Human bikunin

• US 6,583,108 B1
• Filed: 08/31/1998
• Issued: 06/24/2003
• Est. Priority Date: 03/11/1996
• Status: Expired due to Fees

• Current Assignee: Bayer Corporation (Bayer AG)
• Original Assignee: Bayer Corporation (Bayer AG)
• Inventors: Tamburini, Paul P., Muller, Daniel K., Delaria, Katherine A., Marlor, Christopher W., Davis, Gary
• Primary Examiner(s): Low, Christopher S. F.
• Assistant Examiner(s): Bugaisky, Gabriele E
• Application Number:
  US09/144,428
• Time in Patent Office: 1,758 Days
• Field of Search: 530/350, 530/395, 530/324, 514/12, 514/8, 435/69.2, 536/23.5
• US Class Current: 514/13.7
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07K 14/8114 Kunitz type inhibitors
• CPC Class Codes: C07K 14/8117 Bovine/basic pancreatic trypsin inhibitor (BPTI, aprotinin)

Abstract

The instant invention provides for proteins, polypeptides, nucleic acid sequences, constructs, expression vectors, host cells, pharmaceutical compositions of, and methods for using human placental bikunin, serine protease inhibitor domains, and fragments thereof.

Claims

1. A substantially purified protein, having serine protease inhibitory activity, selected from the group of proteins consisting of materials each of which comprises one of the following amino acid sequences, the amino acids of said sequences being numbered in accordance with the amino acid sequence of native human placental bikunin shown in FIG. 4F in which the N-terminal residue generated by removal of signal peptide is designated as residue 1:

4. A protein as in claims 1, 2 or 3 wherein said protein is glycosylated, or contains at least one intra-chain cysteine-cysteine disulfide bond, or is both glycosylated and contains at least one intra-chain cysteine-cysteine disulfide bond.

5. A pharmaceutical composition for inhibiting serine protease activity, comprising a protein of claims 1, 2, 4, or 3 plus a pharmaceutically acceptable carrier.

6. A method for inhibiting serine protease activity comprising contacting serine protease with an effective amount of at least one protein of claims 1, 2, 4, or 3.

7. A method for treating a condition of brain edema, spinal cord edema, multiple sclerosis, ischemia, postoperative blood loss, sepsis, septic shock, fibrosis, disease associated with pathologic blood coagulation or clotting, polytrauma, stroke, cerebral or subarachnoid hemorrhage, inflammation of the brain, inflammation of the spinal cord, cerebral infection, cerebral granulomatosis, spinal infection, spinal granulomatosis, open heart surgery, gastric cancer, cervical cancer, or prevention of metastasis comprising administering to a subject having such a condition an effective amount of the protein of claims 1, 2, 4 or 3.

8. The method of claim 7 wherein said condition is brain edema, spinal cord edema, multiple sclerosis, ischemia, perioperative blood loss, sepsis, septic shock, fibrosis, disease associated with pathologic blood coagulation or clotting, stroke, cerebral or subarachnoid hemorrhage, inflammation of the brain, inflammation of the spinal cord, cerebral infection, cerebral granulomatosis, spinal infection, spinal granulomatosis, or open heart surgery.

9. The method of claim 7 wherein said condition is gastric cancer, cervical cancer, or prevention of metastasis.

2. A substantially purified serine protease inhibitor protein containing at least one Kunitz-like domain comprising an amino acid sequence:

ADRERSIHDF CLVSKVVGRC RASMPRWWYN VTDGSCQLFV YGGCDGNSNN 50

YLTKEECLKK CATVTENATG DLATSRNAAD SSVPSAPRRQ DS 92

(SEQ ID NO.;

     8) with the proviso that the protein does not have the amino acid sequence of SEQ ID NOS.;

49 and b 71.

3. A substantially purified protein, having serine protease inhibitory activity, selected from the group of proteins consisting of materials each of which consists one of the following amino acid sequences, the amino acids of said sequences being numbered in accordance with the amino acid sequence of native human placental bikunin shown in FIG. 4F in which the N-terminal residue generated by removal of the signal peptide is designated as residue 1: