# US 9,750,729 B2 · Immunomodulation by IAP inhibitors

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- Number: US 9,750,729 B2
- Document ID: US9750729B2
- Status: Granted
- Kind: B2
- Application number: 12/992,631
- Filed: 2009-05-14
- Published: 2011-06-09
- Granted: 2017-09-05
- Earliest claimed: 2008-05-16
- Assignees: Dana-Farber Cancer Institute, Inc.; Novartis AG
- Applicants: Leigh Zawel; Christopher S. Straub; Brant G. Firestone; Glenn Dranoff; Michael Dougan
- Inventors: Leigh Zawel; Christopher S. Straub; Brant G. Firestone; Glenn Dranoff; Michael Dougan
- Web page: https://patentgrep.com/patent/US9750729B2

## CPC

- A61K 31/4439: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole (nicotine A61K31/465)
- A61K 31/421: 1,3-Oxazoles, e.g. pemoline, trimethadione
- A61K 31/427: not condensed and containing further heterocyclic rings
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 39/0011: {Cancer antigens}
- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 33/00: Antiparasitic agents
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61P 37/04: Immunostimulants
- A61P 37/06: Immunosuppressants, e.g. drugs for graft rejection
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- A61K 2039/55511: {Organic adjuvants}
- A61K 2039/80: {Vaccine for a specifically defined cancer}
- C12N 5/0634: {Cells from the blood or the immune system}
- 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
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## Abstract

The present invention is directed to immune adjuvants containing IAP inhibitors, including Smac mimetics. The invention further provides pharmaceutical compositions and vaccines containing an IAP inhibitor and an antigen. Methods of enhancing an immune response by administration of an IAP inhibitor, methods of treating or preventing cancer, methods of treating or preventing infections, methods of treating autoimmune disorders, and methods of potentiating cytokine or antibody production are also provided.

## Claims

### Claim 1

A method of enhancing an immune response of a subject with melanoma, said method comprising administering to the subject an immune enhancing amount of an IAP inhibitor, wherein the IAP inhibitor is: (S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide; or a pharmaceutically acceptable salt thereof, wherein the administration of the immune enhancing amount of the IAP inhibitor potentiates cytokine production.

### Claim 2 (depends on 1)

The method of claim 1, wherein the immune response is mediated by one or more immune cell types selected from the group consisting of dendritic cells, B cells, T cells, NK cells, NKT cells, macrophages, CD4+ T cells, and CD8+ T cells.

### Claim 3

A method of enhancing an immune response of a subject with melanoma to an antigen, comprising (a) administering to the subject an immunogenic quantity of an antigen, the antigen being a tumor antigen; and (b) administering an immune enhancing amount of an IAP inhibitor selected from the group consisting of:
(S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide
or a pharmaceutically acceptable salt thereof.

### Claim 4 (depends on 3)

The method of claim 3, wherein the immune response is mediated by one or more immune cell types selected from the group consisting of dendritic cells, B cells, T cells, NK cells, NKT cells, macrophages, CD4+ T cells, and CD8+ T cells.

### Claim 5 (depends on 3)

The method of claim 3, wherein the antigen and the TAP inhibitor are administered sequentially.

### Claim 6 (depends on 3)

The method of claim 3, wherein the antigen and the TAP inhibitor are administered simultaneously.

### Claim 7 (depends on 3)

The method of claim 3, wherein the antigen and the TAP inhibitor are administered as a single composition.

### Claim 8 (depends on 3)

The method of claim 3, wherein the antigen comprises a pathogen, an attenuated pathogen, or a portion thereof.

### Claim 9 (depends on 3)

The method of claim 3, wherein the tumor antigen is present in cancer cells and absent from non-cancerous cells, or present at elevated levels in cancer cells relative to non-cancerous cells.

### Claim 10

A method of treating a cancer in a subject, comprising administering to the subject in need thereof a therapeutically effective amount of an IAP inhibitor selected from the group consisting of: (S)—N—((S)-1-Cyclohexyl-2-{(S)-2-[4-(4-fluoro-benzoyl)-thiazol-2-yl]-pyrrolidin-1-yl}-2-oxo-ethyl)-2-methylamino-propionamide;
or a pharmaceutically acceptable salt thereof, and an immunogenic quantity of an antigen, the antigen being a tumor antigen, wherein administration of said IAP inhibitor and said tumor antigen enhances the immune response of the subject to the cancer, and the cancer is melanoma.

### Claim 11 (depends on 10)

The method of claim 10, wherein the cancer is a solid tumor.

### Claim 12 (depends on 10)

The method of claim 10, wherein the antigen comprises a cancer cell.

### Claim 13 (depends on 12)

The method of claim 12, wherein the cancer cell is obtained from the subject.

### Claim 14 (depends on 12)

The method of claim 12, wherein the cancer cell is proliferation incompetent.

### Claim 15 (depends on 10)

The method of claim 10, wherein the antigen and the TAP inhibitor are administered sequentially.

### Claim 16 (depends on 10)

The method of claim 10, wherein the antigen and the TAP inhibitor are administered simultaneously.

### Claim 17 (depends on 10)

The method of claim 10, wherein the antigen and the TAP inhibitor are administered as a single composition.

### Claim 18 (depends on 10)

The method of claim 10, wherein the tumor antigen is present in cancer cells and absent from non-cancerous cells, or present at elevated levels in cancer cells relative to non-cancerous cells.

### Claim 19 (depends on 18)

The method of claim 18, wherein the cancer is a solid tumor.