# US 9,750,803 B2 · Lipid vesicle compositions and methods of use

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- Number: US 9,750,803 B2
- Document ID: US9750803B2
- Status: Granted
- Kind: B2
- Application number: 15/230,736
- Filed: 2016-08-08
- Published: 2017-02-23
- Granted: 2017-09-05
- Earliest claimed: 2010-03-19
- Assignees: Massachusetts Institute of Technology
- Applicants: Massachusetts Institute of Technology
- Inventors: Darrell J. Irvine; Jaehyun Moon
- Web page: https://patentgrep.com/patent/US9750803B2

## 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 9/1271: Non-conventional liposomes, e.g. PEGylated liposomes or liposomes coated or grafted with polymers (liposomes as conjugates {A61K47/6911})
- A61K 9/1273: Polymersomes; Liposomes with polymerisable or polymerised bilayer-forming substances
- A61K 38/193: {Colony stimulating factors [CSF]}
- A61K 38/20: Interleukins [IL]
- A61K 38/2013: {IL-2}
- A61K 38/2046: {IL-7}
- A61K 38/208: {IL-12}
- A61K 38/2086: {IL-13 to IL-16}
- A61K 38/212: {IFN-alpha}
- A61K 38/217: {IFN-gamma}
- A61K 38/45: Transferases (2)
- A61K 39/015: Hemosporidia antigens, e.g. Plasmodium antigens
- A61K 39/12: Viral antigens
- A61K 39/21: Retroviridae, e.g. equine infectious anemia virus
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 39/39533: {against materials from animals}
- A61K 47/6811: {the drug being a protein or peptide, e.g. transferrin or bleomycin}
- A61K 47/6911: {the form being a liposome}
- A61P 33/06: Antimalarials
- C07K 14/005: from viruses
- C12N 15/88: using microencapsulation, e.g. using {amphiphile} liposome vesicle
- A61K 39/00: Medicinal preparations containing antigens or antibodies (materials for immunoassay G01N33/53)
- A61K 2039/55511: {Organic adjuvants}
- A61K 2039/55555: {Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers}
- A61K 2039/55572: {Lipopolysaccharides; Lipid A; Monophosphoryl lipid A}
- A61K 2039/57: {characterised by the type of response, e.g. Th1, Th2}
- A61K 2039/572: {cytotoxic response}
- A61K 2039/575: {humoral response}
- A61K 2039/6018: {Lipids, e.g. in lipopeptides}
- C12N 2740/15034: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12N 2740/16234: Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
- C12Y 207/10001: Receptor protein-tyrosine kinase (2.7.10.1)
- 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
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- C12Y: ENZYMES
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The invention provides delivery systems comprised of stabilized multilamellar vesicles, as well as compositions, methods of synthesis, and methods of use thereof. The stabilized multilamellar vesicles comprise terminal-cysteine-bearing antigens or cysteine-modified antigens, at their surface and/or internally.

## Claims

### Claim 1

A multilamellar lipid vesicle comprising at least one terminal-cysteine-bearing antigen, and having covalent crosslinks between lipid bilayers, wherein at least two lipid bilayers in the multilamellar lipid vesicle are covalently crosslinked to each other through headgroups that react with covalent crosslinkers to form the covalent crosslinks between lipid bilayers, and wherein the terminal-cysteine bearing antigen is a toll-like receptor (TLR) agonist or a microbial antigen.

### Claim 2 (depends on 1)

The multilamellar lipid vesicle of claim 1, wherein the TLR agonist is selected from the group consisting of a TLR3 agonist, a TLR4 agonist, a TLR5 agonist, a TLR7 agonist, a TLR8 agonist, and a TLR9 agonist.

### Claim 3 (depends on 1)

The multilamellar lipid vesicle of claim 1, wherein the multilamellar lipid vesicle comprises a TLR4 agonist and a TLR7 agonist.

### Claim 4 (depends on 1)

The multilamellar lipid vesicle of claim 1, wherein the multilamellar lipid vesicle comprises a TLR7 agonist and a TLR8 agonist.

### Claim 5 (depends on 3)

The multilamellar lipid vesicle of claim 3, wherein TLR4 agonist is a monophosphoryl lipid A (MPLA).

### Claim 6 (depends on 3)

The multilamellar lipid vesicle of claim 3, wherein TLR7 agonist is a resiquimod.

### Claim 7 (depends on 4)

The multilamellar lipid vesicle of claim 4, wherein TLR7 agonist is a resiquimod.

### Claim 8 (depends on 1)

The multilamellar lipid vesicle of claim 1, wherein the multilamellar lipid vesicle comprises a first terminal-cysteine-bearing TLR agonist and a second terminal-cysteine-bearing TLR agonist, wherein the first and the second terminal-cysteine-bearing TLR agonists are different.

### Claim 9 (depends on 1)

The multilamellar lipid vesicle of claim 1, wherein the TLR agonist is selected from the group consisting of an imiquimod, a resiquimod, an imidazoquinoline, a nucleic acid comprising an unmethylated CpG dinucleotide, a monophosphoryl lipid A (MPLA), a lipopolysaccharide derivative, a single-stranded or double-stranded RNA, a flagellin, a muramyl dipeptide, a threonyl-muramyl dipeptide, OM-174, an oligoribonucleotide, an oligodeoxynucleotide, and a viral or bacterial DNA.

### Claim 10 (depends on 1)

The multilamellar lipid vesicle of claim 1, wherein the microbial antigen is a bacterial antigen, a viral antigen, a fungal antigen, a parasitic antigen, or a mycobacterial antigen.

### Claim 11 (depends on 1)

The multilamellar lipid vesicle of claim 1, wherein the microbial antigen is a vivax malaria protein (VMP) antigen.

### Claim 12 (depends on 1)

The multilamellar lipid vesicle of claim 1, wherein the microbial antigen comprises a part of a microbial species or an entire microbe.

### Claim 13 (depends on 1)

The multilamellar lipid vesicle of claim 1, wherein the multilamellar lipid vesicle comprises a first terminal-cysteine-bearing microbial antigen and a second terminal-cysteine-bearing microbial antigen, wherein the first and the second terminal-cysteine-bearing microbial antigens are different.

### Claim 14 (depends on 1)

The multilamellar lipid vesicle of claim 1, wherein the vesicle comprises phosphocholine and/or v.

### Claim 15 (depends on 1)

The multilamellar lipid vesicle of claim 1, wherein the vesicle comprises a maleimide functionalized lipid.

### Claim 16 (depends on 1)

The multilamellar lipid vesicle of claim 1, wherein the TLR agonist or the microbial antigen is present on the surface of the vesicles, encapsulated between lipid bilayers, and/or is present in the core of the vesicle.

### Claim 17 (depends on 1)

The multilamellar lipid vesicle of claim 1, wherein the vesicle is surface-conjugated to polyethylene glycol (PEG).

### Claim 18 (depends on 1)

The multilamellar lipid vesicle of claim 1, wherein said terminal-cysteine-bearing antigen is a cysteine-modified antigen.

### Claim 19 (depends on 1)

The multilamellar lipid vesicle of claim 1 further comprising an adjuvant.

### Claim 20 (depends on 1)

A composition comprising multilamellar lipid vesicles of claim 1.

### Claim 21 (depends on 20)

The composition of claim 20, further comprising a pharmaceutically acceptable carrier.

### Claim 22 (depends on 20)

The composition of claim 20, further comprising an adjuvant.