# US 10,308,942 B2 · Methods and compositions for treating autoimmune disorders by targeting Kv1.3 ion channels with functionalized lipid-derived nanovesicles

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- Number: US 10,308,942 B2
- Document ID: US10308942B2
- Status: Granted
- Kind: B2
- Application number: 15/683,180
- Filed: 2017-08-22
- Published: 2017-12-14
- Granted: 2019-06-04
- Earliest claimed: 2014-09-24
- Assignees: University of Cincinnati; North Carolina Agricultural and Technical State University
- Applicants: University of Cincinnati; North Carolina Agricultural and Technical State University
- Inventors: Laura Conforti; Yeoheung Yun
- Web page: https://patentgrep.com/patent/US10308942B2

## CPC

- C12N 15/1138: {against receptors or cell surface proteins}
- 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 9/1272: comprising non-phosphatidyl surfactants as bilayer-forming substances, e.g. cationic lipids or non-phosphatidyl liposomes coated or grafted with polymers (lipids as modifying agents {A61K47/543})
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 47/6913: {the liposome being modified on its surface by an antibody}
- C07K 16/289: {against CD45}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- 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)
- 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

Synthesis and pharmaceutical compositions of antibody-functionalized nanovesicles encapsulating ion channel knockout siRNA, and methods of treating autoimmune diseases associated with increased expression and/or hyperactivity of T cells by selectively targeting memory T cells with the nanoparticles, which deliver their siRNA cargo into the cytosol of the TM cell thus reducing ion channel expression and decreasing Ca2+ influx.

## Claims

### Claim 1

A method of treating a patient suffering from a condition of the immune system characterized by overexpressed and/or hyperexcitable T-cells, the method comprising administering to the patient a composition formulated to selectively bind to a CD45RO-positive isoform of the T-cells and transfect it with siRNA, the composition comprising: lipid nanovesicles functionalized with surface-bound antibody selective for a membrane protein unique to the CD45RO-positive isoform; and siRNA effective for inhibiting expression of a Kv1.3 ion channel of the CD45RO-positive isoform cells upon transfection, said siRNA encapsulated within the lipid nanovesicle and comprising one or more Kv1.3-specific siRNA.

### Claim 2 (depends on 1)

The method according to claim 1, wherein the antibody comprises anti-CD45LRO.

### Claim 3 (depends on 1)

The method according to claim 1, wherein the T-cell comprises a TM cell.

### Claim 4 (depends on 2)

The method according to claim 2, wherein the antibody comprises monoclonal antibody.

### Claim 5 (depends on 1)

The method according to claim 1, wherein the siRNA is selected from the group consisting of GUAACUCGACUCUGAGUAAtt (SEQ ID NO: 1), UUACUCAGAGUCGAGUUACtt (SEQ ID NO: 2), CUUACCCUCUCUCUCUUAAtt (SEQ ID NO: 3), UUAAGAGAGAGAGGGUAAGtt (SEQ ID NO: 4), GAUGGACCUUUCAACGUUAtt (SEQ ID NO: 5), UAACGUUGAAAGGUCCAUCtt (SEQ ID NO: 6), and duplexes thereof.

### Claim 6 (depends on 1)

The method according to claim 1, wherein administering is via a systemic route.

### Claim 7 (depends on 6)

The method according to claim 6, wherein administering is via intravenous administration.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the condition of the immune system comprises an autoimmune disorder selected from Rheumatoid arthritis, Type 1 diabetes, Multiple Sclerosis, Psoriasis, Vasculitis, Alopecia areata, Systemic Lupus Erythematosus, Polymyalgia rheumatica, Ankylosing spondylitis, Celiac disease, Sjögren's syndrome, and Temporal arteritis.

### Claim 9 (depends on 8)

The method according to claim 8, wherein the condition of the immune system is Systemic Lupus Erythematosus.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the step of administering comprises dosing according to a schedule based on severity of the disease across a therapeutic time frame.

### Claim 11 (depends on 10)

The method according to claim 10, wherein the severity of the disease is assessed by calculating a ratio of TM to nave T cells in plasma of the patient sampled across the therapeutic time frame.

### Claim 12

A method of treating a patient suffering from chronic systemic lupus erythematosus, the method comprising: administering to the patient a composition comprising lipid nanovesicles surface-functionalized with anti-CD45LRO and encapsulating Kv1.3-specific siRNA.