# US 10,441,651 B2 · Tolerogenic synthetic nanocarriers for generating CD8+ regulatory T cells

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- Number: US 10,441,651 B2
- Document ID: US10441651B2
- Status: Granted
- Kind: B2
- Application number: 14/810,466
- Filed: 2015-07-27
- Published: 2016-02-04
- Granted: 2019-10-15
- Earliest claimed: 2011-04-29
- Assignees: Selecta Biosciences, Inc.
- Applicants: Selecta Biosciences, Inc.
- Inventors: Takashi Kei Kishimoto; Christopher Fraser; Roberto A. Maldonado
- Web page: https://patentgrep.com/patent/US10441651B2

## CPC

- A61K 39/385: Haptens or antigens, bound to carriers
- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)}
- A61K 9/51: Nanocapsules; {Nanoparticles; (nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00)}
- A61K 9/5115: {Inorganic compounds}
- A61K 9/5146: {obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides}
- A61K 9/5153: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)}
- A61K 38/13: Cyclosporins
- A61K 38/1816: {Erythropoietin [EPO]}
- A61K 38/38: Albumins
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61K 39/0008: {Antigens related to auto-immune diseases; Preparations to induce self-tolerance}
- A61K 39/001: {Preparations to induce tolerance to non-self, e.g. prior to transplantation}
- A61K 39/35: Allergens
- A61K 39/36: from pollen
- A61K 47/50: the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K 47/52: the modifying agent being an inorganic compound, e.g. an inorganic ion that is complexed with the active ingredient
- A61K 47/544: {Phospholipids}
- A61K 47/593: {Polyesters, e.g. PLGA or polylactide-co-glycolide}
- A61K 47/643: {Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]}
- A61K 47/69: the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K 47/6923: {the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb}
- A61K 47/6929: {the form being a nanoparticle, e.g. an immuno-nanoparticle}
- A61K 47/6937: {the polymer being PLGA, PLA or polyglycolic acid}
- A61P 1/16: for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
- A61P 7/06: Antianaemics
- A61P 11/02: Nasal agents, e.g. decongestants
- A61P 11/06: Antiasthmatics
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 17/00: Drugs for dermatological disorders
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- A61P 35/00: Antineoplastic agents
- A61P 37/00: Drugs for immunological or allergic disorders
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 41/00: Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- G01N 33/505: {involving T-cells}
- G01N 33/56972: {White blood cells}
- A61K 2039/5154: {Antigen presenting cells [APCs], e.g. dendritic cells or macrophages}
- A61K 2039/55511: {Organic adjuvants}
- A61K 2039/55555: {Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers}
- A61K 2039/577: {tolerising response}
- B82Y 40/00: Manufacture or treatment of nanostructures
- G01N 2333/7051: T-cell receptor (TcR)-CD3 complex
- G01N 2333/70514: CD4
- G01N 2333/70517: CD8
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- G01N: INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES (measuring or testing apparatus or processes other than immunoassay, involving enzymes or microorganisms C12M, C12Q)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Disclosed are synthetic nanocarrier methods, and related compositions, comprising administering MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen and immunosuppressants in order to generate tolerogenic immune responses against the antigen, such as the generation of antigen-specific CD8+ regulatory T cells.

## Claims

### Claim 1

A method comprising:
(A) administering to a subject a composition that comprises:
(i) a first population of polymeric synthetic nanocarriers coupled to rapamycin or an analog thereof, and
(ii) MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen,
wherein the composition is in an amount effective to generate antigen-specific CD8+ regulatory T cells in the subject; or
(B) generating antigen-specific CD8+ regulatory T cells in a subject by administering a composition that comprises:
(i) a first population of polymeric synthetic nanocarriers coupled to rapamycin or an analog thereof, and
(ii) MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen; or
(C) administering to a subject a composition according to a protocol that was previously shown to generate antigen-specific CD8+ regulatory T cells in one or more test subjects;
wherein the composition comprises:
(i) a first population of polymeric synthetic nanocarriers coupled to rapamycin or an analog thereof, and
(ii) MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen;
and wherein the load of the rapamycin or an analog thereof on average across the first population of polymeric synthetic nanocarriers is at least 2% but no more than 25% (weight/weight), and wherein at least 75% of the polymeric synthetic nanocarriers of the first population of polymeric synthetic nanocarriers have a minimum dimension, obtained using dynamic light scattering, that is greater than 110 nm and a maximum dimension, obtained using dynamic light scattering, that is equal to or less than 500 nm.

### Claim 2 (depends on 1)

The method of claim 1, wherein the method further comprises providing or identifying the subject.

### Claim 3 (depends on 1)

The method of claim 1, wherein the antigen is a therapeutic protein, an autoantigen or an allergen, or is associated with an inflammatory disease, an autoimmune disease, organ or tissue rejection or graft versus host disease.

### Claim 4 (depends on 1)

The method of claim 1, wherein the method further comprises assessing the generation of antigen-specific CD8+ regulatory T cells in the subject prior to and/or after the administration of the composition.

### Claim 5 (depends on 1)

The method of claim 1, wherein
the subject has or is at risk of having an inflammatory disease, an autoimmune disease, an allergy, organ or tissue rejection or graft versus host disease;
the subject has undergone or will undergo transplantation; and/or
the subject has or is at risk of having an undesired immune response against a therapeutic protein that is being administered or will be administered to the subject.

### Claim 6 (depends on 1)

The method of claim 1, wherein one or more maintenance doses of the composition comprising the first population of synthetic nanocarriers and MHC Class I-restricted and/or MHC Class II-restricted epitopes of an antigen is administered to the subject.

### Claim 7 (depends on 1)

The method of claim 1, wherein the administering is by intravenous, intraperitoneal, transmucosal, oral, subcutaneous, pulmonary, intranasal, intradermal or intramuscular administration.

### Claim 8 (depends on 1)

The method of claim 1, wherein the administering is by inhalation or intravenous, subcutaneous or transmucosal administration.

### Claim 9 (depends on 1)

The method of claim 1, wherein the method further comprises collecting the generated antigen-specific CD8+ regulatory T cells.

### Claim 10 (depends on 1)

The method of claim 1, wherein the polymeric synthetic nanocarriers comprise polymer that is a non-methoxy-terminated polymer.

### Claim 11 (depends on 1)

The method of claim 1, wherein the polymeric synthetic nanocarriers comprise a polyester, a polyester coupled to a polyether, polyamino acid, polycarbonate, polyacetal, polyketal, polysaccharide, polyethyloxazoline or polyethyleneimine.

### Claim 12 (depends on 11)

The method of claim 11, wherein the polyester comprises a poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid) or polycaprolactone.

### Claim 13 (depends on 11)

The method of claim 11, wherein the polymeric synthetic nanocarriers comprise a polyester and a polyester coupled to a polyether.

### Claim 14 (depends on 13)

The method of claim 13, wherein the polyether comprises polyethylene glycol or polypropylene glycol.

### Claim 15 (depends on 1)

The method of claim 1, wherein the aspect ratio of the synthetic nanocarriers of the first population is greater than 1:1, 1:1.2, 1:1.5, 1:2, 1:3, 1:5, 1:7 or 1:10.