# US 9,750,805 B2 · Calcium flux agonists and methods therefor

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- Number: US 9,750,805 B2
- Document ID: US9750805B2
- Status: Granted
- Kind: B2
- Application number: 15/264,947
- Filed: 2016-09-14
- Published: 2017-05-11
- Granted: 2017-09-05
- Earliest claimed: 2012-11-13
- Assignees: Nant Holdings IP, LLC
- Applicants: Nant Holdings IP, LLC
- Inventors: Kayvan Niazi; Shahrooz Rabizadeh; Justin Golovato; Patrick Soon-Shiong; Anne-Laure Le Ny; Oleksandr Buzko
- Web page: https://patentgrep.com/patent/US9750805B2

## CPC

- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 9/0014: {Skin, i.e. galenical aspects of topical compositions (non-active ingredients are additionally classified in A61K47/00; A61K9/0009, A61K9/0021, A61K9/7015, A61K9/7023 take precedence; cosmetic preparations A61K8/00, A61Q; preparations for wound dressings or bandages A61L26/00)}
- A61K 31/05: Phenols {(cannabinoids A61K31/658)}
- A61K 31/12: Ketones
- A61K 31/16: Amides, e.g. hydroxamic acids
- A61K 31/341: not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
- A61K 31/365: Lactones
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/423: condensed with carbocyclic rings
- A61K 31/66: Phosphorus compounds
- A61K 39/085: Staphylococcus
- A61K 47/06: Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K 47/10: Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
- A61P 17/00: Drugs for dermatological disorders
- A61P 17/02: for treating wounds, ulcers, burns, scars, keloids, or the like
- A61P 31/04: Antibacterial agents
- A61P 37/04: Immunostimulants
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/55511: {Organic adjuvants}
- A61K 2039/57: {characterised by the type of response, e.g. Th1, Th2}
- 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

Calcium flux agonists are used to enhance a TLR- or NOD-mediated stimulus and to so increase an immune response of a host and reduce healing time. Preferred calcium flux agonists include Ca2+ ionophores and SERCA inhibitors and are used in synergistic quantities where a ligand to a TLR or NOD receptor is present.

## Claims

### Claim 1

A method of enhancing an immune response of an immune competent cell to a ligand of a pattern recognition receptor, comprising a step of contacting the immune competent cell with a calcium flux agonist at a concentration effective to enhance the immune response.

### Claim 2 (depends on 1)

The method of claim 1 wherein the calcium flux agonist is a calcium ionophore.

### Claim 3 (depends on 2)

The method of claim 2 wherein the calcium ionophore is ionomycin, calcimycin, calcium ionophore II, calcium ionophore IV, calcium ionophore V, or calcium ionophore VI.

### Claim 4 (depends on 1)

The method of claim 1 wherein the calcium flux agonist is a SERCA inhibitor.

### Claim 5 (depends on 4)

The method of claim 4 wherein the SERCA inhibitor is 2,5-Di-tert-butylhydroquinone, thapsigargin, ruthenium red, gingerol, paxilline, or cyclopiazonic acid.

### Claim 6 (depends on 1)

The method of claim 1 wherein the enhanced immune response is increased IL-8 secretion or increased activation of NF-κB signaling.

### Claim 7 (depends on 1)

The method of claim 1 wherein the immune competent cell is a cell residing in an epidermis or a dermis.

### Claim 8 (depends on 7)

The method of claim 7 wherein the epidermis or dermis is injured.

### Claim 9 (depends on 8)

The method of claim 8 wherein the epidermis or dermis is infected with a bacterial pathogen.

### Claim 10 (depends on 9)

The method of claim 9 wherein the bacterial pathogen comprises a ligand for a TLR receptor or a NOD receptor.

### Claim 11 (depends on 7)

The method of claim 7 wherein the calcium flux agonist is topically applied to the dermis or epidermis.

### Claim 12 (depends on 1)

The method of claim 1 wherein the immune competent cell expresses at least one of a TLR receptor or a NOD receptor.

### Claim 13 (depends on 1)

The method of claim 1 wherein the pattern recognition receptor is a TLR receptor or a NOD receptor.

### Claim 14 (depends on 1)

The method of claim 1 wherein the ligand of the pattern recognition receptor is a PAMP.

### Claim 15 (depends on 1)

The method of claim 1 wherein the immune response is enhanced in a synergistic manner in the presence of the ligand, and wherein the calcium flux agonist is used in the presence of the ligand at a suboptimal concentration with respect to a maximum effect of the calcium flux agonist in the absence of the ligand.

### Claim 16

A method of enhancing an immune response of an immune competent cell to a ligand of a pattern recognition receptor, comprising:
contacting the immune competent cell with a calcium flux agonist at a concentration effective to enhance the immune response;
wherein the immune response is an increased IL-8 secretion or an increased activation of NF-κB signaling; and
wherein the pattern recognition receptor is a TLR receptor or a NOD receptor.

### Claim 17 (depends on 16)

The method of claim 16 wherein the calcium flux agonist is a calcium ionophore.

### Claim 18 (depends on 16)

The method of claim 16 wherein the calcium flux agonist is a SERCA inhibitor.

### Claim 19 (depends on 16)

The method of claim 16 wherein the immune competent cell is a cell residing in an epidermis or a dermis.

### Claim 20 (depends on 19)

The method of claim 19 wherein the epidermis or the dermis is injured or infected.