Conformationally stabilized RSV pre-fusion F proteins

Inventors: Christopher Marshall (New York, NY); Mark Yondola (New York, NY); Roberto Mariani (New York, NY); Aaron Zomback (Cheshire, CT); Sonal Gidwani (New York, NY)

C07K14/005 A61K39/155 A61P31/14 C12N7/00 C12N2760/18522 C12N2760/18534 C12N2760/18571

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Quick Facts

Patent No.: US 12703721
App. No.: 18/601,398
Granted: Aug 11, 2026
Kind: B2

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Abstract

The present invention provides mutant RSV F molecules, such as those that can be, or are stabilized, in a pre-fusion conformation by the introduction of one or more DT cross-links. The present invention also provides methods of making such mutant RSV F molecules, compositions comprising such mutant RSV F molecules, and methods of use of such mutant RSV F molecules, for example in vaccination methods, therapeutic methods, and antibody production methods.

Claims (20)

1 . A mutant RSV F molecule comprising: (a) an F2 polypeptide comprising amino acid residues 26-109 of SEQ ID NO 81, and (b) an F1 polypeptide comprising amino acid residues 137-513 of SEQ ID NO 81; wherein the F2 polypeptide is linked to the F1 polypeptide by a disulfide bond.

2 . The mutant RSV F molecule of claim 1 , wherein the molecule binds to a pre-fusion specific antibody.

3 . The mutant RSV F molecule of claim 1 , wherein the molecule binds to an antibody selected from the group consisting of D25, 5C4, AM22 and AM14.

4 . The mutant RSV F molecule of claim 1 , wherein the molecule further comprises one or more tags useful for detection or purification of the RSV F molecule.

5 . The mutant RSV F molecule of claim 4 , wherein the tag is selected from the group consisting of: Strep tags, Strep II tags, FLAG tags, glutathione S-transferase tags, green fluorescent proteintags, hemagglutinin A tags, histidine tags, luciferase tags, maltose-binding protein tags, c-Myc tags, protein A tags, and protein G tags.

6 . The mutant RSV F molecule of claim 4 , wherein the tag comprises SEQ ID NO. 95.

7 . The mutant RSV F molecule of claim 4 , wherein the tag comprises SEQ ID NO. 96.

8 . The mutant RSV F molecule of claim 4 , wherein the tag is a proteolytically cleavable tag.

9 . A soluble, mature trimeric RSVF molecule consisting of three monomers, wherein each monomer comprises (a) an F2 polypeptide comprising amino acid residues 26-109 of SEQ ID NO 81, and (b) an F1 polypeptide comprising amino acid residues 137-513 of SEQ ID NO. 81, and (c) a heterologous trimerization domain, wherein the F2 polypeptide is linked to the F1 polypeptide by a disulfide bond.

10 . The RSV F molecule of claim 9 , wherein the heterologous trimerization domain is a foldon domain, a GCN4 domain, or a T4 fibrinitin domain.

11 . The RSV F molecule of claim 9 , wherein the heterologous trimerization domain comprises SEQ ID NO. 93.

12 . The RSVF molecule of claim 9 , wherein the molecule comprises one or more DT cross links and is stabilized in the pre-F conformation.

13 . The RSVF molecule of claim 10 , wherein the molecule comprises one or more DT cross links and is stabilized in the pre-F conformation.

14 . The RSVF molecule of claim 11 , wherein the molecule comprises one or more DT cross links and is stabilized in the pre-F conformation.

15 . A pharmaceutical composition comprising the RSV molecule of claim 9 .

16 . A pharmaceutical composition comprising the RSV molecule of claim 10 .

17 . A pharmaceutical composition comprising the RSV molecule of claim 11 .

18 . A pharmaceutical composition comprising the RSV molecule of claim 12 .

19 . A pharmaceutical composition comprising the RSV molecule of claim 13 .

20 . A pharmaceutical composition comprising the RSV molecule of claim 14 .