Immunostimulating-Toxic RNA In Alkaline Earth Metal Formulation

Abstract

A composition including an immunostimulating RNA molecule in a dication containing solution wherein the RNA includes a chemical modification which is toxic to cancer or tumor cells. Pharmaceutical compositions incorporate the immunostimulating RNA with tumor cytotoxicity. Methods for treating cancer and tumors use the solution of the immunostimulating RNA with tumor cytotoxicity.

1 . A composition comprising:
 an RNA molecule having an immunostimulating activity in a dication containing solution, wherein the RNA molecule comprises one or more of a tumor cytotoxic nucleotide, a tumor cytotoxic chemical moiety, and a tumor cytotoxic nucleotide analogue having a chemical modification at a base moiety and/or a sugar moiety thereof.   
     
     
         2 . The composition of  claim 1  wherein the tumor cytotoxic nucleotide analogue has a chemical modification at the base moiety. 
     
     
         3 . The composition of  claim 2  wherein the tumor cytotoxic nucleotide analogue is selected from the group consisting of 5-fluoro-uridine, 6-mercaptopurine, pentostatin and 2-chloro-adenine. 
     
     
         4 . The composition of  claim 1  wherein the tumor cytotoxic nucleotide analogue has a chemical modification at the sugar moiety. 
     
     
         5 . The composition of  claim 4  wherein the tumor cytotoxic nucleotide analogue is selected from the group consisting of cytarabine, fludarabine and gemcitabine. 
     
     
         6 . The composition of  claim 1  wherein the RNA molecule activates TLR-3 and/or TLR-7 and/or TLR-8 and/or RIG-I. 
     
     
         7 . The composition of  claim 1  wherein the RNA molecule comprises a sequence of at least four consecutive G residues and/or a sequence of at least five consecutive U residues and/or the sequence motif GPunG (with Pu being G or A and n being an integer of from 1 to 4 or more) and/or the sequence motif GGAmAGG (with m being an integer of from 0 to 4 or more). 
     
     
         8 . The composition according to  claim 1  wherein the RNA molecule is an ssRNA oligonucleotide of 6 to 100 nucleotides. 
     
     
         9 . The composition according to  claim 1  wherein the RNA molecule comprises more than 100 nucleotides. 
     
     
         10 . The composition according to  claim 1  wherein the RNA molecule is present in complex with alkali metal ions. 
     
     
         11 . The composition of  claim 10  wherein the alkali metal ions are Na + . 
     
     
         12 . The composition according to  claim 10  wherein the dication is Ca 2+ . 
     
     
         13 . The composition of  claim 1  wherein the solution comprises Ringer lactate. 
     
     
         14 . A method for concurrent treatment of tumor in a subject and stimulating a host immune response in the subject, comprising administering to the subject an effective amount of a pharmaceutical composition comprising an RNA molecule having an immunostimulating activity in a dication containing solution, wherein the RNA molecule comprises one or more of a tumor cytotoxic nucleotide, a tumor cytotoxic chemical moiety, and a tumor cytotoxic nucleotide analogue having a chemical modification at a base moiety and/or a sugar moiety thereof. 
     
     
         15 . The method of  claim 14 , wherein the RNA molecule is linked to a tumor cytotoxic chemical moiety being a cyanide group, or an inhibitor of tyrosine kinase, or an inhibitor of mutated oncogene. 
     
     
         16 . The method of  claim 14 , wherein the RNA molecule comprises a tumor toxin selected from the group consisting of sunitinib, sorafenib and vemurafenib. 
     
     
         17 . The method of  claim 14 , wherein the RNA molecule comprises a tumor cytotoxic nucleotide analogue having a chemical modification at the base moiety 
     
     
         18 . The method of  claim 17 , wherein the tumor cytotoxic nucleotide analogue is selected from the group consisting of 5-fluoro-uridine, 6-mercaptopurine, pentostatin and 2-chloro-adenine. 
     
     
         19 . The method of  claim 14  wherein the RNA molecule comprises a tumor cytotoxic nucleotide analogue having a chemical modification at the sugar moiety. 
     
     
         20 . The method of  claim 19 , wherein the tumor cytotoxic nucleotide analogue is selected from the group consisting of selected from the group consisting of cytarabine, fludarabine and gemcitabine. 
     
     
         21 . The method of  claim 14 , wherein the RNA molecule activates TLR-3 and/or TLR-7 and/or TLR-8 and/or RIG-I. 
     
     
         22 . The method of  claim 14 , wherein the RNA molecule comprises a sequence of at least four consecutive G residues and/or a sequence of at least five consecutive U residues and/or the sequence motif GPunG (with Pu being G or A and n being an integer of from 1 to 4 or more) and/or the sequence motif GGAmAGG (with m being an integer of from 0 to 4 or more). 
     
     
         23 . The method of  claim 14 , wherein the RNA molecule is an ssRNA oligonucleotide of 6 to 100 nucleotides. 
     
     
         24 . The method of  claim 14 , wherein the RNA molecule comprises more than 100 nucleotides. 
     
     
         25 . The method of  claim 14 , wherein the RNA molecule is present in complex with alkali metal ions. 
     
     
         26 . The method of  claim 25 , wherein the alkali metal ions are Na + . 
     
     
         27 . The method of  claim 25 , wherein the dication is Ca 2+ . 
     
     
         28 . The method of  claim 14 , wherein the solution comprises Ringer lactate.