# US 11,298,342 B2 · Methods providing a therapeutic macromolecule and synthetic nanocarriers comprising immunosuppressant locally and concomitantly to reduce both type I and type IV hypersensitivity

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- Number: US 11,298,342 B2
- Document ID: US11298342B2
- Status: Granted
- Kind: B2
- Application number: 16/438,147
- Filed: 2019-06-11
- Published: 2020-03-12
- Granted: 2022-04-12
- Earliest claimed: 2013-05-03
- Assignees: Selecta Biosciences, Inc.
- Applicants: Selecta Biosciences, Inc.
- Inventors: Roberto A. Maldonado
- Web page: https://patentgrep.com/patent/US11298342B2

## CPC

- A61K 31/436: the heterocyclic ring system containing a six-membered ring having oxygen as a ring hetero atom, e.g. rapamycin
- 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 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 9/5115: {Inorganic compounds}
- A61K 9/5153: {Polyesters, e.g. poly(lactide-co-glycolide)}
- A61K 9/5192: {Processes}
- A61K 31/192: having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid {(cannabinoids A61K31/658)}
- A61K 38/19: Cytokines; Lymphokines; Interferons
- A61K 38/21: Interferons {[IFN]}
- A61K 38/37: Factors VIII
- A61K 38/43: Enzymes; Proenzymes; Derivatives thereof
- A61K 38/47: acting on glycosyl compounds (3.2), e.g. cellulases, lactases
- A61K 39/39533: {against materials from animals}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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 47/6935: {the polymer being obtained otherwise than by reactions involving carbon to carbon unsaturated bonds, e.g. polyesters, polyamides or polyglycerol}
- A61K 47/6937: {the polymer being PLGA, PLA or polyglycolic acid}
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- 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 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 37/08: Antiallergic agents (antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14)
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/18: against material from animals or humans
- C07K 16/241: {Tumor Necrosis Factors}
- C07K 16/40: against enzymes
- A61K 2039/505: {comprising antibodies}
- C12Y 305/01001: Asparaginase (3.5.1.1)
- 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)
- C12Y: ENZYMES

## Abstract

Disclosed are methods and related compositions for concomitantly, locally administering immunosuppressants and doses of therapeutic macromolecules for reducing Type I and Type IV hypersensitivity.

## Claims

### Claim 1

A method comprising:
providing a therapeutic dose of a therapeutic macromolecule, wherein the therapeutic macromolecule is not attached to synthetic nanocarriers;
providing a composition comprising synthetic nanocarriers that are attached to immunosuppressants; and
locally administering the composition and the therapeutic dose of the therapeutic macromolecule to a subject concomitantly,
wherein the local concomitant administration of the composition and the therapeutic dose of the therapeutic macromolecule reduces both Type 1 hypersensitivity and Type IV hypersensitivity in the subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein the subject is
(a) a nave subject; or
(b) at risk of a local inflammatory reaction due to the administration of the therapeutic dose of the therapeutic macromolecule.

### Claim 3 (depends on 1)

The method of claim 1, wherein the composition and the therapeutic dose of the therapeutic macromolecule are administered to the same location.

### Claim 4 (depends on 1)

The method of claim 1, wherein the composition and the therapeutic dose of the therapeutic macromolecule are administered to different locations.

### Claim 5 (depends on 1)

The method of claim 1, wherein the concomitant local administration is according to a protocol that has been demonstrated to result in a reduction of both Type 1 hypersensitivity and Type IV hypersensitivity with the composition and therapeutic dose of the therapeutic macromolecule, as compared to local administration of the therapeutic dose of the therapeutic macromolecule in the absence of concomitant local administration of the composition.

### Claim 6 (depends on 5)

The method of claim 5, wherein the method further comprises determining the protocol.

### Claim 7 (depends on 1)

The method of claim 1, wherein the method further comprises assessing a local inflammatory response in the subject prior to and/or after the administration.

### Claim 8 (depends on 7)

The method of claim 7, wherein the method further comprises assessing Type 1 hypersensitivity and Type IV hypersensitivity in the subject prior to and/or after the administration.

### Claim 9 (depends on 1)

The method of claim 1, wherein the method further comprises recording a reduction or prevention of a local inflammatory response.

### Claim 10 (depends on 9)

The method of claim 9, wherein the method further comprises recording a reduction in both Type 1 hypersensitivity and Type IV hypersensitivity.

### Claim 11 (depends on 1)

The method of claim 1, wherein the immunosuppressant comprises a statin, an mTOR inhibitor, a TGF-β signaling agent, a corticosteroid, an inhibitor of mitochondrial function, a P38 inhibitor, an NF-κB inhibitor, an adenosine receptor agonist, a prostaglandin E2 agonist, a phosphodiesterase 4 inhibitor, an HDAC inhibitor or a proteasome inhibitor.

### Claim 12 (depends on 1)

The method of claim 1, wherein the therapeutic macromolecule comprises a/an infusible or injectable therapeutic protein, enzyme, enzyme cofactor, hormone, blood or blood coagulation factor, cytokine, interferon, growth factor, monoclonal antibody, polyclonal antibody, or protein associated with Pompe's disease.

### Claim 13 (depends on 1)

The method of claim 1, wherein a load of immunosuppressant attached to the synthetic nanocarriers, on average across the synthetic nanocarriers, is between 0.1% and 50%.

### Claim 14 (depends on 1)

The method of claim 1, wherein the synthetic nanocarriers comprise lipid nanoparticles, polymeric nanoparticles, metallic nanoparticles, surfactant-based emulsions, dendrimers, buckyballs, nanowires, virus-like particles or peptide or protein particles.

### Claim 15 (depends on 14)

The method of claim 14, wherein the synthetic nanocarriers comprise polymeric nanoparticles.

### Claim 16 (depends on 15)

The method of claim 15, wherein the polymeric nanoparticles comprise polymer that is a non-methoxy-terminated, pluronic polymer.

### Claim 17 (depends on 15)

The method of claim 15, wherein the polymeric nanoparticles comprise a polyester, polyester attached to a polyether, polyamino acid, polycarbonate, polyacetal, polyketal, polysaccharide, polyethyloxazoline or polyethyleneimine.

### Claim 18 (depends on 17)

The method of claim 17, wherein the polyester comprises a poly(lactic acid), poly(glycolic acid), poly(lactic-co-glycolic acid) or polycaprolactone.

### Claim 19 (depends on 1)

The method of claim 1, wherein the mean of a particle size distribution obtained using dynamic light scattering of the synthetic nanocarriers is a diameter greater than 100 nm.

### Claim 20 (depends on 1)

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