# US 12,109,271 B2 · Microparticle systems and their use for the treatment of multiple sclerosis

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- Number: US 12,109,271 B2
- Document ID: US12109271B2
- Status: Granted
- Kind: B2
- Application number: 17/257,731
- Filed: 2019-07-03
- Published: 2021-06-10
- Granted: 2024-10-08
- Earliest claimed: 2018-07-03
- Assignees: University of Florida Research Foundation, Inc.
- Applicants: University of Florida Research Foundation, Incorporated
- Inventors: Dorina Avram; Benjamin George Keselowsky; Joshua Stewart; Jonathan Joseph Cho
- Web page: https://patentgrep.com/patent/US12109271B2

## CPC

- A61K 47/593: {Polyesters, e.g. PLGA or polylactide-co-glycolide}
- 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 9/0021: {Intradermal administration, e.g. through microneedle arrays or needleless injectors}
- A61K 9/1635: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/1647: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 31/203: Retinoic acids {; Salts thereof}
- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- A61K 31/593: 9,10-Secocholestane derivatives, e.g. cholecalciferol, i.e. vitamin D3
- A61K 38/18: Growth factors; Growth regulators
- A61K 38/1841: {Transforming growth factor [TGF]}
- A61K 38/1866: {Vascular endothelial growth factor [VEGF]}
- A61K 38/193: {Colony stimulating factors [CSF]}
- A61K 38/2066: {IL-10}
- A61K 39/0005: {Vertebrate antigens (from snakes A61K39/38)}
- A61K 39/0008: {Antigens related to auto-immune diseases; Preparations to induce self-tolerance}
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 25/00: Drugs for disorders of the nervous system
- A61P 25/28: for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
- A61P 37/02: Immunomodulators
- A61K 2039/55555: {Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers}
- A61K 2039/622: {non-covalent binding}
- 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

## Abstract

Provided are a dual microparticle system to treat Multiple Sclerosis, the system comprising phagocytosable and non-phagocytosable microparticles for delivery of at least one antigen, at least one immunomodulatory agent, at least one immunosuppressive agent and at least one chemoattractant to a subject suffering from Multiple Sclerosis to generate tolerogenic dendritic cells in the subject and treat the Multiple Sclerosis.

## Claims

### Claim 1

A dual microparticle system for targeting an antigen-presenting immune cell in a subject who is suspected of having, at risk of having or has Multiple Sclerosis, wherein the microparticle system is a composition that comprises: microparticles that are phagocytosable by the antigen-presenting immune cell, and microparticles that are non-phagocytosable by the antigen-presenting immune cell; wherein the phagocytosable microparticles together comprise at least one myelin antigen, the at least one myelin antigen being an antigen involved in pathogenesis of multiple sclerosis, and at least one immunomodulatory agent selected from vitamin D3, vitamin D3 analog, glucocorticoid, estrogen, rapamycin, and retinoic acid; and wherein the non-phagocytosable microparticles comprise at least one immunosuppressive tolerogenic agent selected from IL-10, TGF-p, and nonsteroidal anti-inflammatory drugs (NSAIDs), an agent that recruits the antigen-presenting immune cell of interest selected from GM-CSF, G-CFS, M-CSF, CCL19, CCL20, CCL21, and VEGF-C, wherein the microparticle system further comprises a remyelinating agent selected from clemastine, clobetasol, digoxin, miconazole, phenytoin, and quetiapine.

### Claim 2 (depends on 1)

The microparticle system of claim 1, wherein the remyelinating agent is administered in soluble form by intravenous injection or is incorporated into the non-phagocytosable microparticles.

### Claim 3 (depends on 1)

The microparticle system of claim 1, wherein the phagocytosable microparticle has a diameter of 0.2 μm-5.0 μm and the non-phagocytosable microparticle has a diameter of 15.0 μm-50.0 μm.

### Claim 4 (depends on 1)

The microparticle system of claim 1, wherein the phagocytosable microparticle or non-phagocytosable microparticle are fabricated from poly(lactic-co-glycolic acid) (PLGA).

### Claim 5 (depends on 1)

The microparticle system of claim 1, wherein the at least one myelin antigen comprises at least one of SEQ ID NOs 1-25 or a contiguous fragment thereof.

### Claim 6 (depends on 5)

The microparticle system of claim 5, wherein the at least one myelin-antigen comprises at least one of SEQ ID NOs 12-25 or a fragment thereof comprising contiguous amino acids of said SEQ ID NOs.

### Claim 7 (depends on 6)

The microparticle system of claim 6, wherein at least one myelin-antigen comprises SEQ ID NO. 23.

### Claim 8 (depends on 1)

The microparticle system of claim 1, wherein the composition is in a liquid formulation further comprising a pharmaceutically acceptable carrier.

### Claim 9 (depends on 1)

The microparticle system of claim 1, wherein the phagocytosable MPs comprise the amino acid sequence of SEQ ID NO. 23 and vitamin D3.

### Claim 10 (depends on 1)

The microparticle system of claim 1, wherein the non-phagocytosable MPs comprise TGF-β1 and GM-CSF.

### Claim 11 (depends on 1)

A method of treating a subject who is suspected of having, at risk of having or has MS comprising administering a therapeutically effective amount of a composition of claim 1.

### Claim 12 (depends on 11)

The method, according to claim 11, wherein the ratio of the at least one myelin antigen to the at least one immunomodulatory agent is between 1:20 and 1:1.

### Claim 13

A method of treating a subject who is suspected of having, at risk of having or has MS comprising administering a therapeutically effective amount of a first composition that comprises microparticles that are phagocytosable by the antigen-presenting immune cell, and a second composition comprising microparticles that are non-phagocytosable by the antigen-presenting immune cell; wherein the phagocytosable microparticles together comprise at least one myelin antigen, the at least one myelin antigen being an antigen involved in pathogenesis of multiple sclerosis and at least one immunomodulatory agent selected from vitamin D3, vitamin D3 analog, glucocorticoid, estrogen, rapamycin, and retinoic acid; wherein the non-phagocytosable microparticles comprise at least one immunosuppressive tolerogenic agent selected from IL-10, TGF-p, and nonsteroidal anti-inflammatory drugs (NSAIDs), an agent that recruits the antigen-presenting immune cell of interest selected from GM-CSF, G-CFS, M-CSF, CCL19, CCL20, CCL21, and VEGF-C; wherein and wherein the first composition and second composition are admixed prior administration or are administered separately.

### Claim 14 (depends on 13)

The method of claim 13, wherein the first composition and second composition are administered separately.

### Claim 15 (depends on 14)

The method of claim 14, wherein the first composition and second composition are administered by the same or different modes of administration.

### Claim 16 (depends on 15)

The method of claim 15, wherein the modes of administration comprise subcutaneous, intradermal, intramuscular, or intravenous administration.