VACCINES AGAINST RESPIRATORY DISEASES

RU2025119692A3Pending Publication Date: 2026-09-01PFIZER INC

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Patent Information

Application Number: RU2025119692
Authority / Receiving Office: RU · RU
Patent Type: Applications
Current Assignee / Owner
Filing Date: 2024-01-16
Publication Date: 2026-09-01

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Claims

1. A mutant of a wild-type PIV1 F protein comprising an F1 polypeptide and an F2 polypeptide, wherein the mutant comprises at least one amino acid mutation relative to the amino acid sequence of the wild-type PIV1 F protein, wherein the amino acid mutation is selected from the group consisting of: (1) at least one mutation introducing a disulfide bond; (2) at least one cavity-filling mutation; (3) at least one mutation with substitution to proline; (4) at least one glycine substitution mutation; and (5) cleavage site mutations.

2. The mutant of claim 1, wherein the mutant comprises a mutation introducing a disulfide bond, wherein the mutation introducing a disulfide bond is Q92C-G134C.

3. The mutant of claim 1 or 2, wherein the mutant comprises a cavity-filling mutation, wherein the cavity-filling mutation is selected from T198A, Q92A, Q92L, A466L, A466V, A466I, S473V, S473L, S473I, S473A, A480L and A480V.

4. The mutant of claim 3, wherein the mutant comprises cavity-filling mutations A466L and S473L.

5. The mutant according to claim 4, further comprising a cavity-filling mutation A480L or A480V.

6. The mutant of any one of claims 1-5, wherein the mutant comprises a proline substitution mutation, wherein the proline substitution mutation is A128P.

7. The mutant of any one of claims 1-6, wherein the mutant comprises a glycine substitution mutation, wherein the glycine substitution mutation is G134A or G134L.

8. The mutant of any one of claims 1-7, wherein the mutant comprises a cleavage site mutation, wherein the cleavage site mutation is F113G and F114S.

9. The mutant of claim 1, wherein the mutant comprises mutations selected from the group consisting of: (1) Q92C-G134C; (2) A466L; (3) A466V; (4) S473V; (5) S473L; (6) A480L; (7) A466L and S473A; (8) A466L and S473L; (9) T198A; (10) G134A; (11) A128R; (12) F113G, F114S, Q92C-G134C, A466L, S473L and A480L; (13) Q92C-G134C, A466L, S473L and A480L; (14) Q92C-G134C, A466L and S473L; (15) F113G, F114S, Q92C-G134C, A466V, S473V and A480V; (16) Q92C-G134C, A466V, S473V and A480V; (17) Q92C-G134C, A466V and S473V; (18) F113G, F114S, A466L, S473L, A480L and G134A; (19) A466L, S473L, A480L and G134A; (20) A466L, S473L and G134A; (21) F113G, F114S, A466L, S473L, A480L, Q92A and G134A; (22) F113G, F114S, A466L, S473L and G134A; (23) A466L, S473L, A480L, Q92A, G134A; (24) A466L, S473L, Q92A, G134A; (25) F113G, F114S, Q92L, G134A; (26) A466L, S473L, A480L, Q92L and G134A; (27) A466L, S473L, Q92L and G134A; (28) F113G, F114S, A466L, S473L, A480L, Q92A and G134L; (29) A466L, S473L, A480L, Q92A and G134L; (30) F113G, F114S, Q92C-G134C, A466I, S473I and A480L; (31) F113G, F114S, Q92C-G134C, A466I and S473I; And (32) A466I, S473I, A480L, Q92L and G134A.

10. The mutant according to claim 1, wherein the mutant contains mutations (1) A466L, S473L, A480L and G134A, (2) F113G, F114S, A466L, S473L and G134A, (3) F113G, F114S, A466L, S473L, A480L and G134A, or (4) F113G, F114S, Q92C, G134C, A466L, S473L and A480L.

11. The mutant of claim 1, wherein the mutant comprises leucine at positions 466, 473 and 480 (466L, 473L and 480L) and alanine at position 134 (134A), and wherein the mutant comprises an F1 polypeptide and an F2 polypeptide selected from the group consisting of: (1) an F2 polypeptide comprising the amino acid sequence of SEQ ID NO:255 and an F1 polypeptide comprising the amino acid sequence of SEQ ID NO:254; (2) an F2 polypeptide comprising an amino acid sequence that is at least 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:255, and an F1 polypeptide comprising an amino acid sequence that is at least 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:254, or wherein the mutant comprises glycine (G) at position 113 (113G), serine at position 114 (114S), leucine at positions 466 and 473 (466L and 473L) and alanine at position 134 (134A), and wherein the mutant comprises an F1 polypeptide and an F2 polypeptide selected from the group consisting of: (1) an F2 polypeptide comprising the amino acid sequence of SEQ ID NO:291 and an F1 polypeptide comprising the amino acid sequence of SEQ ID NO:290; (2) an F2 polypeptide comprising an amino acid sequence that is at least 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:291, and an F1 polypeptide comprising an amino acid sequence that is at least 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:290, or wherein the mutant comprises glycine (G) at position 113 (113G), serine at position 114 (114S), leucine at positions 466, 473 and 480 (466L, 473L and 480L) and alanine at position 134 (134A), and wherein the mutant comprises an F1 polypeptide and an F2 polypeptide selected from the group consisting of: (1) an F2 polypeptide comprising the amino acid sequence of SEQ ID NO:277 and an F1 polypeptide comprising the amino acid sequence of SEQ ID NO:276; (2) an F2 polypeptide comprising an amino acid sequence that is at least 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:277, and an F1 polypeptide comprising an amino acid sequence that is at least 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:276, or wherein the mutant comprises glycine (G) at position 113 (113G), serine at position 114 (114S), leucine at positions 466, 473 and 480 (466L, 473L and 480L) and cysteine at positions 92 and 134 (92C and 134C), wherein the mutant comprises an F1 polypeptide and an F2 polypeptide selected from the group consisting of: (1) an F2 polypeptide comprising the amino acid sequence of SEQ ID NO:273 and an F1 polypeptide comprising the amino acid sequence of SEQ ID NO:272; (2) an F2 polypeptide comprising an amino acid sequence that is at least 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:273, and an F1 polypeptide comprising an amino acid sequence that is at least 97%, 98%, or 99% identical to the amino acid sequence of SEQ ID NO:

272.

12. A mutant according to any one of claims 1-11, wherein the F1 polypeptide does not contain a cytoplasmic domain and a transmembrane domain.

13. The mutant of any one of claims 1-11, wherein the F1 polypeptide comprises or consists of amino acid residues 113-477 or comprises or consists of amino acid residues 113-480.

14. The mutant of any one of claims 1-11, wherein the F1 polypeptide comprises an ectodomain, a transmembrane domain and a cytoplasmic domain.

15. The mutant of any one of claims 1-14, wherein the mutant is linked to a trimerization domain, wherein the trimerization domain is a T4 phage fibritin foldon, wherein the trimerization domain is linked to the C-terminus of the F1 polypeptide via a linker, and The linker is GGGS.

16. A mutant according to any one of claims 1-14, wherein the mutant is in the form of a trimer, and / or where the mutant is in the prefusion conformation.

17. The mutant of any one of claims 1-16, wherein the wild-type PIV1 is SEQ ID NO:

206.

18. A mutant according to any one of claims 1-17, wherein the amino acid positions correspond to the amino acid sequence given in SEQ ID NO:

206.

19. A nucleic acid comprising at least one coding sequence that encodes at least one mutant of the wild-type PIV 1 F protein according to any one of claims 1-18, or an immunogenic fragment or immunogenic variant thereof, wherein the nucleic acid comprises at least one heterologous untranslated region (UTR).

20. The nucleic acid of claim 19, wherein the at least one heterologous untranslated region is selected from at least one heterologous 5'-UTR and / or at least one heterologous 3'-UTR.

21. The nucleic acid of claim 19 or 20, wherein the at least one heterologous 3'-UTR comprises or consists of a nucleic acid sequence that is at least, no more than, exactly, or in the range between any two of 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identical to CΨCGAGCΨGGΨ ACΨGCAΨGCA CGCAAΨGCΨA GCΨGCCCCΨΨ ΨCCCGΨCCΨG GGΨACCCCGA GΨCΨCCCCCG ACCΨCGGGΨC CCAGGΨAΨGC ΨCCCACCΨCC ACCΨGCCCCA CΨCACCACCΨC CΨGCΨAGΨΨC CAGACACCΨC CCAAGCACGC AGCAAΨGCAG CΨCAAAACGC ΨΨAGCCΨAGC CACACCCCCA CGGGAAACAG CAGΨGAΨΨAA CCΨΨΨAGCAA ΨAAACGAAAG ΨΨΨAACΨAAG CΨAΨACΨAAC CCCAGGGΨΨG GΨCAAΨΨΨCG ΨGCCAGCCAC ACCCΨGGAGC ΨAGC.

22. The nucleic acid of any one of claims 19-21, wherein the at least one heterologous 5'-UTR comprises or consists of a nucleic acid sequence that is at least, no more than, exactly, or in the range between any two of 99%, 98%, 97%, 96%, 95%, 90%, 85%, or 80% identical to GAAΨAAAC ΨAGΨAΨΨCΨ CΨGGΨCCCCA CAGACΨCAGA GAGAACCCGC CACC.

23. The nucleic acid of any one of claims 19 to 22, wherein the nucleic acid comprises at least one poly(A) sequence, preferably containing from 30 to 200 adenosine nucleotides and / or at least one poly(C) sequence, preferably containing from 10 to 40 cytosine nucleotides.

24. The nucleic acid of any one of claims 19 to 23, wherein the nucleic acid is DNA or RNA.

25. The nucleic acid of claim 24, wherein the nucleic acid is mRNA, self-replicating RNA, circular RNA, or replicon RNA.

26. The nucleic acid of claim 25, wherein the nucleic acid is mRNA.

27. The nucleic acid of any one of claims 24 to 26, wherein the RNA comprises a 5'-cap structure, preferably m7G, capO, cap1, cap2, a modified capO or a modified cap1 structure, preferably a 5'-cap1 structure.

28. The nucleic acid of any one of claims 25-27, wherein the RNA comprises a 1-methylpseudouridine substitution, and where all RNA uridines are replaced by 1-methylpseudouridine.

29. The nucleic acid of any one of claims 24-28, wherein the RNA comprises a nucleic acid sequence of any one of SEQ ID NO:403, SEQ ID NO:405, SEQ ID NO:407 and SEQ ID NO:

409.

30. A composition comprising at least one nucleic acid according to any one of claims 19-29, wherein the composition comprises at least one pharmaceutically acceptable carrier.

31. A composition comprising at least one nucleic acid according to any one of claims 19-29, wherein the at least one nucleic acid forms a complex with one or more lipids to form lipid nanoparticles (LNPs).

32. The composition of claim 31, wherein the LNP comprises a cationic lipid of formula III-3:

33. The composition according to claim 31 or 32, wherein the LNP comprises a PEG lipid of formula (IVa): where n has an average value in the range from 30 to 60.

34. The composition according to any one of claims 31-33, wherein the LNP comprises a PEG lipid of formula (IVa): where n is an integer chosen such that the average molecular weight of the PEG lipid is approximately 2500 g / mol.

35. The composition of any one of claims 31-34, wherein the LNP comprises one or more neutral lipids and / or one or more steroids or steroid analogues, wherein the neutral lipid is 1,2-distearoyl-ep-glycero-3-phosphocholine (DSPC), and and the steroid is cholesterol.

36. The composition of any one of claims 31 to 35, wherein the LNP comprises (i) at least one cationic lipid, preferably a lipid of formula (III), more preferably lipid III-3; (ii) at least one neutral lipid, preferably 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); (iii) at least one steroid or steroid analogue, preferably cholesterol; and (iv) at least one polymeric conjugated lipid, preferably a PEG lipid derived from formula (IVa, with n=49), wherein components (i) to (iv) are in a molar ratio of about 20-60% cationic lipid, 5-25% neutral lipid, 25-55% sterol and 0.5-15% PEG lipid.

37. The composition of any one of claims 31 to 36, wherein the LNP comprises (i) at least one cationic lipid, preferably a lipid of formula (III), more preferably lipid III-3; (ii) at least one neutral lipid, preferably 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC); (iii) at least one steroid or steroid analogue, preferably cholesterol; and (iv) at least one polymeric conjugated lipid, preferably a PEG lipid derived from formula (IVa, with n=45), wherein components (i) to (iv) are in a molar ratio of about 20-60% cationic lipid, 5-25% neutral lipid, 25-55% sterol and 0.5-151 PEG lipid.

38. The composition of any one of claims 31-37, wherein the Z-average size of the LNPs is in the range of from about 60 nm to about 120 nm.

39. The composition of any one of claims 31-38, wherein the LNP comprises (i) at least one cationic lipid of formula III-3; (ii) DSPC; (iii) cholesterol; and (iv) a PEG lipid of formula IVa, wherein components (i)-(iv) are in a molar ratio of approximately 20-60% cationic lipid, 5-25% neutral lipid, 25-55% sterol, and 0.5-15% PEG lipid.

40. An immunogenic composition comprising a mutant according to any one of claims 1-18 or a nucleic acid according to any one of claims 19-29, or a composition according to any one of claims 30-39.

41. The immunogenic composition according to claim 40, further comprising an hMPV A antigen selected from the group consisting of a mutant of the wild-type hMPV A protein F and a nucleic acid encoding a mutant of the wild-type hMPV A protein F and / or, an hMPV B antigen selected from the group consisting of a mutant of the wild-type hMPV B protein F and a nucleic acid encoding a mutant of the wild-type hMPV B protein F, and / or, a PIV1 antigen selected from the group consisting of a mutant of the wild-type PIV1 F protein and a nucleic acid encoding a mutant of the wild-type PIV1 F protein, and / or, an RSV antigen selected from the group consisting of a mutant of the wild-type RSV F protein subtype A and a nucleic acid encoding a mutant of the wild-type RSV F protein subtype A, and / or, an RSV antigen selected from the group consisting of a mutant of the wild-type RSV subtype B F protein and a nucleic acid encoding a mutant of the wild-type RSV subtype B F protein.

42. A mutant of the wild-type hMPV F protein, wherein the mutant comprises at least one amino acid mutation relative to the amino acid sequence of the wild-type hMPV F protein, and wherein the amino acid mutation is selected from the group consisting of: (1) an artificially created disulfide mutation selected from the group consisting of G366C and D454C, T411C and Q434C, I137C and A159C, A140C and S149C, L141C and A159C, L141C and A161C, E146C and T160C, V148C and L158C and T150C and R156C; (2) a cavity-filling mutation selected from the group consisting of T49I, S149T, A159V, S291I, T365I, and L473F; (3) mutations with substitution to proline selected from the group consisting of L66P, L110P, S132P, N145P, L187P, V449P and A459P, (4) mutations with a glycine substitution selected from the group consisting of G106A, G121A and G239A.

43. A nucleic acid comprising at least one coding sequence that encodes at least one mutant of the wild-type hMPV F protein according to claim 42.

44. A mutant of a wild-type PIV3 F protein comprising an F1 polypeptide and an F2 polypeptide, wherein the mutant comprises at least one amino acid mutation relative to the amino acid sequence of the wild-type PIV3 F protein, and wherein the amino acid mutation is selected from the group consisting of: (1) an artificially created disulfide mutation selected from the group consisting of V175C-A202C, S160C-V170C, E209C-L234C, E209C-S233C, G85C-E209C, and Q162C-L168C; (2) a cavity-filling mutation selected from the group consisting of S470A, I474F, S477A, and A463L; (3) mutations with substitution to proline selected from the group consisting of S164P or G219P; (4) mutations with a glycine substitution selected from the group consisting of G196A or G230A; and (5) an electrostatic mutation selected from the group consisting of E182L or D455S; (6) mutations at the cleavage site.

45. The mutant according to claim 44, wherein the mutant contains the mutations E209C and L234C.

46. The mutant according to claim 45, wherein the mutant contains the mutations E20 9C, L234C, S160C and V170C.

47. The mutant of claim 44, wherein the mutant comprises mutations selected from the group consisting of (1) G230A, S470A and S477A; (2) S160C, V170C, G230A and A463L; (3) S160C, V170C, S470A and S477A; (4) S160C, V170C, G230A, S470A and S477A; (5) S160C, V170C, G230A, A463L, S470A and S477A (6) S160C, V170C, E209C, L234C, A463L and S470L; (7) S160C, V170C, E209C, L234C, A463L and I474F; (8) S160C, V170C, E209C, L234C, A463L, S470L, F110G, F111S; (9) S160C, V170C, A463L and S470L, and (10) E209C, L234C.

48. A nucleic acid comprising at least one coding sequence that encodes at least one mutant of the wild-type PIV3 F protein according to any one of claims 44-47.

49. The nucleic acid of claim 48, wherein the nucleic acid is mRNA and comprises a nucleic acid sequence of any of SEQ ID NO:411, SEQ ID NO:413, SEQ ID NO:415, SEQ ID NO:417 and SEQ ID NO:419, SEQ ID NO:504, SEQ ID NO:506, SEQ ID NO:508 and SEQ ID NO:510, SEQ ID NO:295, SEQ ID NO:297 and SEQ ID NO:299.