# US 10,369,168 B2 · Administration of polynucleotide toll-like receptor 9 agonists for treating cancer

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- Number: US 10,369,168 B2
- Document ID: US10369168B2
- Status: Granted
- Kind: B2
- Application number: 16/141,828
- Filed: 2018-09-25
- Published: 2019-05-23
- Granted: 2019-08-06
- Earliest claimed: 2015-05-29
- Assignees: Dynavax Technologies Corporation
- Applicants: Dynavax Technologies Corporation
- Inventors: Cristiana Guiducci; Robert L. Coffman
- Web page: https://patentgrep.com/patent/US10369168B2

## CPC

- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 9/00: Medicinal preparations characterised by special physical form {(nuclear magnetic resonance contrast preparations or magnetic resonance imaging contrast preparations A61K49/18; preparations containing radioactive substances A61K51/12)}
- A61K 9/0073: {Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy; (nasal sprays A61K9/0043; inhalation of vapours of volatile or heated drugs, e.g. essential oils or nicotine, A61K9/007; devices A61M)}
- A61K 31/7125: Nucleic acids or oligonucleotides having modified internucleoside linkage, i.e. other than 3'-5' phosphodiesters
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61N 5/00: Radiation therapy (ultrasound therapy A61N7/00; devices or apparatus applicable to both therapy and diagnosis A61B6/00)
- A61P 35/00: Antineoplastic agents
- C07K 14/435: from animals; from humans
- A61K 2039/53: {DNA (RNA) vaccination}
- A61K 2039/543: {intranasal}
- A61K 2039/55511: {Organic adjuvants}
- 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)
- A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B)
- 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

The present disclosure relates to methods for treating cancer by intrapulmonary administration of a polynucleotide Toll-like receptor 9 agonist. The methods of the present disclosure are suitable for treating primary cancer of the lung, as well as metastatic cancer to the lung and extra pulmonary cancers thereof. Additionally, the present disclosure provides polynucleotide Toll-like receptor 9 agonists with immune stimulatory and toxicity profiles suitable for intrapulmonary administration.

## Claims

### Claim 1

A method of treating cancer in a mammalian subject in need thereof, the method comprising administering to the subject by injection an effective amount a pharmaceutical composition comprising a pharmaceutically acceptable excipient and an isolated polynucleotide, wherein the polynucleotide is a 2′-deoxyribopolynucleotide consisting of the sequence of:
5′-TCGTAACGTTCGAACGTTCGANx-3′ (SEQ ID NO:2), wherein x is 0, 1 or 2, each N is A, C or T, and wherein all internucleotide linkages are phosphorothioate linkages.

### Claim 2 (depends on 1)

The method of claim 1, wherein the polynucleotide consists of SEQ ID NO:7, SEQ ID NO:8, or SEQ ID NO:9.

### Claim 3 (depends on 1)

The method of claim 1, wherein the polynucleotide is double stranded.

### Claim 4 (depends on 1)

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

### Claim 5 (depends on 1)

The method of claim 1, wherein the composition is a sterile, isotonic solution.

### Claim 6 (depends on 1)

The method of claim 1, wherein the composition is a dehydrated solid.

### Claim 7 (depends on 1)

The method of claim 1, wherein the subject has a primary cancer selected from the group consisting of primary lung cancer and extrapulmonary cancer.

### Claim 8 (depends on 7)

The method of claim 7, wherein the subject has primary lung cancer.

### Claim 9 (depends on 8)

The method of claim 8, wherein the primary lung cancer is non-small-cell lung carcinoma (NSCLC) or small-cell lung carcinoma (SCLC).

### Claim 10 (depends on 8)

The method of claim 8, wherein the primary lung cancer is a non-small-cell lung cancer selected from the group consisting of adenocarcinoma, squamous-cell carcinoma, and large-cell carcinoma.

### Claim 11 (depends on 7)

The method of claim 7, wherein the subject has metastatic cancer to the lung.

### Claim 12 (depends on 11)

The method of claim 11, wherein the metastatic cancer is a metastasis of a primary cancer selected from the group consisting of bladder cancer, breast cancer, colorectal cancer, head and neck cancer, kidney cancer, melanoma, pancreatic cancer, prostate cancer, and ovarian cancer.

### Claim 13 (depends on 11)

The method of claim 11, wherein the metastatic cancer is from a cancer of unknown primary origin.

### Claim 14 (depends on 1)

The method of claim 1, wherein the mammalian subject is a human.

### Claim 15 (depends on 1)

The method of claim 1, further comprising administering an effective amount of a second therapeutic agent to the subject.

### Claim 16 (depends on 15)

The method of claim 15, wherein the second therapeutic agent comprises a chemotherapeutic agent selected from the group consisting of actinomycin, afatinib, alectinib, asparaginase, azacitidine, azathioprine, bicalutamide, bleomycin, bortezomib, camptothecin, carboplatin, capecitabine, certinib, cisplatin, chlorambucil, crizotinib, cyclophosphamide, cytarabine, daunorubicin, docetaxel, doxifluridine, doxorubicin, erlotinib, epirubicin, epothilone, etoposide, fludarabine, flutamine, fluorouracil, gefitinib, gemcitabine, hydroxyurea, idarubicin, ifosfamide, imatinib, irinotecan, lapatinib, letrozole, mechlorethamine, mercaptopurine, methotrexate, mitomycin, mitoxantrone, octreotide, oxaliplatin, paclitaxel, pemetrexed, raltitrexed, sorafenib, sunitinib, tamoxifen, temozolomide, teniposide, tioguanine, topotecan, valrubicin, vinblastine, vincristine, vindesine, vinorelbine, and combinations thereof.

### Claim 17 (depends on 15)

The method of claim 15, wherein the second therapeutic agent is an antagonist of an inhibitory immune checkpoint molecule.

### Claim 18 (depends on 17)

The method of claim 17, wherein the inhibitory immune checkpoint molecule is selected from the group consisting of PD-1, PD-L1, PD-L2, CTLA-4 (CD152), LAG-3, TIM-3, TIGIT, IL-10, and TGF-beta.

### Claim 19 (depends on 17)

The method of claim 17, wherein the inhibitory immune checkpoint molecule is indoleamine 2,3-dioxygenase (IDO) or tryptophan 2,3-dioxygenase (TDO).

### Claim 20 (depends on 15)

The method of claim 15, wherein the second therapeutic agent is an agonist of an immune stimulatory molecule.

### Claim 21 (depends on 20)

The method of claim 20, wherein the immune stimulatory molecule is selected from the group consisting of CD27, CD40, OX40 (CD134), GITR, CD137, CD28 and ICOS (CD278).

### Claim 22 (depends on 15)

The method of claim 15, wherein the second therapeutic agent comprises an antibody, fragment or derivative thereof.

### Claim 23 (depends on 7)

The method of claim 7, further comprising one or both of resecting the primary cancer and administering radiation therapy.