# US 10,500,277 B2 · Combination tumor treatment with drug-loaded, bispecific ligand-targeted minicells and interferon-gamma

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- Number: US 10,500,277 B2
- Document ID: US10500277B2
- Status: Granted
- Kind: B2
- Application number: 15/663,562
- Filed: 2017-07-28
- Published: 2017-11-16
- Granted: 2019-12-10
- Earliest claimed: 2013-10-04
- Assignees: EnGeneIC Molecular Delivery Pty Ltd
- Applicants: EnGeneIC Molecular Delivery Pty Ltd
- Inventors: Himanshu Brahmbhatt; Jennifer MacDiarmid
- Web page: https://patentgrep.com/patent/US10500277B2

## CPC

- A61K 39/44: Antibodies bound to carriers
- A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)}
- A61K 35/74: Bacteria (therapeutic use of a bacterial protein A61K38/00)
- A61K 38/217: {IFN-gamma}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 39/39583: {against materials not provided for elsewhere, e.g. haptens, coenzymes}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/2863: {against receptors for growth factors, growth regulators}
- C07K 16/44: against material not provided for elsewhere {, e.g. haptens, metals, DNA, RNA, amino acids}
- C07K 2317/31: multispecific
- 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)

## Abstract

Compositions and methods are provided for cancer treatments. The methodology entails, for instance, administering to a cancer patient a first composition comprising a plurality of bacterially derived intact minicells or intact killed bacterial cells, each of which encompasses an anti-neoplastic agent and carries a bispecific ligand on the surface, the ligand having specificity for a mammalian cell component, and a second composition comprising interferon-gamma (IFN-gamma) or an agent that increases the expression of IFN-gamma in the subject. The compositions include the first composition and the second composition as described, optionally with additional anti-neoplastic agents.

## Claims

### Claim 1

A package, product, or kit comprising:
(a) a first composition comprising a plurality of intact bacterial minicells or intact killed bacterial cells, each of which(i) encompasses an anti-neoplastic agent selected from the group consisting of a radionucleotide; a chemotherapy drugs; a functional nucleic acid selected from the group consisting of siRNA, miRNA, shRNA, lincRNA, antisense RNA, and ribozyme; and a polynucleotide that transcribes a functional nucleic acid selected from the group consisting of siRNA, miRNA, shRNA, lincRNA, antisense RNA, and ribozyme and (ii) carries a ligand on the surface of the intact minicells or intact killed bacterial cells, wherein the ligand has specificity to a tumor cell antigen; and
(b) a second composition comprising interferon-gamma (IFN-gamma).

### Claim 2

A composition comprising:
(a) a plurality of intact bacterial minicells or intact killed bacterial cells, each of which(i) encompasses an anti-neoplastic agent selected from the group consisting of a radionucleotide; a chemotherapy drugs; a functional nucleic acid selected from the group consisting of siRNA, miRNA, shRNA, lincRNA, antisense RNA, and ribozyme; and a polynucleotide that transcribes a functional nucleic acid selected from the group consisting of siRNA, miRNA, shRNA, lincRNA, antisense RNA, and ribozyme and (ii) carries a ligand on the surface of the intact minicells or bacterial cells, wherein the ligand has specificity to a non-phagocytic mammalian cell surface receptor, wherein the non-phagocytic mammalian cell surface receptor is a tumor cell antigen; and
(b) interferon-gamma (IFN-gamma).

### Claim 3 (depends on 2)

The composition of claim 2, wherein:
(a) the anti-neoplastic agent is a functional nucleic acid or a polynucleotide from which a functional nucleic acid is transcribed; and
(b) the functional nucleic acid inhibits a gene that promotes resistance to chemotherapy, wherein the gene is ribonucleotide reductase catalytic subunit M1 (RRM1).

### Claim 4 (depends on 1)

The package, product, or kit of claim 1, wherein the second composition comprises purified IFN-gamma protein.

### Claim 5 (depends on 1)

The package, product, or kit of claim 1, wherein the anti-neoplastic agent is a radionuclide.

### Claim 6 (depends on 1)

The package, product, or kit of claim 1, wherein the anti-neoplastic agent is a chemotherapy drug.

### Claim 7 (depends on 6)

The package, product, or kit of claim 6, wherein the chemotherapy drug is a small molecule drug having a molecular weight of less than about 900 Dalton.

### Claim 8 (depends on 7)

The package, product, or kit of claim 7, wherein the small molecule drug is cytotoxic.

### Claim 9 (depends on 7)

The package, product, or kit of claim 7, wherein the small molecule drug is a morpholinyl anthracycline derivative.

### Claim 10 (depends on 1)

The package, product, or kit of claim 1, wherein the functional nucleic acid inhibits a gene that promotes tumor cell proliferation, angiogenesis or resistance to chemotherapy and/or that inhibits apoptosis or cell cycle arrest.

### Claim 11 (depends on 1)

The package, product, or kit of claim 1, wherein the functional nucleic acid is siRNA or miRNA.

### Claim 12 (depends on 1)

The package, product, or kit of claim 1, wherein the functional nucleic acid inhibits the gene ribonucleotide reductase M1 (RRM1).

### Claim 13 (depends on 1)

The package, product, or kit of claim 1, wherein the composition comprises from about 109 to about 1010 minicells or killed bacterial cells.

### Claim 14 (depends on 2)

The composition of claim 2, wherein the interferon-gamma (IFN-gamma) comprises purified IFN-gamma protein.

### Claim 15 (depends on 2)

The composition of claim 2, wherein the anti-neoplastic agent is a radionuclide.

### Claim 16 (depends on 2)

The composition of claim 2, wherein the anti-neoplastic agent is a chemotherapy drug.

### Claim 17 (depends on 16)

The composition of claim 16, wherein the chemotherapy drug is a small molecule drug having a molecular weight of less than about 900 Dalton.

### Claim 18 (depends on 17)

The composition of claim 17, wherein the small molecule drug is cytotoxic.

### Claim 19 (depends on 17)

The composition of claim 17, wherein the small molecule drug is a morpholinyl anthracycline derivative.

### Claim 20 (depends on 2)

The composition of claim 2, wherein the functional nucleic acid inhibits a gene that promotes tumor cell proliferation, angiogenesis or resistance to chemotherapy and/or that inhibits apoptosis or cell cycle arrest.

### Claim 21 (depends on 2)

The composition of claim 2, wherein the functional nucleic acid is siRNA or miRNA.

### Claim 22 (depends on 2)

The composition of claim 2, wherein the composition comprises from about 109 to about 1010 minicells or killed bacterial cells.