# US 11,077,172 B2 · IL-2 variants for the treatment of psoriasis

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- Number: US 11,077,172 B2
- Document ID: US11077172B2
- Status: Granted
- Kind: B2
- Application number: 15/806,787
- Filed: 2017-11-08
- Published: 2018-05-10
- Granted: 2021-08-03
- Earliest claimed: 2016-11-08
- Assignees: Delinia, Inc.
- Applicants: Delinia, Inc.
- Inventors: Jeffrey Greve
- Web page: https://patentgrep.com/patent/US11077172B2

## CPC

- A61K 38/2013: {IL-2}
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/06: Antipsoriatics
- A61P 17/14: for baldness or alopecia
- A61P 21/00: Drugs for disorders of the muscular or neuromuscular system
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 27/02: Ophthalmic agents
- A61P 37/02: Immunomodulators
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07K 14/4713: {Autoimmune diseases, e.g. Insulin-dependent diabetes mellitus, multiple sclerosis, rheumathoid arthritis, systemic lupus erythematosus; Autoantigens}
- C07K 14/55: IL-2
- A61K 2039/505: {comprising antibodies}
- C07K 2319/30: Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
- 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)

## Abstract

This disclosure provides for a method for treating a condition by administering to a subject in need thereof a therapeutically-effective amount of a compound that comprises an IL-2 receptor-binding moiety. The methods described in the present disclosure provide enhanced pharmacokinetic profiles. The disclosure also provides methods for treating autoimmune disease comprising administering a therapeutically-effective amount of a fusion protein comprising an IL-2 variant protein.

## Claims

### Claim 1

A method for treating an autoimmune disease in a subject in need thereof, the method comprising administering to the subject at least two doses of a pharmaceutical composition comprising a therapeutically-effective amount of a fusion protein comprising:
a. a human IL-2 variant protein domain comprising a substitution selected from the group consisting of T3A and C125S relative to the amino acid sequence of SEQ ID NO: 2, and a substitution selected from the group consisting of D20H, N88I, N88G, N88R, Q126L, and Q126F relative to the amino acid sequence of SEQ ID NO: 2;
b. a peptide linker domain comprising the amino acid sequence (GGGGS)n (SEQ ID NO: 8), wherein n is 1, 2, 3 or 4; and
c. an IgG Fc protein domain,
wherein each domain has an amino-terminus (N-terminus) and a carboxy terminus (C-terminus);
and wherein the fusion protein is configured so that the C-terminus of the human IL-2 variant protein domain is fused through a peptide bond to the N-terminus of the peptide linker domain, and the N-terminus of the IgG Fc protein domain is fused through a peptide bond to the C-terminus of the peptide linker domain,
wherein the composition is administered to the subject at a dosing frequency from once every week to once every month and at a dose of 20 μg/kg to 2 mg/kg,
wherein administration of the pharmaceutical composition to the subject increases the ratio of regulatory T cells to conventional T cells (Treg/Tconv) by at least 2.9-fold six days after administration relative to the Treg/Tconv ratio in the subject before treatment with the pharmaceutical composition,
and wherein the autoimmune disease is selected from the group consisting of psoriasis, ulcerative colitis, and Crohn's disease.

### Claim 2 (depends on 1)

The method of claim 1, wherein administration of the pharmaceutical composition to the subject increases the ratio of regulatory T cells (Treg) to conventional T cells (Tconv) to at least 0.2.

### Claim 3 (depends on 1)

The method of claim 1, wherein the dosing frequency ranges from once every week to once every 2 weeks.

### Claim 4 (depends on 1)

The method of claim 1, wherein the human IL-2 variant protein domain comprises the N88R substitution relative to the amino acid sequence of SEQ ID NO: 2.

### Claim 5 (depends on 1)

The method of claim 1, wherein the human IL-2 variant protein domain comprises the amino acid sequence of SEQ ID NO: 1 or SEQ ID NO: 3.

### Claim 6 (depends on 1)

The method of claim 1, wherein the peptide linker domain comprises the amino acid sequence of SEQ ID NO: 6.

### Claim 7 (depends on 1)

The method of claim 1, wherein the IgG Fc protein domain comprises the amino acid sequence of SEQ ID NO: 7.

### Claim 8 (depends on 1)

The method of claim 1, wherein the fusion protein comprises the amino acid sequence of SEQ ID NO: 4 or SEQ ID NO: 5.

### Claim 9 (depends on 1)

The method of claim 1, wherein the pharmaceutical composition is administered to the subject by subcutaneous administration.

### Claim 10

A method for increasing proliferation of regulatory T cells in a subject in need thereof, the method comprising administering to the subject at least two doses of a pharmaceutical composition comprising a therapeutically effective amount of a fusion protein comprising:
a. a human IL-2 variant protein domain comprising a substitution selected from the group consisting of T3A and C125S relative to the amino acid sequence of SEQ ID NO: 2, and a substitution selected from the group consisting of D2OH, N88I, N88G, N88R, Q126L, and Q126F relative to the amino acid sequence of SEQ ID NO: 2;
b. a peptide linker domain comprising the amino acid sequence (GGGGS)n (SEQ ID NO: 8), wherein n is 1, 2, 3 or 4; and
c. an IgG Fc protein domain,
wherein each domain has an amino-terminus (N-terminus) and a carboxy terminus (C-terminus);
and wherein the fusion protein is configured so that the C-terminus of the human IL-2 variant protein domain is fused through a peptide bond to the N-terminus of the peptide linker domain, and the N-terminus of the IgG Fc protein domain is fused through a peptide bond to the C-terminus of the peptide linker domain,
wherein the composition is administered to the subject at a dosing frequency from once every week to once every month and at a dose of 20 μg/kg to 2 mg/kg, and wherein administration of the pharmaceutical composition to the subject increases the ratio of regulatory T cells to conventional T cells (Treg/Tconv) by at least 2.9-fold six days after administration relative to the Treg/Tconv ratio in the subject before treatment with the pharmaceutical composition.

### Claim 11 (depends on 10)

The method of claim 10, wherein administration of the pharmaceutical composition to the subject does not increase the proliferation of conventional T cells or CD8+T cells.

### Claim 12

A method for maintaining the ratio of regulatory T cells (Treg) to conventional T cells (Tconv) at a level of at least 0.2 in a subject, the method comprising administering to the subject at least two doses of a pharmaceutical composition comprising a therapeutically effective amount of a fusion protein comprising:
a. a human IL-2 variant protein domain comprising a substitution selected from the group consisting of T3A and C125S relative to the amino acid sequence of SEQ ID NO: 2, and a substitution selected from the group consisting of D2OH, N88I, N88G, N88R, Q126L, and Q126F relative to the amino acid sequence of SEQ ID NO: 2;
b. a peptide linker domain comprising the amino acid sequence (GGGGS)n (SEQ ID NO: 8), wherein n is 1, 2, 3 or 4; and
c. an IgG Fc protein domain,
wherein each domain has an amino-terminus (N-terminus) and a carboxy terminus (C-terminus);
and wherein the fusion protein is configured so that the C-terminus of the human IL-2 variant protein domain is fused through a peptide bond to the N-terminus of the peptide linker domain, and the N-terminus of the IgG Fc protein domain is fused through a peptide bond to the C-terminus of the peptide linker domain,
wherein the composition is administered to the subject at a dosing frequency from once every week to once every month and at a dose of 20 μg/kg to 2 mg/kg,
and wherein administration of the pharmaceutical composition to the subject increases the Treg/Tconv ratio by at least 2.9-fold six days after administration relative to the Treg/Tconv ratio in the subject before treatment with the pharmaceutical composition.

### Claim 13 (depends on 12)

The method of claim 12, wherein five days after the pharmaceutical composition is administered to the subject the Treg/Tconv ratio is at least 0.2.