# US 11,993,638 B2 · GM-CSF mimetics and methods of making and using same

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- Number: US 11,993,638 B2
- Document ID: US11993638B2
- Status: Granted
- Kind: B2
- Application number: 17/589,154
- Filed: 2022-01-31
- Published: 2022-05-19
- Granted: 2024-05-28
- Earliest claimed: 2017-06-09
- Assignees: The Regents of the University of Colorado, a body corporate
- Applicants: The Regents of the University of Colorado, a body corporate
- Inventors: Huntington Potter; Glenn Simon
- Web page: https://patentgrep.com/patent/US11993638B2

## CPC

- C07K 14/535: Granulocyte CSF; Granulocyte-macrophage CSF
- A61K 47/65: Peptidic linkers, binders or spacers, e.g. peptidic enzyme-labile linkers
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K 2319/00: Fusion polypeptide
- 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)

## Abstract

The present invention provides novel GM-CSF constructs and methods of using the same. In certain embodiments, the constructs of the invention comprise certain peptide fragments from GM-CSF. In other embodiments, the invention provides certain GM-CSF peptides that act as GM-CSF mimetics.

## Claims

### Claim 1

A construct comprising
M1-L-M2, M2-L-M1, M1-L-M1, M2-L-M2, or consecutively-linked combinations of two or more thereof;
wherein:
L is a linker;
M1 consists of a peptide represented by amino acid residues 11-X of SEQ ID NO:2, wherein X is an integer selected from the group consisting of 23, 24, 25, 26, 27, and 28; and
M2 comprises a peptide represented by amino acid residues X-118 of SEQ ID NO:2, wherein X is an integer selected from the group consisting of 103, 104, 105, 106, 107, 108, 109, 110, and 111.

### Claim 2 (depends on 1)

The construct according to claim 1, wherein the consecutively-linked combinations of the constructs comprise at least one of:
M1-L-M1-L-M1-L-M1;
M1-L-M1-L-M2-L-M2;
M1-L-M2-L-M2-L-M1;
M2-L-M2-L-M1-L-M1;
M1-L-M2-L-M1-L-M2;
M2-L-M1-L-M2-L-M1;
M2-L-M2-L-M2-L-M2;
M1-L-M1-L-M1-L-M2;
M1-L-M1-L-M2-L-M1;
M1-L-M2-L-M1-L-M1;
M2-L-M1-L-M1-L-M1;
M2-L-M2-L-M2-L-M1;
M2-L-M2-L-M1-L-M2;
M2-L-M1-L-M2-L-M2;
M1-L-M2-L-M2-L-M2; and
M2-L-M1-L-M2-L-M2.

### Claim 3 (depends on 1)

The construct according to claim 1, wherein M1 consists of residues 11-28 of SEQ ID NO:2 (QPWEHVNAIQEARRLLNL).

### Claim 4 (depends on 1)

The construct according to claim 1, wherein M2 comprises residues 103-118 of SEQ ID NO:2 (FESFKENLKDFLLVIP).

### Claim 5 (depends on 1)

The construct according to claim 1, wherein the construct comprises M1-L-M2 or M2-L-M1 and M1 consists of residues 11-28 of SEQ ID NO:2 (QPWEHVNAIQEARRLLNL).

### Claim 6 (depends on 1)

The construct according to claim 1, wherein the construct comprises M1-L-M2 or M2-L-M1 and M2 comprises residues 103-118 of SEQ ID NO:2 (FESFKENLKDFLLVIP).

### Claim 7 (depends on 1)

The construct according to claim 1, wherein M1 consists of a peptide represented by amino acid residues 11-X of SEQ ID NO:2, wherein X is an integer selected from the group consisting of 23, 24, 25, 26, 27, and 28 and wherein amino acid position 23 is a leucine.

### Claim 8 (depends on 1)

The construct according to claim 1, wherein each L comprises a polypeptide, polyethylene glycol (PEG), or a derivative thereof.

### Claim 9 (depends on 1)

The construct according to claim 1, wherein when each L is PEG or a derivative thereof, the PEG or derivative thereof comprises (CH2CH2O)n wherein n is an integer from 2 to 30.

### Claim 10 (depends on 1)

The construct according to claim 1, wherein when L is a polypeptide, the polypeptide comprises (G4S)n, (G)m or (A)m, wherein n is an integer ranging from 1 to 6 and m is an integer ranging from 1 to 200.

### Claim 11 (depends on 1)

The construct according to claim 1, wherein Lin at least one occurrence is a peptide linker (G4S)n, (G)m or (A)m, wherein n is an integer ranging from 1 to 6, and each occurrence of m is independently an integer ranging from 1 to 200.

### Claim 12 (depends on 1)

The construct according to claim 1, wherein L comprises a hairpin linker.

### Claim 13 (depends on 1)

The construct according to claim 1, wherein L is (CH2CH2O)n wherein n is 4, 6, or 8.

### Claim 14 (depends on 1)

The construct according to claim 1, wherein the construct is part of a composition, and the composition further comprises a pharmaceutically acceptable carrier or excipient.

### Claim 15 (depends on 14)

A method for using the composition according to claim 14 to treat a subject in need of Granulocyte-macrophage colony-stimulating factor (GM-CSF) therapy.

### Claim 16 (depends on 15)

The method of claim 15, wherein using the composition to treat the subject comprises administering the composition subcutaneously, by inhalation, orally, intranasally, rectally, parenterally, sublingually, transdermally, transmucosally, intravesically, intrapulmonarily, intraduodenally, intragastrically, intrathecally, epidurally, intrapleurally, intraperitoneally, intratracheally, otically, intraocularly, intramuscularly, intradermally, intra-arterially, intravenously, intrabronchially, or topically to the subject.

### Claim 17 (depends on 16)

The method according to claim 16, wherein the subject is a mammalian subject.

### Claim 18 (depends on 1)

A kit comprising the constructs of claim 1; and at least one container.

### Claim 19 (depends on 15)

The method of claim 15, wherein the subject comprises a subject in need of neurite outgrowth or neurogenesis, in need of promoting myeloid reconstitution, having neuronal loss; having a traumatic brain injury (TBI), in need of improving cognition, in need of stabilizing cognition, in need of reversing loss of cognition; in need of increasing or stabilizing neutrophil levels, having type I or type 2 diabetes, having or developing chemobrain, having Down Syndrome (DS), having Alzheimer's Disease (AD), having Parkinson's Disease, or having cerebral palsy, or a combination thereof.

### Claim 20 (depends on 1)

The construct according to claim 1, wherein the construct is M1-L-M2-L-M2-L-M1.

### Claim 21 (depends on 20)

The construct according to claim 20, wherein L is polyethylene glycol (PEG).

### Claim 22 (depends on 21)

The construct according to claim 21, wherein M1 is amino acid residues 11-23 of SEQ ID NO:2 (QPWEHVNAIQEAR) and M2 is amino acid residues 112 to 118 of SEQ ID NO:2 (DFLLVIP).

### Claim 23 (depends on 20)

The construct according to claim 20, wherein the middle linker, L, is PEG and the PEG is PEG8.

### Claim 24 (depends on 15)

The method of claim 15, wherein the subject is a subject in need of at least one of, improving cognition, stabilizing cognition, and reversing loss of cognition.

### Claim 25 (depends on 15)

The method of claim 15, wherein the subject is a subject having at least one of Type 2 diabetes, Alzheimer's Disease (AD), Parkinson's Disease and Down's Syndrome.