# US 2026/0234589 A1 · Influenza neuraminidase tetramers

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- Number: US 2026/0234589 A1
- Document ID: US20260234589A1
- Status: Published application
- Kind: A1
- Application number: 19/398,620
- Filed: 2025-11-24
- Published: 2026-08-13
- Earliest claimed: 2023-06-01
- Assignees: Icosavax, Inc.
- Applicants: Icosavax, Inc.
- Inventors: Daniel ELLIS
- Web page: https://patentgrep.com/patent/US20260234589A1

## CPC

- C12N 9/2402: {hydrolysing O- and S- glycosyl compounds (3.2.1)}
- A61K 39/12: Viral antigens
- A61K 39/145: Orthomyxoviridae, e.g. influenza virus
- A61P 37/04: Immunostimulants
- C07K 14/005: from viruses
- C07K 14/195: from bacteria
- C12Y 302/01018: Exo-alpha-sialidase (3.2.1.18), i.e. trans-sialidase
- A61K 2039/55566: {Emulsions, e.g. Freund's adjuvant, MF59}
- A61K 2039/575: {humoral response}
- A61K 2039/6068: {Other bacterial proteins, e.g. OMP}
- A61K 2039/645: {Dendrimers; Multiple antigen peptides}
- A61K 2039/70: {Multivalent vaccine}
- C07K 2319/55: containing a fusion with a toxin, e.g. diphteria toxin
- C07K 2319/73: containing coiled-coiled motif (leucine zippers)
- C07K 2319/735: containing a domain for self-assembly, e.g. a viral coat protein (includes phage display)
- C12N 2760/16022: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2760/16034: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2760/16122: New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
- C12N 2760/16134: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12Y: ENZYMES

## Abstract

The disclosure relates to compositions that include a recombinant influenza neuraminidase tetramer that includes four copies of a fusion protein which includes a DA4B tetramerization domain, optionally a linker, and an influenza NA head domain, and uses thereof. Novel linkers are provided. The disclosure further relates to a recombinant influenza neuraminidase (NA) polypeptide, comprising an influenza NA head domain comprising one or more amino acid substitutions selected from the group consisting of I99P, Y100L, T131Q, C161V, E165S, S172A, V177I, S196T, V205I, Q408M, R419V, and V453T. Further provided are compositions, methods of making, and methods of use, for example as vaccines for influenza.

## Claims

### Claim 1

A recombinant influenza neuraminidase (NA) tetramer, comprising four copies of a fusion protein, said fusion protein comprising, in N- to C-terminal order, a DA4B tetramerization domain and an influenza NA head domain,
wherein the DA4B tetramerization domain comprises, consists essentially of, or consists of a DA4B polypeptide sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 1-5.

### Claim at position 2

-9. (canceled)

### Claim 10 (depends on 1)

The tetramer of claim 1, further comprising a linker between said DA4B tetramerization domain and said influenza NA head domain, wherein the linker consists of GGSGGSGG (SEQ ID NO: 11) or comprises the polypeptide sequence GGSGGSGG (SEQ ID NO: 11), the linker consists of ATPRGG (SEQ ID NO: 12) or comprises the polypeptide sequence ATPRGG (SEQ ID NO: 12), the linker consists of ATPRGSGG (SEQ ID NO: 13) or comprises the polypeptide sequence ATPRGSGG (SEQ ID NO: 13), or the linker consists of GGATPRGSGG (SEQ ID NO: 14) or comprises the polypeptide sequence GGATPRGSGG (SEQ ID NO: 14).

### Claim at position 4

-13. (canceled)

### Claim 14 (depends on 1)

The tetramer of claim 1, wherein the influenza NA head domain comprises an NA polypeptide sequence that is at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 15-31 or 423.

### Claim 15

(canceled)

### Claim 16 (depends on 1)

The tetramer of claim 1, wherein the influenza NA head domain comprises three or more amino acid substitutions selected from the group consisting of I99P, Y100L, T131Q, C161V, E165S, S172A, V177I, S196T, V205I, Q408M, R419V, and V453T, numbered relative SEQ ID NO: 15.

### Claim 17 (depends on 1)

The tetramer of claim 1, wherein the influenza NA head domain comprises the amino acid substitutions, numbered relative SEQ ID NO: 15, selected from:
a) I99P, C161V, E165S, S172A, S196T;
b) I99P, T131Q, C161V, E165S, S172A, S196T;
c) I99P, T131Q, C161V, E165S, S172A, V177I, S196T;
d) I99P, T131Q, C161V, E165S, S172A, S196T, V453T;
e) I99P, T131Q, C161V, E165S, S172A, V177I, S196T, V205I;
f) I99P, Y100L, T131Q, C161V, E165S, S172A, V177I, S196T, V205I, Q408M, R419V;
g) I99P, C161V, E165S, S172A, V177I, S196T;
h) I99P, C161V, S172A, S196T; or
i) I99P, C161V, S172A, V177I, S196T.

### Claim 18 (depends on 1)

The tetramer of claim 1, wherein:
a) the NA head domains are in a closed conformation;
b) the tetramer has increased thermal stability in the presence of chelating agent compared to a tetramer with tetrabrachion tetramerization domain;
c) the tetramer has increased interaction to neuraminidase inhibitor compared to a tetramer with tetrabrachion tetramerization domain; and/or
d) the tetramer is expressed in recombinant cell culture at increased yield compared to a tetramer with a tetrabrachion tetramerization domain.

### Claim 19 (depends on 1)

A fusion protein comprised by the tetramer of claim 1.

### Claim 20

(canceled)

### Claim 21 (depends on 19)

A polynucleotide encoding the fusion protein of claim 19, optionally wherein said polynucleotide is an mRNA.

### Claim 22

(canceled)

### Claim 23 (depends on 1)

A pharmaceutical composition, comprising the tetramer of claim 1 and a pharmaceutically acceptable carrier.

### Claim 24

(canceled)

### Claim 25 (depends on 23)

A method of immunizing a subject in need thereof against infection by influenza or of treating and/or preventing influenza in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition of claim 23.

### Claim 26

(canceled)

### Claim 27 (depends on 25)

The method of claim 25, wherein the method generates an antibody response to the tetramer equivalent to or greater than the antibody response to administration of a tetramer with a tetrabrachion tetramerization domain and/or at least as effectively as administering a tetramer with a tetrabrachion tetramerization domain.

### Claim at position 19

-29. (canceled)

### Claim 30 (depends on 21)

A host cell comprising the polynucleotide of claim 21.

### Claim 31 (depends on 30)

A method of producing a recombinant influenza neuraminidase (NA) tetramer, comprising culturing the host cell of claim 30 in cell culture media, and harvesting the recombinant influenza neuraminidase (NA) tetramer from the cell culture media or from the host cell.

### Claim at position 22

-33. (canceled)

### Claim 34

A recombinant influenza neuraminidase (NA) polypeptide, comprising an influenza NA head domain comprising one or more amino acid substitutions selected from the group consisting of I99P, Y100L, T131Q, C161V, E165S, S172A, V177I, S196T, V205I, Q408M, R419V, and V453T, numbered relative SEQ ID NO: 15.

### Claim at position 24

-53. (canceled)

### Claim 54 (depends on 1)

A pharmaceutical composition, comprising a recombinant influenza neuraminidase (NA) tetramer according to claim 1 and an influenza HA vaccine antigen, wherein the influenza HA vaccine antigen is a protein nanostructure comprising an influenza HA ectodomain.

### Claim 55

(canceled)

### Claim 56 (depends on 54)

The pharmaceutical composition of claim 54, wherein the protein nanostructure comprises a trimeric component comprising a trimer protein comprising a fusion protein, wherein the fusion protein comprises, in N- to C-terminal order, the influenza HA ectodomain, a polypeptide linker, and an assembly domain.

### Claim 57

(canceled)

### Claim 58 (depends on 56)

The pharmaceutical composition of claim 56,
wherein the assembly domain comprises a polypeptide sequence that is at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 458-460;
wherein the influenza HA ectodomain comprises a polypeptide sequence that is at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 452-455, or 465;
wherein the pentamer protein comprises a polypeptide sequence that is at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 461-463;
wherein the trimer protein comprises a polypeptide sequence that is at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 448-451, or 464; and/or
wherein the polypeptide linker comprises a polypeptide sequence that is at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 456 or 457.

### Claim at position 30

-63. (canceled)

### Claim 64 (depends on 56)

The pharmaceutical composition of claim 56, wherein the composition comprises one or more pharmaceutically acceptable diluents, adjuvants, or excipients.

### Claim at position 32

-69. (canceled)

### Claim 70 (depends on 56)

A method of immunizing a subject in need thereof against infection by influenza or of treating and/or preventing influenza in a subject in need thereof, the method comprising administering to the subject an effective amount of the pharmaceutical composition according to claim 56.

### Claim at position 34

-73. (canceled)

### Claim 74

A protein nanostructure comprising a trimeric component comprising a trimer polypeptide and a pentameric component comprising a pentamer polypeptide, wherein the trimer polypeptide is a fusion protein comprising, in N- to C-terminal order, an influenza HA ectodomain, a polypeptide linker, and an assembly domain,
wherein the assembly domain comprises a polypeptide sequence at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 458-460;
wherein the influenza HA ectodomain comprises a polypeptide sequence that is at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 452-455, or 465;
wherein the pentamer protein comprises a polypeptide sequence that is at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 461-463;
wherein the trimer protein comprises a polypeptide sequence that is at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to any one of SEQ ID NOs: 448-451, or 464; and/or
wherein the polypeptide linker comprises a polypeptide sequence that is at least 70%, at least 75%, at least 80%, at least 81%, at least 82%, at least 83%, at least 84%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, at least 99%, or 100% identical to SEQ ID NO: 456 or 457.

### Claim at position 36

-81. (canceled)