Composition for treating lung cancer, particularly of non-small lung cancers (nsclc)

Abstract

The present invention relates to an active (immunostimulatory) composition comprising at least one RNA, preferably a mRNA, encoding at least two (preferably different) antigens capable of eliciting an (adaptive) immune response in a mammal. The invention furthermore relates to a vaccine comprising said active (immunostimulatory) composition, and to the use of said active (immunostimulatory) composition (for the preparation of a vaccine) and/or of the vaccine for eliciting an (adaptive) immune response for the treatment of lung cancer, particularly of non-small cell lung cancers (NSCLC), preferably selected from the three main sub-types squamous cell lung carcinoma, adenocarcinoma and large cell lung carcinoma, or of disorders related thereto. Finally, the invention relates to kits, particularly to kits of parts, containing the active (immunostimulatory) composition and/or the vaccine.

1 - 24 . (canceled) 
     
     
         25 . An active immunostimulatory composition comprising at least five RNAs, each RNA encoding a different antigen, wherein the at least five RNAs are:
 an isolated NY-ESO-1 antigen coding RNA complexed with protamine;   (ii) an isolated MAGE-C1 antigen coding RNA complexed with protamine;   (iii) an isolated MAGE-C2 antigen coding RNA complexed with protamine;   (iv) an isolated 5T4 antigen coding RNA complexed with protamine; and   (v) an isolated Survivin antigen coding RNA complexed with protamine;   or   (i) an isolated NY-ESO-1 antigen coding RNA comprising a globin 3′ untranslated region (3′UTR);   (ii) an isolated MAGE-C1 antigen coding RNA comprising a globin 3′ untranslated region (3′UTR);   (iii) an isolated MAGE-C2 antigen coding RNA comprising a globin 3′ untranslated region (3′UTR);   (iv) an isolated 5T4 antigen coding RNA comprising a globin 3′ untranslated region (3′UTR); and   (v) an isolated Survivin antigen coding RNA comprising a globin 3′ untranslated region (3′UTR);   or   (i) an isolated NY-ESO-1 antigen coding RNA comprising a G/C content of the antigen coding region that is increased compared to the G/C content of a wild-type RNA encoding the antigen;   (ii) an isolated MAGE-C1 antigen coding RNA comprising a G/C content of the antigen coding region that is increased compared to the G/C content of a wild-type RNA encoding the antigen;   (iii) an isolated MAGE-C2 antigen coding RNA comprising a G/C content of the antigen coding region that is increased compared to the G/C content of a wild-type RNA encoding the antigen;   (iv) an isolated 5T4 antigen coding RNA comprising a G/C content of the antigen coding region that is increased compared to the G/C content of a wild-type RNA encoding the antigen; and   (v) an isolated Survivin antigen coding RNA comprising a G/C content of the antigen coding region that is increased compared to the G/C content of a wild-type RNA encoding the antigen;   or   (i) an isolated NY-ESO-1 antigen coding RNA comprising a 5′ untranslated region (5′UTR) and/or a 3′ untranslated region (3′UTR) that is modified compared to a wild-type RNA encoding the antigen;   (ii) an isolated MAGE-C1 antigen coding RNA comprising a 5′ untranslated region (5′UTR) and/or a 3′ untranslated region (3′UTR) that is modified compared to a wild-type RNA encoding the antigen;   (iii) an isolated MAGE-C2 antigen coding RNA comprising a 5′ untranslated region (5′UTR) and/or a 3′ untranslated region (3′UTR) that is modified compared to a wild-type RNA encoding the antigen;   (iv) an isolated 5T4 antigen coding RNA comprising a 5′ untranslated region (5′UTR) and/or a 3′ untranslated region (3′UTR) that is modified compared to a wild-type RNA encoding the antigen; and   (v) an isolated Survivin antigen coding RNA comprising a 5′ untranslated region (5′UTR) and/or a 3′ untranslated region (3′UTR) that is modified compared to a wild-type RNA encoding the antigen.   
     
     
         26 . The active immunostimulatory composition according to  claim 25 , wherein the at least five RNAs are:
 (i) an isolated NY-ESO-1 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 21, or at least 80% identical to SEQ ID NO: 21, complexed with protamine;   (ii) an isolated MAGE-C1 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 24, or at least 80% identical to SEQ ID NO: 24, complexed with protamine;   (iii) an isolated MAGE-C2 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 26, or at least 80% identical to SEQ ID NO: 26, complexed with protamine;   (iv) an isolated 5T4 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 4, or at least 80% identical to SEQ ID NO: 4, complexed with protamine; and   (v) an isolated Survivin antigen coding RNA comprising the RNA sequence of SEQ ID NO: 19, or at least 80% identical to SEQ ID NO: 19, complexed with protamine;   or   (i) an isolated NY-ESO-1 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 21, or at least 80% identical to SEQ ID NO: 21, comprising a globin 3′ untranslated region (3′UTR);   (ii) an isolated MAGE-C1 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 24, or at least 80% identical to SEQ ID NO:24, comprising a globin 3′ untranslated region (3′UTR);   (iii) an isolated MAGE-C2 antigen coding RNA comprising the RNA sequence of SEQ ID NO:26, or at least 80% identical to SEQ ID NO:26, comprising a globin 3′ untranslated region (3′UTR);   (iv) an isolated 5T4 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 4, or at least 80% identical to SEQ ID NO: 4, comprising a globin 3′ untranslated region (3′UTR); and   (v) an isolated Survivin antigen coding RNA comprising the RNA sequence of SEQ ID NO:19, or at least 80% identical to SEQ ID NO:19, comprising a globin 3′ untranslated region (3′UTR);   or   (i) an isolated NY-ESO-1 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 21, or at least 80% identical to SEQ ID NO 21, comprising a G/C content of the antigen coding region that is increased compared to the G/C content of a wild-type RNA encoding the antigen;   (ii) an isolated MAGE-C1 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 24, or at least 80% identical to SEQ ID NO: 24, comprising a G/C content of the antigen coding region that is increased compared to the G/C content of a wild-type RNA encoding the antigen;   (iii) an isolated MAGE-C2 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 26, or at least 80% identical to SEQ ID NO: 26, comprising a G/C content of the antigen coding region that is increased compared to the G/C content of a wild-type RNA encoding the antigen;   (iv) an isolated 5T4 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 4, or at least 80% identical to SEQ ID NO 4, comprising a G/C content of the antigen coding region that is increased compared to the G/C content of a wild-type RNA encoding the antigen; and   (v) an isolated Survivin antigen coding RNA comprising the RNA sequence of SEQ ID NO: 19, or at least 80% identical to SEQ ID NO: 19, comprising a G/C content of the antigen coding region that is increased compared to the G/C content of a wild-type RNA encoding the antigen;   or   (i) an isolated NY-ESO-1 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 21, or at least 80% identical to SEQ ID NO: 21, comprising a 5′ untranslated region (5′UTR) and/or a 3′ untranslated region (3′UTR) that is modified compared to a wild-type RNA encoding the antigen;   (ii) an isolated MAGE-C1 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 24, or at least 80% identical to SEQ ID NO 24, comprising a 5′ untranslated region (5′UTR) and/or a 3′ untranslated region (3′UTR) that is modified compared to a wild-type RNA encoding the antigen;   (iii) an isolated MAGE-C2 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 26, or at least 80% identical to SEQ ID NO 26, comprising a 5′ untranslated region (5′UTR) and/or a 3′ untranslated region (3′UTR) that is modified compared to a wild-type RNA encoding the antigen;   (iv) an isolated 5T4 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 4, or at least 80% identical to SEQ ID NO 4, comprising a 5′ untranslated region (5′UTR) and/or a 3′ untranslated region (3′UTR) that is modified compared to a wild-type RNA encoding the antigen; and   (v) an isolated Survivin antigen coding RNA comprising the RNA sequence of SEQ ID NO: 19, or at least 80% identical to SEQ ID NO 19,   comprising a 5′ untranslated region (5′UTR) and/or a 3′ untranslated region (3′UTR) that is modified compared to a wild-type RNA encoding the antigen.   
     
     
         27 . The active immunostimulatory composition according to  claim 25 , further comprising an isolated MUC-1 antigen coding RNA, wherein said MUC-1 antigen coding RNA is complexed with protamine or comprises:
 a globin 3′ untranslated region (3′UTR); or   a G/C content of the antigen coding region that is increased compared to the G/C content of a wild-type RNA encoding the antigen; or   a 5′ untranslated region (5′UTR) and/or a 3′ untranslated region (3′UTR) that is modified compared to a wild-type RNA encoding the antigen.   
     
     
         28 . The active immunostimulatory composition according to  claim 26 , further comprising
 (vi) an isolated MUC-1 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 2, or at least 80% identical to SEQ ID NO: 2, complexed with protamine; or   (vi) an isolated MUC-1 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 2, or at least 80% identical to SEQ ID NO 2, comprising a globin 3′ untranslated region (3′UTR); or   (vi) an isolated MUC-1 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 2, or at least 80% identical to SEQ ID NO: 2, comprising a G/C content of the antigen coding region that is increased compared to the G/C content of a wild-type RNA encoding the antigen; or   (vi) an isolated MUC-1 antigen coding RNA comprising the RNA sequence of SEQ ID NO: 2, or at least 80% identical to SEQ ID NO 2, comprising a 5′ untranslated region (5′UTR) and/or a 3′ untranslated region (3′UTR) that is modified compared to a wild-type RNA encoding the antigen.   
     
     
         29 . The active immunostimulatory composition according to  claim 25 , wherein at least one of said at least five RNAs is an mRNA. 
     
     
         30 . The active immunostimulatory composition according to  claim 29 , wherein at least one of said at least five RNAs is an monocistronic RNA. 
     
     
         31 . The active immunostimulatory composition according to  claim 29 , wherein the mRNA comprises a G/C content of the antigen coding region that is increased compared to the G/C content of a wild-type RNA encoding the antigen. 
     
     
         32 . The active immunostimulatory composition according to  claim 29 , wherein the mRNA comprises a A/U content in the environment of the ribosome binding site that is increased compared with the A/U content of a wild-type RNA encoding the antigen. 
     
     
         33 . The active immunostimulatory composition according to  claim 29 , wherein the mRNA comprises a 5′ untranslated region (5′UTR) and/or 3′ untranslated region (3′UTR) that is modified compared to a wild-type RNA encoding the antigen. 
     
     
         34 . The active immunostimulatory composition according to  claim 29 , wherein the mRNA comprises a 5′ cap structure; a poly(A) tail; a poly(C) tail; and/or a globin 3′UTR. 
     
     
         35 . The active immunostimulatory composition according to  claim 25  comprising at least one adjuvant. 
     
     
         36 . The active immunostimulatory composition according to  claim 25  comprising a pharmaceutically acceptable carrier. 
     
     
         37 . The active immunostimulatory composition of  claim 25 , wherein at least one of said at least five RNAs comprises a globin 3′ UTR. 
     
     
         38 . The active immunostimulatory composition according to  claim 29 , wherein the mRNA comprises a 3′UTR that does not comprise an AU-rich sequence. 
     
     
         39 . The active immunostimulatory composition according to  claim 29 , wherein at least one of said RNA comprises RNA that does not comprise the sequence GAACAAG. 
     
     
         40 . The active immunostimulatory composition according to  claim 25 , wherein the active immunostimulatory composition elicits an adaptive immune response when administered to a subject.