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 one or in combination with known cytotoxic agents for the treatment of solid tumors. Also disclosed are aptarmers having one or more CpG motifs embedded therein or appended thereto.

1 . An aptamer that binds to PDGF and VEGF and comprises a sequence of SEQ ID NO:9 or SEQ NO: 10. 
     
     
         2 - 12 . (canceled) 
     
     
         13 . A composition comprising a therapeutically effective amount of the aptamer of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         14 . The composition of  claim 13 , further comprising a cytotoxic agent. 
     
     
         15 . The composition of  claim 14 , wherein the cytotoxic agent is a tubulin stabilizer, a tubulin destabilizer, an anti-metabolite, a purine synthesis inhibitor, a nucleotide analog, a DNA alkylating agent, a DNA modifying agent, or a vascular disrupting agents agent. 
     
     
         16 . The composition of  claim 14 , further comprising calicheamycin, doxorubicin, taxol, methotrexate, gemcitabine, cytarabine, vinblastin, daunorubicin, docetaxel, irinotecan, epothilone B, epothilone D, cisplatin, carboplatin, or 5-fluoro-U. 
     
     
         17 .- 24 . (canceled) 
     
     
         25 . A method of inhibiting growth of a tumor, comprising the step of administering to a mammal having a tumor a therapeutically effective amount of the aptamer of  claim 1 . 
     
     
         26 . A method of inhibiting growth of a tumor comprising the step of administering to a mammal having a tumor a therapeutically effective amount of a composition of  claim 14 . 
     
     
         27 . The method of  claim 26 , wherein the cytotoxic agent is a tubulin stabilizer, a tubulin destabilizer, an anti-metabolite, a purine synthesis inhibitor, a nucleotide analog, a DNA alkylating agent, a DNA modifying agent, or a vascular disrupting agent. 
     
     
         28 . The method of  claim 26 , further comprising administering calicheamycin, doxorubicin, taxol, methotrexate, gemcitabine, cytarabine, vinblastin, daunorubicin, docetaxel, irinotecan, epothilone B, epothilone D, cisplatin, carboplatin, or 5-fluoro-U. 
     
     
         29 .- 44 . (canceled) 
     
     
         45 . The method of  claim 25  wherein the tumor is a PDGF mediated cancer or tumor. 
     
     
         46 . The method of  claim 45  wherein the PDGF mediated cancer or tumor is a glioblastoma, a chronic myelomonocytic leukemia, a dermafibrosarcoma protuberan, a gastrointestinal stromal tumor or a soft tissue sarcoma. 
     
     
         47 . The method of  claim 25 , wherein the tumor is a cancer. 
     
     
         48 . A method of inhibiting growth of a tumor comprising the step of administering to a mammal having a tumor the composition of  claim 13 . 
     
     
         49 . The method of  claim 48 , wherein the tumor is a cancer. 
     
     
         50 . The method of  claim 48 , wherein the e tumor is a PDGF mediated cancer or tumor. 
     
     
         51 . The method of  claim 50 , wherein the PDGF mediated cancer or tumor is a glioblastoma, a chronic myelomortocytic leukemia, a dermafibrosarcoma protuberan, gastrointestinal stromal tumor or a soft tissue sarcoma. 
     
     
         52 . The aptamer of  claim 1 , wherein the aptamer comprises a sequence of SEQ ID NO:9. 
     
     
         53 . The aptamer of  claim 1 , wherein the aptamer comprises a sequence of SEQ ID NO:10. 
     
     
         54 . The aptamer of  claim 1 , wherein the aptamer is conjugated to a PEG polymer. 
     
     
         55 . The composition of  claim 13 , wherein the aptamer comprises a sequence of SEQ ID NO:9. 
     
     
         56 . The composition of  claim 13 , wherein the aptamer comprises a sequence of SEQ ID NO:10.