# US 2020/0399642 A1 · Methods and compositions for treating and preventing metastatic tumors > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2020/0399642 A1 - Document ID: US20200399642A1 - Status: Published application - Kind: A1 - Application number: 16/773,094 - Filed: 2020-01-27 - Published: 2020-12-24 - Earliest claimed: 2017-07-27 - Assignees: Immune Pharmaceuticals Ltd. - Applicants: Immune Pharmaceuticals, Inc. - Inventors: Anna Martner; Kristoffer Hellstrand - Web page: https://patentgrep.com/patent/US20200399642A1 ## CPC - C12N 15/1137: {against enzymes (viral enzymes C12N15/1131; receptors C12N15/1138)} - A61K 31/417: Imidazole-alkylamines, e.g. histamine, phentolamine - A61K 31/7088: Compounds having three or more nucleosides or nucleotides - A61K 31/7105: Natural ribonucleic acids, i.e. containing only riboses attached to adenine, guanine, cytosine or uracil and having 3'-5' phosphodiester links - A61K 31/713: Double-stranded nucleic acids or oligonucleotides - A61K 38/20: Interleukins [IL] - A61K 38/2086: {IL-13 to IL-16} - A61K 38/217: {IFN-gamma} - A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca - A61P 35/04: specific for metastasis - C12N 15/11: DNA or RNA fragments; Modified forms thereof (DNA or RNA not used in recombinant technology, C07H21/00); {Non-coding nucleic acids having a biological activity} - C12N 2310/11: Antisense - C12N 2320/31: Combination therapy - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) - 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 ## Abstract Some embodiments of the methods and compositions provided herein relate to the treatment and amelioration of metastatic tumors and to the prevention of distant metastasis. In some embodiments, a metastatic tumor, such as a melanoma, can be treated by reducing the activity of NOX2 in a cell of a subject. In some embodiments, the activity of NOX2 can be reduced by administering a NOX2 inhibitor, such as histamine dihydrochloride (HDC). ## Claims ### Claim 1 A method of preventing metastasis of a primary tumor in a subject, or treating or ameliorating a metastatic tumor in a subject, the method comprising reducing the activity of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) or the expression level of a nucleic acid encoding NOX2 or the expression level of NOX2 protein in a cell of the subject. ### Claim 2 (depends on 1) The method of claim 1, wherein reducing the activity of NOX2 comprises administering an effective amount of a NOX2 inhibitor to the subject. ### Claim 3 (depends on 2) The method of claim 2, wherein the NOX2 inhibitor is selected from the group consisting of histamine dihydrochloride (HDC), histamine, N-methyl-histamine, 4-methyl-histamine, histamine phosphate, histamine diphosphate, GSK2795039, apocynin, GKT136901, GKT137831, ML171, VAS2870, VAS3947, celastrol, ebselen, perhexiline, grindelic acid, NOX2ds-tat, NOXAlds, fulvene-5, ACD 084, NSC23766, CAS 1177865-17-6, and CAS 1090893-12-1, and shionogi. ### Claim 4 (depends on 3) The method of claim 3, wherein the NOX2 inhibitor is HDC. ### Claim 5 (depends on 4) The method of claim 4, wherein reducing the expression level of a nucleic acid encoding NOX2 or the expression level of NOX2 protein in a cell comprises contacting the cell with an isolated nucleic acid selected from the group consisting of a guide RNA (gRNA), a small hairpin RNA (shRNA), a small interfering RNA (siRNA), a micro RNA (miRNA), an antisense polynucleotide, and a ribozyme. ### Claim 6 (depends on 5) The method of claim 5, wherein the isolated nucleic acid comprises a sequence encoding NOX2 or a fragment thereof, a sequence encoding antisense NOX2 or a fragment thereof, or an antisense nucleic acid complementary to a sequence encoding NOX2 or a fragment thereof. ### Claim 7 (depends on 6) The method of claim 6, wherein the isolated nucleic acid comprises a gRNA comprising a sequence complementary to the sequence of a target gene selected from the group consisting of NOX2, CYBA, NCF1, NCF2, NCF4, RAC1, and RAC2. ### Claim 8 (depends on 7) The method of claim 7, wherein the target gene is NOX2. ### Claim 9 (depends on 1) The method of claim 1, further comprising administering an additional therapeutic agent in combination with the NOX2 inhibitor or the isolated nucleic acid. ### Claim 10 (depends on 9) The method of claim 9, wherein the additional therapeutic agent is a NK cell activating agent. ### Claim 11 (depends on 10) The method of claim 10, wherein the NK cell activating agent is selected from the group consisting of IL-15, IFN-γ, IL-12, IL-18, IL-2, and CCL5. ### Claim 12 (depends on 1) The method of claim 1, wherein the additional therapeutic agent is IL-15 or IFN-γ. ### Claim 13 (canceled) ### Claim 14 (canceled) ### Claim 15 (canceled) ### Claim 16 (depends on 1) The method of claim 1, wherein the primary or metastatic tumor is selected from the group consisting of a melanoma, a bladder cancer, a breast cancer, a pancreatic cancer, a colorectal cancer, a renal cancer, a prostate cancer, a stomach cancer, a thyroid cancer, a uterine cancer, and an ovarian cancer. ### Claim 17 (canceled) ### Claim 18 (depends on 1) The method of claim 1, wherein the metastatic tumor comprises a melanoma, and wherein the melanoma is selected from the group consisting of lentigo maligna, lentigo maligna melanoma, superficial spreading melanoma, acral lentiginous melanoma, mucosal melanoma, nodular melanoma, polypoid melanoma, desmoplastic melanoma, melanoma with small nevus-like cells, melanoma with features of a Spitz nevus, uveal melanoma, and vaginal melanoma. ### Claim 19 (depends on 1) The method of claim 1, wherein the primary or metastatic tumor is located at a site selected from the group consisting of lung, liver, brain, peritoneum, adrenal gland, skin, muscle, vagina, and bone. ### Claim 20 (canceled) ### Claim 21 (depends on 1) The method of claim 1, wherein the cell is a hematopoietic cell or a myeloid cell. ### Claim 22 (canceled) ### Claim 23 (canceled) ### Claim 24 (canceled) ### Claim 25 (canceled) ### Claim 26 A method of increasing the level of natural killer (NK) cells in a metastatic tumor of a subject, the method comprising reducing the activity of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) or the expression level of a nucleic acid encoding NOX2 or the expression level of NOX2 protein in a cell of the subject, wherein the level of NK cells in the metastatic tumor is increased compared to a metastatic tumor in an untreated subject in which the activity of NOX2 or the expression level of a nucleic acid encoding NOX2 or the expression level of NOX2 protein in a cell of the untreated subject has not been reduced. ### Claim 27 A method of decreasing the level of reactive oxygen species (ROS) in a metastatic tumor of a subject, the method comprising reducing the activity of nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) or the expression level of a nucleic acid encoding NOX2 or the expression level of NOX2 protein in a cell of the subject, wherein the level of ROS in the metastatic tumor is increased compared to a metastatic tumor in an untreated subject in which the activity of NOX2 or the expression level of a nucleic acid encoding NOX2 or the expression level of NOX2 protein in a cell of the untreated subject has not been reduced. ### Claim at position 28 28-76. (canceled)