# US 10,945,962 B2 · Controlled-release peptide compositions and uses thereof

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- Number: US 10,945,962 B2
- Document ID: US10945962B2
- Status: Granted
- Kind: B2
- Application number: 16/209,300
- Filed: 2018-12-04
- Published: 2019-03-21
- Granted: 2021-03-16
- Earliest claimed: 2011-12-02
- Assignees: Board of Regents of the University of Nebraska
- Applicants: Board of Regents of the University of Nebraska
- Inventors: Joseph A. Vetro; Sam D. Sanderson
- Web page: https://patentgrep.com/patent/US10945962B2

## CPC

- A61K 9/48: Preparations in capsules, e.g. of gelatin, of chocolate {(A61K9/0004 takes precedence; bite capsules A61K9/0056)}
- A61K 38/08: Peptides having 5 to 11 amino acids {(A61K38/043 - A61K38/046 take precedence)}
- A61K 38/1725: {Complement proteins, e.g. anaphylatoxin, C3a or C5a}
- A61K 39/0005: {Vertebrate antigens (from snakes A61K39/38)}
- C07K 16/18: against material from animals or humans
- C07K 16/28: against receptors, cell surface antigens or cell surface determinants
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/5031: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- 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)
- 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

Controlled-release formulations of carboxy-terminal C5a analogs (such as sustained-release formulations of the analogs), and their use in methods for treating and preventing an infection or a disease such as cancer, for directly killing microorganisms, for vaccine preparation, for inducing an immune response and for targeting antigen-presenting cells and other cells bearing a C5a receptor, are provided.

## Claims

### Claim 1

A controlled-release formulation comprising:
an encapsulating material having an external surface,
a therapeutic or prophylactic compound encapsulated in said encapsulating material, and
a C5a analog attached to the external surface of the encapsulating material, said C5a analog being a C5a receptor agonist having response-selective C5a receptor binding activity, said binding activity comprising activation of antigen presenting cells,
wherein the C5a analog is selected from the group consisting of:
(SEQ ID NO: 4)
(a)
Tyr-Ser-Phe-Lys-Asp-Met-Pro-MeL-(D-Ala)-Arg;
(SEQ ID NO: 3)
(b)
Tyr-Ser-Phe-Lys-Pro-Met-Pro-Leu-(D-Ala)-Arg;
(SEQ ID NO: 7)
(c)
Tyr-Ser-Phe-Lys-Asp-Ala-Pro-Leu-(D-Ala)-Arg;
(SEQ ID NO: 8)
(d)
Tyr-Ser-Phe-Lys-Asp-Met-Pro-Leu-(D-Ala)-Arg;
(SEQ ID NO: 9)
(e)
Tyr-Ser-Phe-Lys-Asp-Met-Pro-Leu-Gly-Arg;
(SEQ ID NO: 10)
(f)
Tyr-Ser-Phe-Lys-Asp-Ala-Pro-Leu-Gly-Arg;
(SEQ ID NO: 11)
(g)
Tyr-Ser-Phe-Lys-Asp-Cys-Pro-Leu-Gly-Arg;
(SEQ ID NO: 12)
(h)
Tyr-Ser-Phe-Lys-Asp-Met-Pro-Leu-(D-Pro)-Arg;
(SEQ ID NO: 13)
(i)
Tyr-Ser-Phe-Lys-Asp-Met-Gln-Leu-(D-Ala)-Arg;
(SEQ ID NO: 14)
(j)
Tyr-Ser-Phe-Lys-Asp-Met-Gln-Leu-Gly-Arg;
(SEQ ID NO: 15)
(k)
Tyr-Ser-Phe-Lys-Asp-Met-Gln-Pro-Gly-Arg;
(SEQ ID NO: 16)
(l)
Tyr-Ser-Phe-Lys-Asp-Met-Pro-Leu-Aib-Arg;
(SEQ ID NO: 17)
(m)
Tyr-Ser-Phe-Lys-Gly-Met-Pro-Leu-Gly-Arg;
and
(SEQ ID NO: 18)
(n)
Tyr-Ser-Phe-Lys-Gly-Leu-Leu-Leu-Gly-Arg.

### Claim 2 (depends on 1)

The controlled-release formulation of claim 1, wherein the encapsulating material is a form selected from the group consisting of a nanoparticle, a nanogel, a microparticle, a microgel, a microcapsule, a nanocapsule, a polyelectrolyte capsule, a biodegradable lattice, a polysaccharide capsule, a block co-polymer micelle, a polyelectrolyte complex, an injectable implant, a diffusion-controlled hydrogel and a micro-emulsion.

### Claim 3 (depends on 2)

The controlled-release formulation of claim 2, wherein said encapsulating material is nanoparticles or microparticles, said C5a analog being disposed on the external surface of each particle.

### Claim 4 (depends on 3)

The controlled-release formulation of claim 3, wherein said C5a analog is covalently conjugated to said particle surface.

### Claim 5 (depends on 3)

The controlled-release formulation of claim 3, wherein said C5a analog is non-covalently associated with said particle surface.

### Claim 6 (depends on 3)

The controlled-release formulation of claim 3, wherein said particle is polymer-based nanoparticles or microparticles.

### Claim 7 (depends on 6)

The controlled-release formulation of claim 6, wherein said polymer is poly (lactic-co-glycolic acid) (PLGA), ethyl cellulose, polymethyl methacrylate, polyethylene glycol, poly-3-hydroxy butyrate, alginate, collagen, gelatin, a chitin, a chitosan, styrene copolymer, maleic anhydride and poly (N-isopropylacrylamide) copolymer, hyaluronic acid, polyester, polylactide, polyorthoester, polycarbonate, polycaprolactone, or polyethylene oxide.

### Claim 8 (depends on 1)

The controlled-release formulation of claim 1, wherein said therapeutic or prophylactic compound is an immunogen.

### Claim 9 (depends on 8)

The controlled-release formulation of claim 8, wherein said immunogen is a peptide immunogen characteristic of a biological entity selected from the group consisting of a diseased cell, an infectious bacterium, an infectious parasite, an infectious fungus, an infectious protozoan, an infectious prion, an infectious virus and a biofilm.

### Claim 10 (depends on 8)

The controlled-release formulation of claim 8, wherein said immunogen is selected from the group consisting of peptides and proteins, glycopeptides and glycoproteins, phosphopeptides and phosphoproteins, lipopeptides and lipoproteins, carbohydrates, nucleic acids, small molecules and lipids.

### Claim 11 (depends on 1)

The controlled-release formulation of claim 1, wherein the C5a analog is EP67 bearing the sequence Tyr-Ser-Phe-Lys-Asp-Met-Pro-MeL-(D-Ala)-Arg (SEQ ID NO: 4) or EP54 bearing the sequence Tyr-Ser-Phe-Lys-Pro-Met-Pro-Leu-(D-Ala)-Arg (SEQ ID NO: 3).

### Claim 12 (depends on 1)

A method of selectively activating an immune cell at a site of infection or disease comprising administering an effective amount of a controlled-release formulation according to claim 1 to a patient in need thereof.

### Claim 13 (depends on 12)

The method of claim 12, wherein the infection is caused by a bacterium, a parasite, a virus, a fungus, a prion, or a microbial biofilm.

### Claim 14 (depends on 12)

The method of claim 12, wherein the disease is cancer.

### Claim 15 (depends on 12)

The method of claim 12, wherein said formulation is prophylactically administered to said patient.

### Claim 16 (depends on 12)

The method of claim 12, wherein the immune cell is an antigen presenting cell.

### Claim 17 (depends on 16)

The method of claim 16, wherein activation of said antigen presenting cells induces an innate and/or acquired immune response in said patient.