# US 11,439,632 B2 · Use of neuronal nitric oxide synthase inhibitors for immunotherapy in melanoma patients

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- Number: US 11,439,632 B2
- Document ID: US11439632B2
- Status: Granted
- Kind: B2
- Application number: 16/703,009
- Filed: 2019-12-04
- Published: 2020-06-11
- Granted: 2022-09-13
- Earliest claimed: 2018-12-05
- Assignees: Northwestern University; Chapman University
- Applicants: Northwestern University; Chapman University
- Inventors: Richard B. Silverman; Sun Yang
- Web page: https://patentgrep.com/patent/US11439632B2

## CPC

- A61K 31/47: Quinolines; Isoquinolines
- A61K 31/381: having five-membered rings
- A61P 35/00: Antineoplastic agents
- A61K 31/4164: 1,3-Diazoles
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 38/212: {IFN-alpha}
- C07K 16/2818: {against CD28 or CD152}
- 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

Disclosed herein are methods and compositions for administering immunotherapy to a subject in need thereof and for treating a subject in need thereof, where in the methods the subject is administered an effective amount of an inhibitor of nNOS for inducing an immunotherapeutic response in the subject and for treating the subject. The disclosed methods and composition may be utilized for treating a subject having a cell proliferative disease or disorder such as melanoma.

## Claims

### Claim 1

A method for treating melanoma characterized by elevated expression levels of programmed death-ligand 1 (PD-L1) in a subject in need thereof, the method comprising administering to the subject an effective amount of an inhibitor of neuronal nitric oxide synthase (nNOS) for decreasing expression of PD-L1 and treating the melanoma, wherein the inhibitor of nNOS is the compound MAC-3-190 having a formula:
or a suitable pharmaceutical salt, solvate, or hydrate thereof.

### Claim 2 (depends on 1)

The method of claim 1, further comprising administering to the subject IFN-α.

### Claim 3 (depends on 1)

The method of claim 1, further comprising administering to the subject a PD-L1 inhibitor or a programmed death-receptor 1 (PD-1) inhibitor.

### Claim 4 (depends on 1)

The method of claim 1, further comprising administering dacarbazine to the subject.

### Claim 5 (depends on 1)

The method of claim 1, further comprising administering temozolomide to the subject.

### Claim 6

A method for treating melanoma characterized by elevated expression levels of programmed death-ligand 1 (PD-L1) in a subject in need thereof, the method comprising administering to the subject an effective amount of an inhibitor of neuronal nitric oxide synthase (nNOS) for decreasing expression of PD-L1 and treating the melanoma, wherein the inhibitor of nNOS is the compound HH044 having a formula:
or a suitable pharmaceutical salt, solvate, or hydrate thereof.

### Claim 7 (depends on 6)

The method of claim 6, further comprising administering to the subject IFN-α.

### Claim 8 (depends on 6)

The method of claim 6, further comprising administering to the subject a PD-L1 inhibitor or a programmed death-receptor 1 (PD-1) inhibitor.

### Claim 9 (depends on 6)

The method of claim 6, further comprising administering dacarbazine to the subject.

### Claim 10 (depends on 6)

The method of claim 6, further comprising administering temozolomide to the subject.