# US 11,433,143 B2 · Nano-enabled immunotherapy in cancer

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,433,143 B2
- Document ID: US11433143B2
- Status: Granted
- Kind: B2
- Application number: 16/687,368
- Filed: 2019-11-18
- Published: 2020-06-25
- Granted: 2022-09-06
- Earliest claimed: 2017-05-18
- Assignees: The Regents of the University of California
- Applicants: The Regents of the University of California
- Inventors: Andre E. Nel; Huan Meng; Kuo-Ching Mei
- Web page: https://patentgrep.com/patent/US11433143B2

## CPC

- A61K 47/6911: {the form being a liposome}
- A61K 47/6929: {the form being a nanoparticle, e.g. an immuno-nanoparticle}
- A61K 47/542: {Carboxylic acids, e.g. a fatty acid or an amino acid}
- A61K 47/544: {Phospholipids}
- A61K 47/551: {one of the codrug's components being a vitamin, e.g. niacinamide, vitamin B3, cobalamin, vitamin B12, folate, vitamin A or retinoic acid}
- A61K 47/554: {the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid}
- A61K 47/6905: {the form being a colloid or an emulsion}
- A61K 47/6923: {the form being an inorganic particle, e.g. ceramic particles, silica particles, ferrite or synsorb}
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- 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)
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES

## Abstract

In certain embodiments a platform technology for the facilitating immune therapy in the treatment of cancer is provided. In certain embodiments nanocarriers are provided that facilitate delivery of an IDO inhibitor in conjunction with an inducer of cell death (ICD-inducer). In certain embodiments the IDO inhibitor is conjugated to a component of a lipid bilayer forming a nanovesicle. In still another embodiment, methods and compositions are provided where an ICD-inducing agent (e.g., doxorubicin, oxaliplatin, mitoxantrone etc.) and an IDO pathway inhibitor (e.g., an IDO inhibitor-prodrug) are integrated into a nanocarrier (e.g. a lipid-bilayer (LB)-coated nanoparticle), that allows systemic delivery to orthotopic pancreatic cancer site.

## Claims

### Claim 1

A nanovesicle drug carrier for the combined delivery of an IDO inhibitor and an inducer of immunogenic cell death (ICD), said nanovesicle drug carrier comprising:
a liposome comprising a lipid bilayer, where said lipid bilayer comprises cholesterol and cholesterol hemisuccinate, wherein said cholesterol or said cholesterol hemisuccinate is conjugated to the IDO inhibitor 1-methyl-D-tryptophan (indoximod); and
a cargo within said liposome where said cargo comprises an agent that induces immunogenic cell death (ICD) (ICD-inducer), where said agent is mitoxantrone or oxaliplatin.

### Claim 2 (depends on 1)

The nanovesicle drug carrier of claim 1, wherein said indoximod is conjugated to cholesterol.

### Claim 3 (depends on 2)

The nanovesicle drug carrier of claim 2, wherein said lipid bilayer comprises:
a phospholipid; and
cholesterol conjugated to indoximod (Chol-IND).

### Claim 4 (depends on 3)

The nanovesicle drug carrier of claim 3, wherein said phospholipid comprises:
a saturated fatty acid with a C14-C20 carbon chain, and/or an unsaturated fatty acid with a C14-C20 carbon chain, and/or a natural lipid comprising a mixture of fatty acids with C12-C20 carbon chains; and/or
a phospholipid selected from the group consisting of phosphatidylcholine (DPPC), 1,2-dimyristoleoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-distearoyl-sn-glycero-3-phospho-rac-glycerol (DSPG), 1,2-dipalmitoyl-sn-glycero-3-phosphoglycerol (DPPG), distearoylphosphatidylcholine (DSPC), 1,2-dieicosenoyl-sn-glycero-3-phosphocholine, and diactylphosphatidylcholine (DAPC); or
a natural lipid selected from the group consisting of egg phosphatidylcholine (egg PC), and soy phosphatidylcholine (soy PC); and/or
distearoylphosphatidylcholine (DSPC).

### Claim 5 (depends on 3)

The nanovesicle drug carrier of claim 3, wherein said lipid bilayer comprises an mPEG phospholipid with a phospholipid C14-C18 carbon chain, and a PEG molecular weight ranging from about 350 Da to 5000 Da.

### Claim 6 (depends on 5)

The nanovesicle drug carrier of claim 5, wherein said lipid bilayer comprises 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-PEG (DSPE-PEG).

### Claim 7 (depends on 3)

The nanovesicle drug carrier of claim 3, wherein said lipid bilayer comprises DSPC:Chol-IND:DSPE-PEG or DPPG:Chol-IND:DSPE-PEG.

### Claim 8 (depends on 7)

The nanovesicle drug carrier of claim 7, wherein:
the ratio of DSPC:Chol-IND:DSPE-PEG ranges from 40-90% DSPC:10%-50% Chol-IND:1%-10% DSPE-PEG (molar ratio); or
the ratio of DSPC:Chol-IND:DSPE-PEG is about 50:40:5 (molar ratio);
the ratio of DPPG:Chol-IND:DSPE-PEG ranges from 40-90% DPPG:10%-50% Chol-IND:1%-10% DSPE-PEG (molar ratio); or
the ratio of DPPG:Chol-IND:DSPE-PEG is about 50:40:5 (molar ratio).

### Claim 9 (depends on 3)

The nanovesicle drug carrier of claim 3, wherein said lipid bilayer comprises a cholesterol derivative selected from the group consisting of cholesterol hemisuccinate (CHEMS), lysine-based cholesterol (CHLYS), and PEGylated cholesterol (Chol-PEG).

### Claim 10 (depends on 3)

The nanovesicle drug carrier of claim 3, wherein the indoximod conjugated to cholesterol comprises a compound having the structure:

### Claim 11 (depends on 1)

The nanovesicle drug carrier of claim 1, wherein said cargo within said vesicle comprises oxaliplatin.

### Claim 12 (depends on 11)

The nanovesicle drug carrier of claim 11, wherein said cargo comprises mitoxantrone (MTX).

### Claim 13 (depends on 1)

The nanovesicle drug carrier of claim 1, wherein said liposome contains a cargo-trapping agent.

### Claim 14 (depends on 13)

The nanovesicle drug carrier of claim 13, wherein said cargo trapping agent before reaction with the cargo loaded in the vesicle, is selected from the group consisting of citric acid, triethylammonium sucrose octasulfate (TEA8SOS), (NH4)2SO4, an ammonium salt, a trimethylammonium salt, and a triethylammonium salt.

### Claim 15 (depends on 1)

The nanovesicle drug carrier of claim 1, wherein said drug carrier is conjugated to a moiety selected from the group consisting of a targeting moiety, a fusogenic peptide, and a transport peptide.

### Claim 16 (depends on 1)

The nanovesicle drug carrier of claim 1, wherein the indoximod and the ICD inducer are synergistic in their activity against a cancer.

### Claim 17 (depends on 1)

A pharmaceutical formulation comprising a nanovesicle drug carrier of claim 1 and a pharmaceutically acceptable carrier.

### Claim 18 (depends on 1)

A method of treating a cancer, said method comprising:
administering to a subject in need thereof an effective amount of a nanovesicle drug carrier of claim 1.

### Claim 19 (depends on 1)

A method of treating a cancer in a mammal, said method comprising:
administering to an intra-tumoral or peri-tumoral site an effective amount of a nanovesicle drug carrier of claim 1;
wherein said cancer is selected from the group consisting of colon cancer, pancreatic cancer, and breast cancer.

### Claim 20 (depends on 1)

A kit for the treatment or prophylaxis of a cancer said kit comprising:
a container containing:
a nanovesicle drug carrier of claim 1.

### Claim 21 (depends on 19)

The method of claim 19, wherein said nanovesicle drug carrier is administered via a route selected from the group consisting of intravenous administration, intraarterial administration, intracerebral administration, intrathecal administration, oral administration, aerosol administration, administration via inhalation, intracranial administration via a cannula, and subcutaneous or intramuscular depot deposition.