# US 10,869,887 B2 · Biologically relevant orthogonal cytokine/receptor pairs

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- Number: US 10,869,887 B2
- Document ID: US10869887B2
- Status: Granted
- Kind: B2
- Application number: 15/916,689
- Filed: 2018-03-09
- Published: 2018-08-16
- Granted: 2020-12-22
- Earliest claimed: 2015-09-11
- Assignees: The Board of Trustees of the Leland Stanford Junior University
- Applicants: The Board of Trustees of the Leland Stanford Junior University
- Inventors: Kenan Christopher Garcia; Jonathan Sockolosky; Lora Picton
- Web page: https://patentgrep.com/patent/US10869887B2

## CPC

- A61K 38/2013: {IL-2}
- A61K 35/17: Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes (when activated by a specific antigen A61K39/00)
- A61K 38/1793: {for cytokines; for lymphokines; for interferons}
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/4217: {Receptors for interleukins [IL]}
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- C07K 14/55: IL-2
- C12N 5/0636: {T lymphocytes}
- C12N 5/0638: {Cytotoxic T lymphocytes [CTL] or lymphokine activated killer cells [LAK]}
- C12N 15/1034: {Isolating an individual clone by screening libraries}
- A61K 2039/5156: {expressing foreign proteins}
- A61K 2300/00: Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
- C12N 2740/10043: viral genome or elements thereof as genetic vector
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Engineered orthogonal cytokine receptor/ligand pairs, and methods of use thereof, are provided.

## Claims

### Claim 1

An engineered human IL-2 polypeptide, which comprises amino acid substitutions, numbered relative to reference SEQ ID NO:4:
E15S, E15T, E15Q, or E15H;
H16Q;
L19V or L19I;
D20T, D20S, D20L or D20M; and
M23L, M23S, M23V, M23A, or M23T;
and optionally comprises Q22K, Q22N, R81D, R81Y, T51I or a combination thereof.

### Claim 2 (depends on 1)

The engineered human IL-2 polypeptide of claim 1, comprising amino acid substitution Q22K.

### Claim 3 (depends on 1)

The engineered human IL-2 polypeptide of claim 1, comprising amino acid substitution T51I.

### Claim 4 (depends on 1)

The engineered human IL-2 polypeptide of claim 1, comprising amino acid substitution R81D or R81Y.

### Claim 5 (depends on 1)

The engineered human IL-2 polypeptide of claim 1, wherein the polypeptide binds to and activates an orthogonal human CD122 protein.

### Claim 6 (depends on 5)

The engineered human IL-2 polypeptide of claim 5, wherein the orthogonal human CD122 protein is modified at one or more residues selected from R41, R42, Q70, K71, T73, T74, V75, S132, H133, Y134, F135, E136, Q214.

### Claim 7 (depends on 5)

The engineered human IL-2 polypeptide of claim 5, wherein the orthogonal human CD122 protein is modified at H133 and Y134.

### Claim 8 (depends on 7)

The engineered human IL-2 polypeptide of claim 7, wherein the orthogonal human CD122 protein comprises amino acid substitutions H133D and Y134F.

### Claim 9 (depends on 1)

A system for selective activation of a receptor in a cell, the system comprising:
(a) an orthogonal human CD122 receptor comprising amino acid substitutions at H133 and Y134; and
(b) the engineered human IL-2 polypeptide of claim 1.

### Claim 10 (depends on 9)

The system of claim 9, wherein the orthogonal receptor is expressed by a mammalian cell.

### Claim 11 (depends on 10)

The system of claim 10, wherein the cell is an immune cell or a stem cell.

### Claim 12 (depends on 11)

The system of claim 11, wherein the immune cell is a T cell.

### Claim 13 (depends on 1)

A pharmaceutical composition comprising the engineered human IL-2 polypeptide of claim 1; and a pharmaceutically acceptable excipient.

### Claim 14 (depends on 9)

A kit comprising the system of claim 9.

### Claim 15 (depends on 1)

The engineered human IL-2 polypeptide of claim 1 comprising substitutions Q22K and M23A.

### Claim 16 (depends on 1)

The engineered human IL-2 polypeptide of claim 1 comprising substitutions M23Q, R81 D and T51I.

### Claim 17 (depends on 1)

The engineered human IL-2 polypeptide of claim 1 comprising substitutions M23Q and R81Y.

### Claim 18 (depends on 1)

The engineered human IL-2 polypeptide of claim 1 comprising substitution M23A.

### Claim 19

An engineered human IL-2 polypeptide that comprises a set of amino acid substitutions, numbered relative to reference SEQ ID NO:4:
E15S;
H16Q;
L19V;
D20L;
M23A; and
Q22K.

### Claim 20 (depends on 1)

The engineered human IL-2 polypeptide of claim 1 that comprises a set of amino acid substitutions, numbered relative to reference SEQ ID NO:4:
E15S;
H16Q;
L19V;
D20L;
M23Q;
R81D; and
T51I.

### Claim 21 (depends on 1)

The engineered human IL-2 polypeptide of claim 1 that comprises a set of amino acid substitutions, numbered relative to reference SEQ ID NO:4:
E15S;
H16Q;
L19V;
D20L;
M230;
and R81Y.

### Claim 22

An engineered human IL-2 polypeptide that comprises a set of amino acid substitutions, numbered relative to reference SEQ ID NO:4:
E1 5S;
H16Q;
L19V;
D20L; and
M23A.

### Claim 23 (depends on 1)

The engineered human IL-2 polypeptide of claim 1, wherein the engineered human IL-2 polypeptide is pegylated.

### Claim 24 (depends on 1)

The engineered human IL-2 polypeptide of claim 1, wherein the engineered human IL-2 polypeptide is fused to an Fc domain of IgG or albumin.

### Claim 25 (depends on 19)

The engineered human IL-2 protein of claim 19, wherein the engineered human IL-2 polypeptide is pegylated.

### Claim 26 (depends on 22)

The engineered human IL-2 protein of claim 22, wherein the engineered human IL-2 polypeptide is pegylated.