# US 12,324,843 B2 · Compositions and methods for delivery of biomacromolecule agents

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- Number: US 12,324,843 B2
- Document ID: US12324843B2
- Status: Granted
- Kind: B2
- Application number: 18/529,758
- Filed: 2023-12-05
- Published: 2024-04-11
- Granted: 2025-06-10
- Earliest claimed: 2015-03-25
- Assignees: The Regents of the University of Michigan
- Applicants: The Regents of the University of Michigan
- Inventors: James J. Moon; Rui Kuai; Anna A. Schwendeman; Jutaek Nam
- Web page: https://patentgrep.com/patent/US12324843B2

## CPC

- A61K 47/6917: {the form being a lipoprotein vesicle, e.g. HDL or LDL proteins}
- A61K 9/127: Synthetic bilayered vehicles, e.g. liposomes or liposomes with cholesterol as the only non-phosphatidyl surfactant
- A61K 31/7088: Compounds having three or more nucleosides or nucleotides
- A61K 31/712: Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 39/0011: {Cancer antigens}
- A61K 39/001106: {Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ErbB4}
- A61K 39/00111: {Hepatocyte growth factor receptor [HGFR or c-met]}
- A61K 39/001132: {Fibroblast growth factors [FGF]}
- A61K 39/001151: {p53}
- A61K 39/001156: {Tyrosinase and tyrosinase related proteinases [TRP-1 or TRP-2]}
- A61K 39/001157: {Telomerase or TERT [telomerase reverse transcriptase]}
- A61K 39/001162: {Kinases, e.g. Raf or Src}
- A61K 39/001164: {GTPases, e.g. Ras or Rho}
- A61K 39/001166: {Adhesion molecules, e.g. NRCAM, EpCAM or cadherins}
- A61K 39/001176: {Heat shock proteins}
- A61K 39/001181: {Alpha-feto protein}
- A61K 39/001182: {Carcinoembryonic antigen [CEA]}
- A61K 39/001184: {Cancer testis antigens, e.g. SSX, BAGE, GAGE or SAGE}
- A61K 39/001186: {MAGE}
- A61K 39/001188: {NY-ESO}
- A61K 39/001189: {PRAME}
- A61K 39/001191: {Melan-A/MART}
- A61K 39/001192: {Glycoprotein 100 [Gp100]}
- A61K 39/001193: {Prostate associated antigens e.g. Prostate stem cell antigen [PSCA]; Prostate carcinoma tumor antigen [PCTA]; PAP or PSGR}
- A61K 39/001194: {Prostate specific antigen [PSA]}
- A61K 39/001195: {Prostate specific membrane antigen [PSMA]}
- A61K 39/001197: {Breakpoint cluster region-abelson tyrosine kinase [BCR-ABL]}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/554: {the modifying agent being a steroid plant sterol, glycyrrhetic acid, enoxolone or bile acid}
- A61P 3/06: Antihyperlipidemics
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 9/10: for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
- A61P 35/00: Antineoplastic agents
- A61P 37/04: Immunostimulants
- C12N 15/111: {General methods applicable to biologically active non-coding nucleic acids}
- C12N 15/113: Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; {Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing (when used in plants C12N15/8218)}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/3515: Lipophilic moiety, e.g. cholesterol
- C12N 2320/32: Special delivery means, e.g. tissue-specific
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present invention relates to nanoparticles complexed with biomacromolecule agents configured for treating, preventing or ameliorating various types of disorders, and methods of synthesizing the same. In particular, the present invention is directed to compositions comprising nanoparticles (e.g., synthetic high density lipoprotein (sHDL)) carrying biomacromolecule agents (e.g., nucleic acid, peptides, glycolipids, etc.), methods for synthesizing such nanoparticles, as well as systems and methods utilizing such nanoparticles (e.g., in diagnostic and/or therapeutic settings).

## Claims

### Claim 1

A method of delivering a sHDL nanoparticle to the lymph nodes of a subject, the method comprising administering to the subject a composition comprising an sHDL nanoparticle, wherein the sHDL nanoparticle comprises (i) a phospholipid selected from 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC) and dipalmitoylphosphatidylcholine (DPPC), (ii) a thiol-reactive phospholipid, and (iii) an apolipoprotein mimetic having the sequence PVLDLFRELLNELLEALKQKLK (SEQ ID NO: 4).

### Claim 2 (depends on 1)

The method of claim 1, wherein the phospholipid is DMPC.

### Claim 3 (depends on 1)

The method of claim 1, wherein the phospholipid is DPPC.

### Claim 4 (depends on 1)

The method of claim 1, wherein the thiol-reactive phospholipid is selected from the group consisting of dioleoyl-sn-glycero-3-phosphoethanolamine-N-[3-(2-pyridyldithio) propionate] (DOPE-PDP), 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine-N-[4-(p-maleimidophenyl) butyramide], 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine-N-[4-(p-maleimidophenyl) butyramide], 1,2-dihexadecanoyl-sn-glycero-3-phosphoethanolamine-N-[4-(p-maleimidomethyl)cyclohexane-carboxamide], and 1,2-di-(9Z-octadecenoyl)-sn-glycero-3-phosphoethanolamine-N-[4-(p-maleimidomethyl)cyclohexane-carboxamide].

### Claim 5 (depends on 1)

The method of claim 1, wherein the composition is administered subcutaneously.

### Claim 6 (depends on 1)

The method of claim 1, wherein the composition further comprises one or more antigens.

### Claim 7 (depends on 6)

The method of claim 6, wherein the antigens are conjugated to the thiol-reactive phospholipid of the sHDL nanoparticle.

### Claim 8 (depends on 6)

The method of claim 6, wherein the antigens are conjugated to the outer surface of the sHDL nanoparticle.

### Claim 9 (depends on 1)

The method of claim 1, wherein the composition further comprises an adjuvant.

### Claim 10 (depends on 9)

The method of claim 9, wherein the adjuvant is conjugated to the outer surface of the sHDL nanoparticle.

### Claim 11 (depends on 9)

The method of claim 9, wherein the adjuvant is selected from the group consisting of a CpG immunostimulatory oligonucleotide, polyIC, poly-ICLC, imiquimod, resiquimod, gardiquimod, a imidazoquinoline, and telratolimod.

### Claim 12 (depends on 11)

The method of claim 11, wherein the adjuvant is modified with cholesterol.

### Claim 13 (depends on 11)

The method of claim 11, wherein the adjuvant is a CpG immunostimulatory oligonucleotide.

### Claim 14 (depends on 1)

The method of claim 1, wherein the composition further comprises one or more nucleic acids.

### Claim 15 (depends on 14)

The method of claim 14, wherein the one or more nucleic acids are siRNAs.

### Claim 16 (depends on 14)

The method of claim 14, wherein the one or more nucleic acids are conjugated to the thiol-reactive phospholipid of the sHDL nanoparticle.

### Claim 17 (depends on 14)

The method of claim 14, wherein the one or more nucleic acids are conjugated to the outer surface of the nanoparticle.

### Claim 18 (depends on 1)

The method of claim 1, wherein the average size of the nanoparticle is between 6 to 500 nm.

### Claim 19 (depends on 18)

The method of claim 18, wherein the average size of the nanoparticle is between 6 to 70 nm.

### Claim 20 (depends on 19)

The method of claim 19, wherein the average size of the nanoparticle is between 4 to 75 nm.