Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
  • C07K14/70578—NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2319/00—Fusion polypeptide
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07K—PEPTIDES
  • C07K2319/00—Fusion polypeptide
  • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
  • C07K2319/02—Fusion polypeptide containing a localisation/targetting motif containing a signal sequence

Definitions

• TRAIL TRAIL
• Certain uses of TRAIL-R flow from this ability to bind TRALL, as discussed further below.
• TRAIL-R finds use in inhibiting biological activities of TRAIL, or in purifying TRAIL by affinity chromatography, for example.
• TRAIL-R protein or immunogenic fragments thereof may be employed as immunogens to generate antibodies that are immunoreactive therewith.
• the antibodies are monoclonal antibodies.
• the present invention encompasses TRAIL-R in various forms, including those that are naturally occurring or produced through various techniques such as procedures involving recombinant DNA technology.
• forms of TRAIL-R include, but are not limited to, fragments, derivatives, variants, and oligomers of TRAIL-R, as well as fusion proteins containing TRAIL-R or fragments thereof.
• a protein preparation may include a mixture of protein molecules having different N-terminal amino acids, resulting from cleavage of the signal peptide at more than one site.
• the TRAIL-R-encoding DNAs of the present invention include variants that differ from a native TRAIL-R DNA sequence because of one or more deletions, insertions or substitutions, but that encode a biologically active TRAIL-R polypeptide.
• One biological activity of TRAIL-R is the ability to bind TRAIL.
• a variant TRAIL-R polypeptide differs in amino acid sequence from a native TRAIL-R, but is substantially equivalent to a native TRAIL-R in a biological activity.
• a variant TRAIL-R that binds TRAIL with essentially the same binding affinity as does a native TRAIL-R. Binding affinity can be measured by conventional procedures, e.g., as described in U.S. Patent no. 5,512,457.
• a promoter nucleotide sequence is operably linked to an TRAIL-R DNA sequence if the promoter nucleotide sequence controls the transcription of the TRAIL-R DNA sequence.
• An origin of replication that confers the ability to replicate in the desired host cells, and a selection gene by which transformants are identified, are generally incorporated into the expression vector.
• glycolytic enzymes Hess et al., J. Adv. Enzyme Reg. 7: 149, 1968; and Holland et al., Biochem. 17:4900, 1978
• enolase glyceraldehyde-3-phosphate dehydrogenase
• hexokinase hexokinase
• pyruvate decarboxylase phosphofructokinase
• glucose-6-phosphate isomerase 3 -phosphogly cerate mutase
• pyruvate kinase triosephosphate isomerase
• phospho-glucose isomerase phospho-glucose isomerase
• glucokinase glucokinase
• the culture medium first may be concentrated using a commercially available protein concentration filter, for example, an Amicon or Millipore Pellicon ultrafiltration unit.
• a purification matrix such as a gel filtration matrix.
• an anion exchange resin can be employed, for example, a matrix or substrate having pendant diethylaminoethyl (DEAE) groups.
• the matrices can be acrylamide, agarose, dextran, cellulose or other support materials commonly employed in protein purification.
• a cation exchange step can be employed.
• Recombinant protein produced in bacterial culture can be isolated by initial disruption of the host cells, centrifugation, extraction from cell pellets if an insoluble polypeptide, or from the supernatant fluid if a soluble polypeptide, followed by one or more concentration, salting-out, ion exchange, affinity purification or size exclusion chromatography steps. Finally, RP-HPLC can be employed for final purification steps. Microbial cells can be disrupted by any convenient method, including freeze-thaw cycling, sonication, mechanical disruption, or use of cell lysing agents.
• TRAIL-R oligomers that contain TRAIL-R polypeptides.
• TRAIL-R oligomers may be in the form of covalently-linked or non- covalently-linked dimers, trimers, or higher oligomers.
• the oligomers comprise from two to four TRAIL-R polypeptides.
• the TRAIL-R moieties of the oligomer may be soluble polypeptides, as described above.
• TRAIL-R finds use as a protein purification reagent.
• TRAIL-R polypeptides may be attached to a solid support material and used to purify TRAIL proteins by affinity chromatography.
• a TRAIL-R polypeptide (in any form described herein that is capable of binding TRALL) is attached to a solid support by conventional procedures.
• chromatography columns containing functional groups that will react with functional groups on amino acid side chains of proteins are available (Pharmacia Biotech, Inc., Piscataway, NJ).
• a TRAIL-R/Fc protein is attached to Protein A- or Protein G-containing chromatography columns through interaction with the Fc moiety.
• Another embodiment of the present invention is directed to the use of TRAIL-R to reduce TRAIL-mediated death of T cells in HIV-infected patients.
• the role of T cell apoptosis in the development of AIDS has been the subject of a number of studies (see, for example, Meyaard et al., Science 257:217-219, 1992; Groux et al., J Exp. Med., 175:331, 1992; and Oyaizu et al., in Cell Activation and Apoptosis in HIV Infection, Andrieu and Lu, Eds., Plenum Press, New York, 1995, pp. 101-114).
• TRAIL-R can be combined in admixture, either as the sole active material or with other known active materials suitable for a given indication, with pharmaceutically acceptable diluents (e.g., saline, Tris-HCl, acetate, and phosphate buffered solutions), preservatives (e.g., thimerosal, benzyl alcohol, parabens), emulsifiers, solubilizers, adjuvants and/or carriers.
• Suitable formulations for pharmaceutical compositions include those described in Remington's Pharmaceutical Sciences, 16th ed. 1980, Mack Publishing Company, East on, PA.
• compositions of the present invention may contain a TRAIL-R polypeptide in any form described herein, such as native proteins, variants, derivatives, oligomers, and biologically active fragments.
• the composition comprises a soluble TRAIL-R polypeptide or an oligomer comprising soluble TRAIL-R polypeptides.
• TRAIL-R nucleotide sequences comprise at least about 30, or at least 60, contiguous nucleotides of a TRALL-R DNA sequence.
• Nucleic acids provided herein include DNA and RNA complements of said fragments, along with both single-stranded and double- stranded forms of the TRALL-R DNA.
• Other useful fragments of the TRALL-R nucleic acids include antisense or sense oligonucleotides comprising a single-stranded nucleic acid sequence (either RNA or DNA) capable of binding to target TRALL-R mRNA (sense) or TRALL-R DNA (antisense) sequences.

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• Health & Medical Sciences (AREA)
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• Organic Chemistry (AREA)
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• General Chemical & Material Sciences (AREA)
• Public Health (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Veterinary Medicine (AREA)
• Pharmacology & Pharmacy (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Animal Behavior & Ethology (AREA)
• Engineering & Computer Science (AREA)
• Toxicology (AREA)
• Biochemistry (AREA)
• Cell Biology (AREA)
• Immunology (AREA)
• Hematology (AREA)
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• Gastroenterology & Hepatology (AREA)
• Diabetes (AREA)
• Biophysics (AREA)
• Genetics & Genomics (AREA)
• Molecular Biology (AREA)
• Proteomics, Peptides & Aminoacids (AREA)
• Peptides Or Proteins (AREA)
• Preparation Of Compounds By Using Micro-Organisms (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

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Cited By (16)

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• 1998
  • 1998-07-10 AU AU83957/98A patent/AU8395798A/en not_active Abandoned
  • 1998-07-10 CA CA002295719A patent/CA2295719A1/en not_active Abandoned
  • 1998-07-10 IL IL13392098A patent/IL133920A0/xx unknown
  • 1998-07-10 JP JP2000503198A patent/JP2001510042A/ja active Pending
  • 1998-07-10 WO PCT/US1998/014410 patent/WO1999003992A1/en not_active Application Discontinuation
  • 1998-07-10 EP EP98934441A patent/EP0998561A4/en not_active Withdrawn
  • 1998-07-10 NZ NZ501951A patent/NZ501951A/en unknown

Non-Patent Citations (4)

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