MRNA THERAPEUTIC COMPOSITIONS
The present disclosed and described technology are directed to multimodal mRNA-based immunotherapies that deliver both antigens and immunomodulators. Related formulations, method of administration, and kits are disclosed and described.
1 . An isolated messenger ribonucleic acid (mRNA) encoding a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 13 and SEQ ID NO: 15.
2 . The isolated mRNA of claim 1 , wherein the isolated mRNA has at least about 80% nucleic acid sequence identity to SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 14, or SEQ ID NO: 16.
3 . A composition comprising the isolated mRNA of claim 1 , wherein the isolated mRNA is at least partially encapsulated with a delivery vehicle.
4 . The composition of claim 3 , wherein the delivery vehicle has a particle size less than or equal to about 200 nm.
5 . The composition of claim 3 , wherein the delivery vehicle is selected from the group consisting of amphipathic molecules, amino-lipidated peptides, tertiary amino lipidated cationic peptides, a cationic component, a peptoid, a lipoid, a liposome, a lipoplex, a lipid nanoparticle, a cationic lipid nanoparticle, a polymeric compound, and a conjugate.
6 . The composition of claim 5 , wherein the delivery vehicle comprises at a compound or pharmaceutically acceptable salt of the compound having a having formula (I)
wherein n is 1, 2, 3, 4, 5, or 6; R 1 is H, C 1-3 alkyl, or hydroxyethyl; and each R 2 independently is C 8-24 alkyl or C 8-24 alkenyl.
7 . The composition of claim 6 , wherein the compound is selected from the group consisting of:
and pharmaceutically acceptable salts of the compound.
8 . The composition of claim 3 , wherein the composition further comprises an additional isolated mRNA that encodes a pro-inflammatory cytokine, wherein the pro-inflammatory cytokine is interleukin −12.
9 . The composition of claim 8 , wherein the pro-inflammatory cytokine comprises the amino acid sequence identified as SEQ ID NO:21.
10 . The composition of claim 8 , wherein the additional isolated mRNA has at least about 80% nucleic acid sequence identity to SEQ ID NO:20.
11 . The composition of claim 3 , wherein the composition further comprises an additional isolated mRNA that encodes an antigen, wherein the antigen is HPV16 E6 E7.
12 . The composition of claim 11 , wherein the antigen has an amino acid sequence identified as SEQ ID NO:24 or SEQ ID NO:27.
13 . The composition of claim 11 , wherein the third isolated mRNA has at least about 80% nucleic acid sequence identity to SEQ ID NO:23 or SEQ ID NO:26.
14 . The composition of claim 3 , wherein the composition is a therapeutic composition or a vaccine.
15 . The composition of claim 14 , wherein the composition is a human papillomavirus (HPV) mRNA vaccine.
16 . The composition of claim 14 , wherein the composition is configured to be administered to a subject known to have cervical cancer, HPV-driven cancer, or a disease associated with HPV.
17 . The composition of claim 14 , wherein the composition is configured to be administered as an injectable preparation.
18 . The composition of claim 14 , wherein the composition further comprises one or more one or more therapeutically acceptable carriers, therapeutically acceptable diluents, therapeutically acceptable excipients or other therapeutic agents.
19 . An isolated polynucleotide comprising a formula:
5′UTR—Signal/Leader—mRNA coding region—3′ UTR—PolyA,
wherein the mRNA coding region encodes a polypeptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 3, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 11, SEQ ID NO: 13, SEQ ID NO: 15, or SEQ ID NO: 17.
20 . The isolated polynucleotide of claim 19 , wherein the isolated polynucleotide comprises a modified 3′UTR, a modified 5′UTR, one or more modifications to a nucleobase-sugar-internucleoside linkage, or a combination thereof;
wherein the isolated polynucleotide comprises a nucleobase-sugar-internucleoside linkage selected from the group consisting of pseudouridine-alpha-thio-MP, 1-methyl-pseudouridine-alpha-thio-MP, 1-ethyl-pseudouridine-MP, 1-propyl-pseudouridine-MP, 1-(2,2,2-trifluoroethyl)-pseudouridine-MP, 2-amino-adenine-MP, xanthosine-MP, 5-bromo-cytidine-MP, 5-aminoallyl-cytidine-MP, 2-aminopurine-riboside-MP, pseudouridine-alpha-thio-MP, 1-methyl-pseudouridine-alpha-thio-MP, 5-bromo-cytidine-MP, and combinations thereof.