# US 10,765,747 B2 · Methods of reducing aggregation of IL-1ra

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- Number: US 10,765,747 B2
- Document ID: US10765747B2
- Status: Granted
- Kind: B2
- Application number: 11/097,993
- Filed: 2005-04-01
- Published: 2005-12-08
- Granted: 2020-09-08
- Earliest claimed: 2004-04-02
- Assignees: Swedish Orphan Biovitrum AB (publ)
- Applicants: Andrei Raibekas; Bruce Kerwin
- Inventors: Andrei Raibekas; Bruce Kerwin
- Web page: https://patentgrep.com/patent/US10765747B2

## CPC

- A61K 47/02: Inorganic compounds
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 31/7012: Compounds having a free or esterified carboxyl group attached, directly or through a carbon chain, to a carbon atom of the saccharide radical, e.g. glucuronic acid, neuraminic acid (gluconic acid A61K31/191; ascorbic acid A61K31/375)
- A61K 33/42: Phosphorus; Compounds thereof
- A61K 38/20: Interleukins [IL]
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61K 47/26: Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
- A61P 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 13/12: of the kidneys
- 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]
- A61P 35/02: specific for leukemia
- C07K 14/54: Interleukins [IL]
- C07K 14/545: IL-1
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

Methods of reducing aggregation of an aggregating IL-1ra comprising incubating IL-1ra with at least one accessory molecule are provided. Kits comprising IL-1ra and at least one accessory molecule are also provided. Pharmaceutical compositions comprising IL-1ra and at least one accessory molecule are also provided.

## Claims

### Claim 1

A method of reducing aggregation of an aggregating interleukin-1 receptor antagonist (IL-1ra) in an aqueous composition comprising
incubating the aqueous composition comprising the IL-1ra with at least one accessory molecule at a concentration sufficient to reduce aggregation of the IL-1ra for at least two hours at 25 to 45° C., and
determining reduced aggregation of the IL-1ra in the aqueous composition by measuring the optical density at 405 nm of the aqueous composition after at least two hours of incubation at 30 to 45° C., wherein the optical density of the aqueous composition comprising the IL-1ra is less than 60% of the optical density of an aqueous composition comprising the IL-1ra without incubating with the accessory molecule, and
wherein the at least one accessory molecule is selected from the group consisting of (1) a sugar at a concentration of from 1 to 2 percent, wherein the sugar is sucrose, glycerol, or sorbitol, (2) a multiple-charge anion, wherein the multiple-charge anion is 1 to 20 mM pyrophosphate or 1 to 20 mM citrate, and (3) a lysine-reactive accessory molecule or an arginine-reactive accessory molecule, selected from the group consisting of the three compounds from 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoic acid (NBD-X), methyl acetyl phosphate (MAP), and citraconic anhydride.

### Claim 2 (depends on 1)

The method of claim 1, wherein the at least one accessory molecule is a sugar, wherein the sugar is sucrose, glycerol, or sorbitol.

### Claim 3 (depends on 1)

The method of claim 1, wherein the at least one accessory molecule is a multiple-charge anion, wherein the multiple-charge anion is 1 to 20 mM pyrophosphate or 1 to 20 mM citrate.

### Claim 4 (depends on 3)

The method of claim 3, wherein said multiple-charge anion is 1 to 20 mM pyrophosphate.

### Claim 5 (depends on 3)

The method of claim 3, wherein said multiple-charge anion is 1 to 20 mM citrate.

### Claim 6 (depends on 1)

The method of claim 1, wherein the at least one accessory molecule is selected from a lysine-reactive accessory molecule and an arginine-reactive accessory molecule, wherein the lysine-reactive accessory molecule and the arginine-reactive accessory molecule are selected from the group consisting of the three compounds from 6-(N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino)hexanoic acid (NBD-X), methyl acetyl phosphate (MAP), and citraconic anhydride, thereby forming an IL-1ra derivatized with NBD-X, MAP, or citraconic anhydride.

### Claim 7 (depends on 1)

The method of claim 1, wherein the step of determining reduced aggregation of the IL-1ra in the aqueous composition comprises measuring the optical density at 405 nm of the aqueous composition after at least two hours of incubation at 35 to 45° C.