# US 11,896,646 B2 · Formulated and/or co-formulated liposome compositions containing toll-like receptor (“TLR”) agonist prodrugs useful in the treatment of cancer and methods thereof

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- Number: US 11,896,646 B2
- Document ID: US11896646B2
- Status: Granted
- Kind: B2
- Application number: 17/803,703
- Filed: 2022-10-14
- Published: 2023-08-31
- Granted: 2024-02-13
- Earliest claimed: 2020-12-21
- Assignees: Nammi Therapeutics, Inc.
- Applicants: Nammi Therapeutics, Inc.
- Inventors: David Stover; Dhruba Bharali; Bruce A Hay; Tahmineh Safaie
- Web page: https://patentgrep.com/patent/US11896646B2

## CPC

- A61K 9/1271: Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911})
- A61K 38/177: {Receptors; Cell surface antigens; Cell surface determinants}
- A61K 31/4164: 1,3-Diazoles
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/543: {Lipids, e.g. triglycerides; Polyamines, e.g. spermine or spermidine}
- A61K 47/554: {the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid}
- A61K 47/6911: {the form being a liposome}
- C07J 43/003: {not condensed}
- 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)
- C07J: STEROIDS (seco-steroids C07C)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Formulated and/or co-formulated liposomes comprising TLR prodrugs and/or TLR Lipid Moieties and methods of making the liposomes are disclosed herein. The TLR prodrug compositions comprise a drug moiety, a lipid moiety, and linkage unit that inhibit Toll-Like Receptor (e.g., TLR1/2, TLR4, and/or TLR7). The TLR prodrugs can be formulated and/or co-formulated into a liposome to provide a method of treating cancer, immunological disorders, and other disease by utilizing a targeted drug delivery vehicle.

## Claims

### Claim 1

A Toll-like receptor (TLR) prodrug composition comprising,
(i) a drug moiety;
(ii) a lipid moiety; and
(iii) a linkage unit (“LU”),
whereby the drug moiety comprises a TLR agonist and whereby the LU conjugates the drug moiety with the lipid moiety and wherein the TLR prodrug has the following chemical structure:

### Claim 2 (depends on 1)

The TLR prodrug of claim 1, wherein the lipid moiety comprises a lipid selected from the group consisting of cholesterol, the sodium salt of 1,2-dipalmitoyl-sn-glycero-3-phospho-(1′-rac-glycerol), the sodium salt of 1,2-dimyristoyl-sn-glycero-3-phospho-(1′-rac-glycerol), 1-decanoyl-2-hydroxy-sn-glycero-3-phosphocholine, the sodium salt of 1,2-dioleoyl-sn-glycero-3-phospho-(1′-rac-glycerol), soy L-α-lysophosphatidylcholine, the sodium salt of 1,2-dilauroyl-sn-glycero-3-phospho-(1′rac-glycerol), the ammonium salt of 1,2-dipalmitoyl-sn-glycero-3-phospho((ethyl-1′,2′, 3′-triazole)triethyleneglycolmannose, N-palmitoyl-sphingosine-1-{succinyl[methoxy(polyethylene glycol)2000]} and monophosphoryl Lipid A.

### Claim 3 (depends on 1)

The TLR prodrug of claim 1, wherein the lipid moiety comprises Stearic Acid.

### Claim 4

A nanocarrier comprising, a TLR prodrug whereby the nanocarrier releases an active TLR inhibitor after cleavage of the LU.

### Claim 5 (depends on 4)

The nanocarrier of claim 4, further comprising a helper lipid, whereby the helper lipid is selected from the group consisting of the chloride salt of 1,2-dioleoyl-3-trimethylammonium-propane, 1,2-dioleyloxy-3-dimethylaminopropane, 1,2-dilinoleyloxy-3-dimethylaminopropane, 2,2-dilinoleyl-4-dimethylaminoethyl-[1,3]-dioxolane, 1,2-Dioleoyl-sn-glycero-3-phosphoethanolamine, 1,2-dioleoyl-sn-glycero-3-phosphocholine, cholesterol, N-[(methoxy poly(ethylene glycol)2000)carbamyI]-1,2-dimyristyloxlpropyl-3-amine, cholesteryl hemisuccinate, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine, 1 2-distearoyl- sn-glycero-3-phosphocholine and 4-(2-aminoethyl)-morpholino-cholesterolhemisuccinate.

### Claim 6 (depends on 4)

The nanocarrier of claim 4, wherein the TLR prodrug comprises TR5.

### Claim 7 (depends on 4)

The nanocarrier of claim 4, whereby the nanocarrier is further co-formulated with an iNKT (i-natural kill T cell) activator.

### Claim 8 (depends on 7)

The nanocarrier of claim 7, wherein the iNKT activator is Alpha-galactosylceramide (α-GalCer).

### Claim 9 (depends on 4)

The nanocarrier of claim 4, whereby the nanocarrier is further co-formulated with an immune modulating agent, wherein the immune modulating agent is selected from the group consisting of other TLR agonists and/or prodrugs, immunogenic-cell death inducing chemotherapeutics, IDO (indoleamine 2,3-dioxygenase) antagonists, STING (stimulator of interferon genes) agonists, CTLA-4 (cytotoxic T-lymphocyte-associated antigen 4) inhibitors, PD-1/PD-L1 (programmed cell death 1/programmed cell death ligan 1) inhibitors and/or prodrugs thereof.

### Claim 10 (depends on 4)

The nanocarrier of claim 4, whereby the nanocarrier is further co-formulated with an ICD (immunogenic cell death)-inducing chemotherapeutic, wherein the ICD-inducing chemotherapeutic is selected from the group consisting of doxorubicin, mitoxantrone, oxaliplatin, cyclophosphamide, Bortezomib, Carfilzimib, or Paclitaxel.

### Claim 11 (depends on 4)

The nanocarrier of claim 4, further comprising doxorubicin (DOX).

### Claim 12 (depends on 4)

The nanocarrier of claim 4, wherein the nanocarrier comprises a liposome.

### Claim 13 (depends on 3, 12)

The liposome of claim 12, wherein the liposome comprises the TLR prodrug of claim 3.

### Claim 14 (depends on 4)

The nanocarrier of claim 4, wherein the nanocarrier comprises a solid-lipid nanoparticle (SLNP).

### Claim 15 (depends on 3, 14)

The SLNP of claim 14, wherein the SLNP comprises the TLR prodrug of claim 3.

### Claim 16

A Toll-like receptor (TLR) prodrug composition comprising,
(i) a drug moiety;
(ii) a lipid moiety; and
(iii) a linkage unit (“LU”),
whereby the drug moiety comprises a TLR agonist and whereby the LU conjugates the drug moiety with the lipid moiety and wherein the TLR prodrug has the following chemical structure: