# US 12,110,339 B2 · ICOS ligand variant immunomodulatory proteins and uses thereof

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- Number: US 12,110,339 B2
- Document ID: US12110339B2
- Status: Granted
- Kind: B2
- Application number: 17/103,807
- Filed: 2020-11-24
- Published: 2021-06-24
- Granted: 2024-10-08
- Earliest claimed: 2016-04-15
- Assignees: Alpine Immune Sciences, Inc.
- Applicants: Alpine Immune Sciences, Inc.
- Inventors: Ryan Swanson; Michael Kornacker
- Web page: https://patentgrep.com/patent/US12110339B2

## CPC

- C07K 16/2896: {against molecules with a "CD"-designation, not provided for elsewhere}
- A61K 40/10: characterised by the cell type used
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/22: Immunosuppressive or immunotolerising
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/418: {Antigens related to induction of tolerance to non-self}
- A61K 40/421: {Immunoglobulin superfamily}
- A61K 40/4211: {CD19 or B4}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 11/06: Antiasthmatics
- A61P 17/06: Antipsoriatics
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07K 14/70532: {B7 molecules, e.g. CD80, CD86}
- C07K 16/461: {Igs containing Ig-regions, -domains or -residues form different species}
- C07K 14/7051: {T-cell receptor (TcR)-CD3 complex}
- C07K 2317/40: characterized by post-translational modification
- C07K 2319/01: containing a localisation/targetting motif
- C07K 2319/03: containing a transmembrane segment
- 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)
- 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

## Abstract

Provided herein are immunomodulatory proteins comprising ICOSL variants and nucleic acids encoding such proteins. The immunomodulatory proteins provide therapeutic utility for a variety of immunological and oncological conditions. Compositions and methods for making and using such proteins are provided.

## Claims

### Claim 1

A variant ICOS Ligand (ICOSL) polypeptide, comprising one or more amino acid substitutions at one or more positions in an unmodified ICOSL corresponding to position(s) selected from the group consisting of 54, 84, 119, 120, 143, 152, 155, 203, and 207 with reference to the numbering of residues in SEQ ID NO:32, wherein the unmodified ICOSL comprises (i) the sequence of amino acids set forth in SEQ ID NO:32, or (ii) a portion of the sequence of (i) comprising an IgV domain, wherein the IgV domain is amino acids 19-129 of SEQ ID NO:5.

### Claim 2 (depends on 1)

The variant ICOSL polypeptide of claim 1, wherein the one or more amino acid substitutions are selected from S54A, S54P, N84Q, N119Q, F120S, I143V, I143T, Y152C, Y152H, N155H, N155Q, L203P, L203F, N207Q, or a conservative amino acid substitution thereof.

### Claim 3 (depends on 1)

The variant ICOSL polypeptide of claim 1, wherein the one or more amino acid substitutions are selected from among, N155Q/N207Q, N119Q/N207Q, N119Q/N155Q, N84Q/N168Q/N207Q, N84Q/N155H/N207Q, N84Q/N119Q/N207Q, N119Q/N155H/N207Q, N84Q/N119Q/N155Q, N84Q/N119Q/N155Q/N207Q.

### Claim 4 (depends on 1)

The variant ICOSL polypeptide of claim 1, wherein the variant ICOSL polypeptide specifically binds to the ectodomain of human ICOS or human CD28 with increased affinity compared to the binding of the unmodified ICOSL polypeptide to the ectodomain of human ICOS or human CD28.

### Claim 5 (depends on 1)

The variant ICOSL polypeptide of claim 1, wherein the IgV domain or specific binding fragment thereof is the only ICOSL immunoglobulin superfamily (IgSF) domain of the variant ICOSL polypeptide.

### Claim 6 (depends on 1)

A variant-Fc fusion protein comprising a variant ICOSL polypeptide of claim 1 and an Fc domain.

### Claim 7 (depends on 6)

The variant-Fc fusion protein of claim 6, wherein the Fc domain is a variant Fc domain with reduced effector function.

### Claim 8 (depends on 1)

The variant ICOSL polypeptide of claim 1 that is a soluble protein and lacks a transmembrane domain.

### Claim 9 (depends on 1)

An immunomodulatory protein, comprising the variant ICOSL polypeptide of claim 1 linked to a second polypeptide comprising an immunoglobulin superfamily (IgSF) domain.

### Claim 10 (depends on 1)

A conjugate, comprising a variant ICOSL polypeptide of claim 1 linked to a targeting moiety that specifically binds to a molecule on the surface of a cell.

### Claim 11 (depends on 1)

A nucleic acid molecule encoding a sequence of amino acids comprising the variant ICOSL polypeptide of claim 1.

### Claim 12 (depends on 1)

An engineered cell, comprising a variant ICOSL polypeptide of claim 1 or a nucleic acid molecule encoding a sequence of amino acids comprising the variant ICOSL polypeptide of claim 1.

### Claim 13 (depends on 12)

The engineered cell of claim 12, wherein the variant ICOSL polypeptide comprises a transmembrane domain and/or is expressed on the surface of the cell.

### Claim 14 (depends on 1)

An infectious agent, comprising a variant ICOSL polypeptide of claim 1 or a nucleic acid molecule encoding a sequence of amino acids comprising the variant ICOSL polypeptide of claim 1.

### Claim 15 (depends on 1)

A pharmaceutical composition, comprising the variant ICOSL polypeptide of claim 1 and a pharmaceutically acceptable carrier.

### Claim 16 (depends on 15)

A method of modulating an immune response in a subject, comprising administering the pharmaceutical composition of claim 15 to the subject, wherein the immune response is decreased.

### Claim 17 (depends on 12)

A method of modulating an immune response in a subject, comprising administering the engineered cell of claim 12 to the subject, wherein the immune response is decreased.

### Claim 18 (depends on 15)

A method of treatment, the method comprising administering the pharmaceutical composition of claim 15 to a subject having a disease or condition, wherein the disease or condition comprises graft-versus-host disease (GvHD) or delayed-type hypersensitivity (DTH).

### Claim 19 (depends on 6)

A pharmaceutical composition, comprising the variant ICOSL polypeptide of claim 6 and a pharmaceutically acceptable carrier.

### Claim 20 (depends on 19)

A method of modulating an immune response in a subject, comprising administering the pharmaceutical composition of claim 19 to the subject, wherein the immune response is decreased.

### Claim 21 (depends on 19)

A method of treatment, the method comprising administering the pharmaceutical composition of claim 19 to a subject having a disease or condition, wherein the disease or condition comprises graft-versus-host disease (GvHD) or delayed-type hypersensitivity (DTH).