# US 11,299,528 B2 · Long acting TRAIL receptor agonists for treatment of autoimmune diseases

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- Number: US 11,299,528 B2
- Document ID: US11299528B2
- Status: Granted
- Kind: B2
- Application number: 14/645,276
- Filed: 2015-03-11
- Published: 2015-09-17
- Granted: 2022-04-12
- Earliest claimed: 2014-03-11
- Assignees: D&D Pharmatech Inc.
- Applicants: D&D Pharmatech Inc.
- Inventors: Kang Choon Lee; Ha Na Eom
- Web page: https://patentgrep.com/patent/US11299528B2

## CPC

- C07K 14/70575: {NGF/TNF-superfamily, e.g. CD70, CD95L, CD153, CD154 (NGF C07K14/48, TNF C07K14/525)}
- A61K 38/177: {Receptors; Cell surface antigens; Cell surface determinants}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61K 47/60: the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
- A61P 19/02: for joint disorders, e.g. arthritis, arthrosis
- A61P 29/00: Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
- C07K 2319/00: Fusion polypeptide
- C07K 2319/73: containing coiled-coiled motif (leucine zippers)
- 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)
- 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

Methods of treating an autoimmune disease such as rheumatoid arthritis, methods of increasing apoptosis of pro-inflammatory immune cells or synoviocytes, methods of increasing the quantity of the anti-inflammatory regulatory T cells, and methods of slowing the progression of inflammation in a subject include systemically administering to the subject a pharmaceutical composition including an effective amount of a TRAIL-conjugate. Preferably, the TRAIL-conjugate is effective for at least 3 days, more preferably at least 7 days, without being part of a nanocomplex that modulates the circulation half-life or release kinetics of the TRAIL-conjugate. Combination therapies including administering a second active agent, most preferably a TNF-α inhibitor, as well as pharmaceutical composition dosage units including a TRAIL-conjugate and a TNF-α inhibitor in an effective amount for a single once weekly dose for treatment of rheumatoid arthritis are also provided.

## Claims

### Claim 1

A method of treating rheumatoid arthritis comprising systemically administering a tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) conjugate to a subject with rheumatoid arthritis by injection twice a week, once a week, once every two weeks, or about once every 28 days, in an amount between 1 mg/kg and 100 mg/kg effective to increase apoptosis of pro-inflammatory immune cells and increase the quantity of anti-inflammatory Foxp3+regulatory T cells (Treg), wherein the TRAIL-conjugate comprises a
TRAIL polypeptide comprising amino acids 114-281 of SEQ ID NO:1 fused to a multimerization domain that allows trimerization, where the fusion polypeptide is conjugated to polyethylene glycol (PEG) or a derivative of PEG, wherein the PEG or the derivative thereof has a molecular weight between 5,000 and 60,000 Da.

### Claim 2 (depends on 1)

The method of claim 1 wherein administration of the TRAIL-conjugate reduces joint swelling, erythema, joint rigidity, and/or inflammatory cell infiltration into the joint(s).

### Claim 3 (depends on 1)

The method of claim 1 wherein the TRAIL-conjugate reduces expression or circulating levels of one or more inflammatory or pro-inflammatory molecules selected from the group consisting of ICAM-1, COX-2, iNOS, TNF-α, IL-1β, IFN-γ, IL-2, IL-6, IL-17, and combinations thereof, which are elevated in rheumatoid arthritis.

### Claim 4 (depends on 1)

The method of claim 1 wherein the TRAIL-conjugate increases the expression or circulating levels of anti-inflammatory cytokines TGF-β or IL-10, or combination thereof.

### Claim 5 (depends on 1)

The method of claim 1 wherein the PEG or the derivative thereof has a molecular weight at least 30,000 Da.

### Claim 6 (depends on 1)

The method of claim 1 wherein the subject does not have cancer.

### Claim 7 (depends on 1)

The method of claim 1 comprising administering to the subject an agent which reduces the expression or circulation of a pro-inflammatory molecule TNF-α.

### Claim 8 (depends on 7)

The method of claim 7 wherein the agent is selected from the group consisting of etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol.

### Claim 9 (depends on 1)

The method of claim 1 wherein the fusion polypeptide of the TRAIL-conjugate is linked to the polyethylene glycol molecule or the derivative thereof via a linker.

### Claim 10 (depends on 1)

The method of claim 1 wherein the multimerization domain comprises a zipper motif.

### Claim 11 (depends on 10)

The method of claim 10 wherein the zipper motif is an isoleucine zipper motif.

### Claim 12 (depends on 1)

The method of claim 1 wherein the polyethylene glycol derivative is selected from the group consisting of methoxypolyethylene glycol succinimidyl propionate, methoxypolyethylene glycol N-hydroxysuccinimide, methoxypolyethylene glycol aldehyde, methoxypolyethylene glycol maleimide, and multiple-branched polyethylene glycol.

### Claim 13 (depends on 1)

The method of claim 1 wherein the TRAIL-conjugate is administered in a dosage of between 5 and 50 mg/kg, or between 10 and 20 mg/kg.

### Claim 14 (depends on 1)

The method of claim 1 wherein the TRAIL-conjugate is administered in a dosage between 40 and 60 mg/m2 or about 45 mg/m2.