# US 10,441,656 B2 · Nanoparticle complexes of paclitaxel, cetuximab, and albumin, and methods of making the same

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- Number: US 10,441,656 B2
- Document ID: US10441656B2
- Status: Granted
- Kind: B2
- Application number: 15/412,596
- Filed: 2017-01-23
- Published: 2017-05-11
- Granted: 2019-10-15
- Earliest claimed: 2012-10-01
- Assignees: Mayo Foundation for Medical Education and Research
- Applicants: Mayo Foundation for Medical Education and Research
- Inventors: Svetomir N. Markovic; Wendy K. Nevala
- Web page: https://patentgrep.com/patent/US10441656B2

## CPC

- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/14: Particulate form, e.g. powders, {Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles (microspheres A61K9/16; microcapsules A61K9/50; nanocapsules, nanoparticles of the matrix type A61K9/51)}
- A61K 9/51: Nanocapsules; {Nanoparticles; (nanotubes A61K9/0092; polymeric micelles A61K9/1075; polymersomes A61K9/1273; pure drug nanoparticles A61K9/14; drug nanoparticles with adsorbed surface modifiers A61K9/141; conjugates, e.g. between drug and non-active nanoparticles, A61K47/50; preparations for in vivo diagnosis A61K49/00; with radioactive substances A61K51/00)}
- A61K 9/5169: {Proteins, e.g. albumin, gelatin}
- A61K 31/282: Platinum compounds
- A61K 31/337: having four-membered rings, e.g. taxol
- A61K 31/555: containing heavy metals, e.g. hemin, hematin, melarsoprol
- A61K 33/243: Platinum; Compounds thereof
- A61K 39/001104: {Epidermal growth factor receptors [EGFR]}
- A61K 39/395: Antibodies (agglutinins A61K38/36 {; as drug carriers A61K47/50}); Immunoglobulins; Immune serum, e.g. antilymphocytic serum
- A61K 41/0052: {Thermotherapy; Hyperthermia; Magnetic induction; Induction heating therapy}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/643: {Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]}
- A61K 47/6801: {Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent}
- A61K 47/6845: {the antibody targeting a cytokine, e.g. growth factors, VEGF, TNF, a lymphokine or an interferon}
- A61K 47/6849: {the antibody targeting a receptor, a cell surface antigen or a cell surface determinant}
- A61K 47/6851: {the antibody targeting a determinant of a tumour cell}
- A61K 47/6855: {the tumour determinant being from breast cancer cell}
- A61K 47/6863: {the tumour determinant being from stomach or intestines cancer cell}
- A61K 47/6865: {the tumour determinant being from skin, nerves or brain cancer cell}
- A61K 47/6867: {the tumour determinant being from a cell of a blood cancer}
- A61K 47/6929: {the form being a nanoparticle, e.g. an immuno-nanoparticle}
- A61K 47/6931: {the material constituting the nanoparticle being a polymer}
- A61P 35/00: Antineoplastic agents
- C07K 16/22: against growth factors {; against growth regulators}
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 16/2887: {against CD20}
- C07K 16/2893: {against CD52}
- C07K 16/3015: {Breast}
- C07K 16/32: against translation products of oncogenes
- A61K 2039/505: {comprising antibodies}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- A61K 2039/6056: {Antibodies}
- B82Y 5/00: Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
- C07K 2317/21: from primates, e.g. man
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C07K 2317/73: Inducing cell death, e.g. apoptosis, necrosis or inhibition of cell proliferation
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- C07K 2317/94: Stability, e.g. half-life, pH, temperature or enzyme-resistance
- 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)
- B82Y: SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES

## Abstract

This invention relates to methods of making antibody-albumin nanoparticle complexes and pharmaceutical compositions thereof, comprising albumin, an antibody with binding specificity for a EGFR cetuximab), and paclitaxel, the methods comprising mixing in vitro an aqueous albumin-paclitaxel nanoparticle with an antibody with binding specificity for EGFR cetuximab) under conditions to form the nanoparticle complexes.

## Claims

### Claim 1

A method of making an antibody-albumin nanoparticle complex, the method comprising mixing in vitro an aqueous albumin-paclitaxel nanoparticle with an antibody with binding specificity for epidermal growth factor receptor (EGFR) under conditions to form the nanoparticle complex, wherein the antibody is cetuximab, and wherein said nanoparticle complexes have an average diameter of between 0.1 μm and 1 μm.

### Claim 2 (depends on 1)

The method of claim 1, wherein the average diameter of said complexes is between about 0.1 μm and 0.9 μm.

### Claim 3 (depends on 1)

The method of claim 1, wherein the ratio of albumm-paelitaxel nanoparticle to antibody is between 5:1 and 1:2.5.

### Claim 4 (depends on 3)

The method of claim 3, wherein the ratio is about 5:1.

### Claim 5 (depends on 1)

The method of claim 1, wherein the aqueous albumin-paclitaxel nanoparticle is incubated with the antibody at an incubation temperature of between 15° C. and 30° C.

### Claim 6 (depends on 1)

The method of claim 1, wherein the aqueous albumin-paclitaxel nanoparticle is incubated with the antibody for between about 5 minutes and about 60 minutes.

### Claim 7 (depends on 1)

The method of claim 1, wherein the aqueous albumin-paclitaxel nanoparticle is incubated with the antibody for between about 20 minutes and about 400 minutes.

### Claim 8

A method of making a pharmaceutical composition comprising a pharmaceutically acceptable carrier and antibody-albumin nanoparticle complexes, the method comprising mixing aqueous albumin-paclitaxel nanoparticles with an antibody with binding specificity for epidermal growth factor receptor (EGFR) in vitro under conditions to firm the nanoparticle complexes, and adding the pharmaceutically acceptable carrier to the nanoparticle complexes, wherein the antibody is cetuximab, and wherein said nanoparticle complexes have an average diameter of between 0.1 μm and 1 μm.

### Claim 9 (depends on 8)

The method of claim 8, wherein the ratio of albumin-paclitaxel nanoparticle to antibody is between 5:1 and 1:2.5.

### Claim 10 (depends on 9)

The method of claim 9, wherein the ratio is about 5:1.

### Claim 11 (depends on 8)

The method of claim 8, wherein the aqueous albumin-paclitaxel nanoparticle is incubated with the antibody at an incubation temperature of between 15 CC and 30° C.

### Claim 12 (depends on 8)

The method of claim 8, wherein the aqueous albumin-paclitaxel nanoparticle is incubated with the antibody for between about 5 minutes and about 60 minutes.

### Claim 13 (depends on 8)

The method of claim 8, wherein the aqueous albumin-paclitaxel nanoparticle is incubated with the antibody for between about 20 minutes and about 400 minutes.

### Claim 14 (depends on 8)

The method of claim 8, wherein the pharmaceutically acceptable carrier is saline, water, lactic acid, mannitol, or a combination thereof.

### Claim 15 (depends on 8)

The method of claim 8, wherein the pharmaceutical composition is formulated for injection into a patient.