# US 10,765,694 B2 · Compositions and methods for delivering inhibitory oligonucleotides

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- Number: US 10,765,694 B2
- Document ID: US10765694B2
- Status: Granted
- Kind: B2
- Application number: 15/204,789
- Filed: 2016-07-07
- Published: 2016-10-27
- Granted: 2020-09-08
- Earliest claimed: 2008-04-15
- Assignees: The United States of America, as represented by the Secretary, Department of Health and Human Services
- Applicants: The United States of America, as represented by the Secretary, Department of Health & Human Services
- Inventors: Bira Arya; Purevdorj Olkhanud; Juan Espinoza
- Web page: https://patentgrep.com/patent/US10765694B2

## CPC

- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 47/642: {the peptide or protein in the drug conjugate being a cytokine, e.g. IL2, chemokine, growth factors or interferons being the inactive part of the conjugate}
- A61K 47/6455: {Polycationic oligopeptides, polypeptides or polyamino acids, e.g. for complexing nucleic acids}
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- C07K 14/005: from viruses
- C07K 14/523: {Beta-chemokines, e.g. RANTES, I-309/TCA-3, MIP-1alpha, MIP-1beta/ACT-2/LD78/SCIF, MCP-1/MCAF, MCP-2, MCP-3, LDCF-1, LDCF-2}
- C12N 15/87: Introduction of foreign genetic material using processes not otherwise provided for, e.g. co-transformation
- C07K 2319/33: fusions for targeting to specific cell types, e.g. tissue specific targeting, targeting of a bacterial subspecies
- C07K 2319/74: containing a fusion for binding to a cell surface receptor
- C07K 2319/85: containing an RNA binding domain
- 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)

## Abstract

The present invention features compositions and methods that make use of complexes comprising one or more inhibitory nucleic acids and a targeting polypeptide, wherein the targeting polypeptide consists of a cell surface receptor ligand. The compositions can be used in methods of silencing gene expression in a cell, delivering agents to a target cell, and in treating or preventing a disease or disorder in a subject.

## Claims

### Claim 1

A fusion molecule comprising a targeting polypeptide, and a nucleic acid binding domain, wherein the targeting, polypeptide is selected from monocyte chemoattractant protein 1 (MCP-1/CCL-2), thymus- and activation-regulated chemokine (TARC/CCL17), Regulation upon Activation Normal T cell Express Sequence (RANTES/CCL5), and a receptor binding fragment of MCP-1, TARC, or RANTES, and the nucleic acid binding domain is amino acids 87 through 102 of SEQ ID NO: 11.

### Claim 2 (depends on 1)

The fusion molecule of claim 1, wherein the fusion molecule includes one or more inhibitory nucleic acids thereby forming an inhibitory nucleic acid-fusion molecule complex.

### Claim 3 (depends on 1)

The fusion molecule of claim 1, wherein the targeting polypeptide is MCP-1 or a receptor binding fragment thereof with an amino acid sequence that is amino acids 3 through 77 of SEQ ID NO: 11.

### Claim 4 (depends on 1)

The fusion molecule of claim 1, wherein the targeting polypeptide is TARC or a receptor binding fragment thereof with an amino acid sequence that is amino acids 1 through 72 of SEQ ID NO: 9.

### Claim 5 (depends on 1)

The fusion molecule of claim 1, wherein the targeting polypeptide is RANTES or a receptor binding fragment thereof with an amino acid sequence that is amino acids 1 through 68 of SEQ ID NO: 10.

### Claim 6 (depends on 1)

The fusion molecule of claim 1, wherein the fusion molecule comprises a spacer sequence in between the targeting polypeptide and nucleic acid binding domain.

### Claim 7 (depends on 6)

The fusion molecule of claim 6, wherein the spacer peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 5 (SDGGGSGGGGSLE), SEQ ID NO: 6 (DGGGSGGGGSL), SEQ ID NO: 7 (GGGSGGGG), and SEQ ID NO: 8 (GGGGSGGGG).

### Claim 8 (depends on 2)

The fusion molecule of claim 2, wherein the inhibitory nucleic acid is selected from the group consisting of antisense nucleic acid, short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA) and combinations thereof.

### Claim 9 (depends on 8)

The fusion molecule of claim 8, wherein the inhibitory nucleic acid comprises a modified nucleotide.

### Claim 10 (depends on 8)

The fusion molecule of claim 8, wherein the inhibitory nucleic acid hybridizes to or is complementary to a nucleic acid that encodes a cytokine.

### Claim 11 (depends on 8)

The fusion molecule of claim 8, wherein the inhibitory nucleic acid hybridizes to or is complementary to a nucleic acid that encodes a chemokine.

### Claim 12 (depends on 10)

The fusion molecule of claim 10, wherein the inhibitory nucleic acid hybridizes to or is complementary to a nucleic acid that encodes IL-10.

### Claim 13

A fusion molecule comprising the amino acid sequence of SEQ ID NO: 11.

### Claim 14 (depends on 1)

A complex comprising an inhibitory nucleic acid and the fusion molecule of claim 1, wherein the fusion molecule comprises the amino acid sequence of SEQ ID NO: 11.

### Claim 15 (depends on 14)

The complex of claim 14, wherein the inhibitory nucleic acid is selected from the group consisting of antisense nucleic acid, short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA) and combinations thereof.

### Claim 16 (depends on 15)

The complex of claim 15, wherein the inhibitory nucleic acid hybridizes to or is complementary to a nucleic acid that encodes IL-10.

### Claim 17

A fusion molecule comprising the amino acid sequence of SEQ ID NO: 9.

### Claim 18

A fusion molecule comprising the amino acid sequence of SEQ ID NO: 10.