegaptanib therapy. 
     
     
         20 . The method of  claim 19 , wherein the patient has less than a 20% decrease in the center 1 mm2 area of the macula after 3 intravitreal injections of ranibizumab, bevacizumab, or aflibercept. 
     
     
         21 .- 24 . (canceled)