Stabilized Aptamers to Platelet Derived Growth Factor and Their Use as Oncology Therapeutics

Abstract

Materials and methods are provided for producing and using aptamers useful as oncology therapeutics capable of binding to PDGF, PDGF isoforms, PDGF receptor, VEGF, and VEGF receptor or any combination thereof with great affinity and specificity. The compositions of the present invention are particularly useful in solid tumor therapy and can be used alone or in combination with known cytotoxic agents for the treatment of solid tumors. Also disclosed are aptamers having one or more CpG motifs embedded therein or appended thereto.

1 . An unpegylated or pegylated aptamer or pharmaceutically acceptable salt thereof that binds to PDGF and comprises 5′-(SEQ ID NO: 55)-PEG-(SEQ ID NO: 40)-PEG-(SEQ ID NO: 41)-3T-3′, wherein PEG is a polyethylene glycol spacer and 3T is an inverted deoxythymidine. 
     
     
         2 .- 46 . (canceled) 
     
     
         47 . The aptamer or pharmaceutically acceptable salt of the aptamer of  claim 1 , wherein the aptamer or pharmaceutically acceptable salt of the aptamer is pegylated. 
     
     
         48 . The aptamer or pharmaceutically acceptable salt of the aptamer of  claim 47 , wherein the aptamer or pharmaceutically acceptable salt of the aptamer is pegylated with a 40 kDa PEG moiety. 
     
     
         49 . The aptamer or pharmaceutically acceptable salt of the aptamer of  claim 48 , wherein the 40 kDa PEG moiety is branched. 
     
     
         50 . The aptamer or pharmaceutically acceptable salt of the aptamer of  claim 49 , wherein the aptamer or pharmaceutically acceptable salt of the aptamer comprises the following structure at its 5′ end: 
       
         
           
           
               
               
           
         
       
     
     
         51 . The aptamer or pharmaceutically acceptable salt of the aptamer of  claim 50 , wherein the polyethylene glycol spacer is a PEG-6 spacer. 
     
     
         52 . A composition comprising a therapeutically effective amount of the aptamer of any one of  claims 1  and  47 - 51 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 
     
     
         53 . An unpegylated or pegylated aptamer or pharmaceutically acceptable salt thereof that binds to PDGF and comprises 5′-(SEQ ID NO: 56)-PEG-(SEQ ID NO: 40)-PEG-(SEQ ID NO: 41)-3T-3′, wherein PEG is a polyethylene glycol spacer and 3T is an inverted deoxythymidine. 
     
     
         54 . The aptamer or pharmaceutically acceptable salt of the aptamer of  claim 53 , wherein the aptamer or pharmaceutically acceptable salt of the aptamer is pegylated. 
     
     
         55 . The aptamer or pharmaceutically acceptable salt of the aptamer of  claim 54 , wherein the aptamer or pharmaceutically acceptable salt of the aptamer is pegylated with a 40 kDa PEG moiety. 
     
     
         56 . The aptamer or pharmaceutically acceptable salt of the aptamer of  claim 55 , wherein the 40 kDa PEG moiety is branched. 
     
     
         57 . The aptamer or pharmaceutically acceptable salt of the aptamer of  claim 56 , wherein the aptamer or pharmaceutically acceptable salt of the aptamer comprises the following structure at its 5′ end: 
       
         
           
           
               
               
           
         
       
     
     
         58 . The aptamer or pharmaceutically acceptable salt of the aptamer of  claim 57 , wherein the polyethylene glycol spacer is a PEG-6 spacer. 
     
     
         59 . A composition comprising a therapeutically effective amount of the aptamer of any one of  claims 53 - 58 , or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.