# US 10,500,252 B2 · Method of treating intracellular infection

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- Number: US 10,500,252 B2
- Document ID: US10500252B2
- Status: Granted
- Kind: B2
- Application number: 14/899,581
- Filed: 2014-06-25
- Published: 2016-05-26
- Granted: 2019-12-10
- Earliest claimed: 2013-06-25
- Assignees: The Walter and Eliza Hall Institute of Medical Research
- Applicants: Walter and Eliza Hall Institute of Medical Research
- Inventors: Marc Pellegrini; Gregor Klaus-Peter Ebert; Colin Glenn Begley
- Web page: https://patentgrep.com/patent/US10500252B2

## CPC

- A61K 38/191: {Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta}
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/522: having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 38/05: Dipeptides
- A61K 38/1761: {Apoptosis related proteins, e.g. Apoptotic protease-activating factor-1 (APAF-1), Bax, Bax-inhibitory protein(s)(BI; bax-I), Myeloid cell leukemia associated protein (MCL-1), Inhibitor of apoptosis [IAP] or Bcl-2}
- A61K 38/19: Cytokines; Lymphokines; Interferons
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 31/00: Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P 31/04: Antibacterial agents
- A61P 31/06: for tuberculosis
- A61P 31/10: Antimycotics
- A61P 31/12: Antivirals
- A61P 31/14: for RNA viruses
- A61P 31/18: for HIV
- A61P 31/20: for DNA viruses
- A61P 31/22: for herpes viruses
- A61P 33/00: Antiparasitic agents
- A61P 33/02: Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 14/4703: {Inhibitors; Suppressors}
- C12N 15/1138: {against receptors or cell surface proteins}
- C12N 2310/14: interfering nucleic acids [NA]
- C12N 2310/141: MicroRNAs, miRNAs
- C12N 2310/531: Stem-loop; Hairpin
- C12N 2320/31: Combination therapy
- C12N 2730/10171: Demonstrated in vivo effect
- C12N 2740/16071: Demonstrated in vivo effect
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention provides a method of treating an intracellular infection in a subject wherein the method comprising administering to the subject an IAP antagonist. In certain embodiments the IAP antagonist is a Smac mimetic.

## Claims

### Claim 1

A method of treating a persistent intracellular infection in which tumor necrosis factor (TNF) is produced, the method comprising administering to a subject in need thereof an effective amount of an Inhibitor of Apoptosis (IAP) antagonist
wherein the intracellular infection is a viral infection caused by a virus selected from the group consisting of Human papillomaviruses, Herpes viruses, Human papovaviruses, adenoviruses, parvoviruses, human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and human T-cell lymphotropic virus (HTLV), or
wherein the intracellular infection is a bacterial infection caused by a bacteria selected from the group consisting of Salmonella spp., Ehrlichia spp., Mycobacteria spp., Spirochetes, Legionella spp Listeria spp., Rickettsia spp., Chlamydia spp., Mycoplasma spp., Coxiella spp., Yersinia spp., Francisella spp., Brucella spp., Neisseria spp, and Nocardia spp.; and
wherein the IAP antagonist is a monovalent IAP antagonist, a bivalent IAP antagonist, a nonpeptidomimetic IAP antagonist, or an IAP antagonist that reduces expression of an IAP gene.

### Claim 2 (depends on 1)

The method as claimed in claim 1 wherein the IAP antagonist is an antagonist for cIAP1 and/or cIAP2.

### Claim 3 (depends on 1)

The method as claimed in claim 1 wherein the IAP antagonist is a second mitochondria-derived activator of caspase (Smac) mimetic.

### Claim 4 (depends on 3)

The method as claimed in claim 3, wherein the Smac mimetic exhibits one or more of the following characteristics:
a. the Smac mimetic is bivalent;
b. the Smac mimetic derepresses X-linked inhibitor of apoptosis-mediated (XIAP-mediated) caspase-3 repression;
c. the Smac mimetic degrades cIAP-1 not bound to TNF receptor associated factor 2 (TRAF2) and cIAP1 bound to TRAF2;
d. the Smac mimetic degrades cIAP-2 bound to TRAF2 but does not degrade cIAP-2 not bound to TRAF2;
e. the Smac mimetic weakly degrades cIAP-2 not bound to TRAF2 relative to degradation of cIAP-2 bound to TRAF; and
f. the Smac mimetic has the general structure [P1-P2-P3-P4] or [P1-P2-P3-P4]-L-[P1′-P2′-P3′-P4′], wherein P1-P2-P3- and P1′-P2′-P3′- correspond to peptide replacements or peptidomimetics of the N-terminal Ala-Val-Pro- tripeptide of mature Smac and P4 and P4′ correspond to amino acid replacements of Phe, Tyr, Ile, or Val, and L is a linking group, or bond, covalently linking [P1-P2-P3-P4] to [P1′-P2′-P3′-P4′].

### Claim 5 (depends on 4)

The method as claimed in claim 4 wherein the Smac mimetic is birinapant.

### Claim 6 (depends on 1)

The method as claimed in claim 1 wherein the IAP antagonist reduces expression of the IAP gene.

### Claim 7 (depends on 6)

The method as claimed in claim 6 wherein the IAP gene is the cIAP1 or cIAP2 gene.

### Claim 8 (depends on 6)

The method as claimed in claim 6 wherein the IAP antagonist is small interfering RNA (siRNA), small hairpin RNA (shRNA) or microRNA (miRNA).

### Claim 9 (depends on 8)

The method as claimed in claim 8 wherein the siRNA, shRNA or miRNA is targeted against a gene encoding cIAP1, cIAP2, or XIAP.

### Claim 10 (depends on 1)

The method as claimed in claim 1 wherein the infection is caused by a virus selected from the group consisting of human immunodeficiency virus (HIV), hepatitis B virus (HBV) and human T-cell lymphotropic virus (HTLV).

### Claim 11 (depends on 1)

The method as claimed in claim 1 wherein the infection is caused by a bacteria selected from the group consisting of Mycobacteria spp., and Legionella spp.

### Claim 12 (depends on 10)

The method as claimed in claim 10 wherein the intracellular infection is a viral infection caused by HIV and the method further comprises administering TNF-α.

### Claim 13 (depends on 1)

The method of claim 1 further comprising administering a TNF receptor agonist.

### Claim 14 (depends on 1)

The method of claim 1 further comprising administering NF-related apoptosis-inducing ligand (TRAIL).

### Claim 15 (depends on 1)

The method of claim 1 further comprising administering an anti-viral nucleoside analogue.

### Claim 16 (depends on 15)

The method of claim 15 wherein the nucleoside analogue is Entacavir.

### Claim 17 (depends on 1)

The method of claim 1 further comprising administering TNF-α.

### Claim 18 (depends on 1)

The method of claim 1, wherein the IAP antagonist is a monovalent IAP antagonist.

### Claim 19 (depends on 10)

The method of claim 10, wherein the IAP antagonist is a monovalent IAP antagonist.

### Claim 20 (depends on 10)

The method of claim 10, wherein the infection is caused by HBV.

### Claim 21 (depends on 10)

The method of claim 10, wherein the infection is caused by HIV.

### Claim 22 (depends on 10)

The method of claim 10, wherein the infection is caused by HTLV.

### Claim 23 (depends on 11)

The method of claim 11, wherein the infection is caused by Mycobacteria tuberculosis (TB).

### Claim 24 (depends on 11)

The method of claim 11, wherein the infection is caused by Legionella pneumophila.