# US 2008/0187509 A1 · Pharmaceutical compositions for the treatment of TNF-alpha related disorders

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- Number: US 2008/0187509 A1
- Document ID: US20080187509A1
- Status: Published application
- Kind: A1
- Application number: 11/472,864
- Filed: 2006-06-22
- Published: 2008-08-07
- Earliest claimed: 2000-03-02
- Assignees: Xencor, Inc.
- Inventors: John R. Desjarlais; Paul Michael Steed; Jonathan Zalevsky; David Edmund Szymkowski; David F. Carmichael
- Web page: https://patentgrep.com/patent/US20080187509A1

## CPC

- A61K 38/191: {Tumor necrosis factors [TNF], e.g. lymphotoxin [LT], i.e. TNF-beta}
- C07K 14/525: Tumour necrosis factor [TNF]
- 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)
- 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

The invention relates to a pharmaceutical composition comprising a variant TNF-α protein that inhibits the activity of soluble TNF-α while substantially maintaining the activity of transmembrane TNF-α, a buffer, and a tonicity agent, wherein said composition has a pH from approximately 5.0 to 8.0.

## Claims

### Claim 1

A pharmaceutical composition comprising: a variant TNF-α protein that inhibits the activity of soluble TNF-α while substantially maintaining the activity of transmembrane TNF-α comprising an amino acid sequence corresponding to wild type amino acids 1-157 of Tumor Necrosis FactorAlpha (TNFα) (SEQ ID NO: 1) that has at least one amino acid substitution in the Large Domain and at least one amino acid substitution in a domain selected from the group consisting of the DE Loop and the Small Domain, wherein the Large Domain substitution is at a position selected from the group consisting of 21, 30, 31, 32, 33, 35, 65, 66, 67,111, 112, 115, 140, 143, 144, 145 and 146, wherein the Small Domain substitution at a position selected from the group consisting of 75 and 97, wherein the DE Loon substitution at a position selected from the group consisting of 84, 86, 87 and 91; a buffer; and, a tonicity agent; wherein said composition has a pH from approximately 5.0 to 8.0.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, further comprising a surfactant.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein the variant TNF-α in the pharmaceutical composition exhibits reduced degradation over time as compared to the TNF-α without said buffer or tonicity agent.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, wherein the variant TNF-α in the pharmaceutical composition exhibits reduced aggregation over time as compared to the TNF-α without said buffer or tonicity agent.

### Claim 5 (depends on 1)

The pharmaceutical composition of claim 1, wherein the concentration 10 mM histidine; and, 150 mM NaCl; wherein said composition is approximately at pH 6.5.

### Claim 6 (depends on 2)

The pharmaceutical composition of claim 2, wherein said surfactant is 0.01% (w/v) polysorbate 20.