Human TRK receptors and neurotrophic factor inhibitors

• US 5,844,092 A
• Filed: 12/20/1994
• Issued: 12/01/1998
• Est. Priority Date: 03/18/1994
• Status: Expired due to Term

• Current Assignee: Genentech, Inc. (Roche Holding AG)
• Original Assignee: Genentech, Inc. (Roche Holding AG)
• Inventors: Urfer, Roman, Presta, Leonard G., Shelton, David L.
• Primary Examiner(s): Huff, Sheela
• Assistant Examiner(s): BURKE, JULIE ELAINE
• Application Number:
  US08/359,705
• Time in Patent Office: 1,442 Days
• Field of Search: 530/387.3, 530/350, 536/23.1, 435/69.1, 435/240.1, 435/320.1, 435/172.3, 514/12, 424/133.1
• US Class Current: 530/387.3
• 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 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• 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 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 9/00 Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/08 Vasodilators for multiple indications
• 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 14/71 for growth factors; for growth regulators
• CPC Class Codes: C07K 19/00 Hybrid peptides , i.e. peptides covalently bound to nucleic acids, or non-covalently bound protein-protein complexes
• CPC Class Codes: C07K 2319/00 : Fusion polypeptide
• CPC Class Codes: C07K 2319/30 : Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Abstract

The invention concerns human trkB and trkC receptors and their functional derivatives. The invention further concerns immunoadhesins comprising trk receptor sequences fused to immunoglobulin sequences.

Claims

1. A chimeric polypeptide comprising an immunoglobulin constant domain sequence fused to a neurotrophin-binding polypeptide sequence comprising a second immunoglobulin-like domain sequence of human trkA, human trkB, or human trkC, wherein the chimeric polypeptide binds a neurotrophin that binds human trkA, human trkB, or human trkC.

2. The chimeric polypeptide of claim 1, wherein the second immunoglobulin-like domain sequence is that in human trkA.

3. The chimeric polypeptide of claim 1, wherein the second immunoglobulin-like domain sequence is that in SEQ ID NO:

2 or in SEQ ID NO;

6.

4. The chimeric polypeptide of claim 1, wherein the neurotrophin-binding polypeptide sequence comprises an extracellular domain of human trkA, human trkB, or human trkC.

5. The chimeric polypeptide of claim 4, wherein the extracellulardomain has amino acids 36 to 402, inclusive, of human trkA SEQ ID NO:

9.

6. The chimeric polypeptide of claim 4, wherein the extracellulardomain has amino acids 32 to 430 of the amino acid sequence SEQ ID NO:

2 or amino acids 32 to 429 of the amino acid sequence SEQ ID NO;

6 with a deletion of amino acids ESTDNFILF (SEQ ID NO;

     36) at amino acid positions 402 to 410.

7. The chimeric polypeptide of claim 6, wherein the extracellulardomain has amino acids 32 to 429, inclusive, of the amino acid sequence SEQ ID NO:

6.

8. The chimeric polypeptide of claim 4, wherein the neurotrophin-binding polypeptide sequence comprises amino acids 36 to 790 of human trkA SEQ ID NO:

9 with amino acid residues 410 to 433 deleted.

9. The chimeric polypeptide of claim 4, wherein the neurotrophin-binding polypeptide sequence comprises amino acids 32 to 822 of the amino acid sequence SEQ. ID. NO:

2, with amino acid residues 430 to 454, deleted.

10. The chimeric polypeptide of claim 9, wherein amino acid residues corresponding to 457 to 822, inclusive, of the amino acid sequence SEQ ID NO:

2 are replaced by the amino acid sequence FVLFHKIPLDG (SEQ ID NO;

     40).

11. The chimeric polypeptide of claim 4, wherein the neurotrophin-binding polypeptide sequence comprises amino acids 32 to 839 of the amino acid sequence SEQ. ID. NO:

6, with amino acid residues 430 to 453 deleted.

12. The chimeric polypeptide of claim 11, wherein amino acid residues corresponding to 529 to 839, inclusive, of the amino acid sequence SEQ ID NO:

6 are replaced by the amino acid sequence encoded by SEQ IDNO;

41.

13. The chimeric polypeptide of claim 1, wherein the immunoglobulin constant domain sequence is an immunoglobulin Fc domain sequence.

14. The chimeric polypeptide of claim 13, wherein the Fc domain sequence is that of an human IgG heavy chain.

15. The chimeric polypeptide of claim 4, wherein the second immunoglobulin-like domain of trkA is substituted for the second-immunoglobulin-like domain within the extracellular domain of trkB or trkC.

16. A composition comprising the polypeptide of claim 1 in admixture with a physiologically acceptable carrier.

17. The composition of claim 16 that is sterile.

18. A method of treating a patient suffering from hyperalgesia related to production of endogenous of nerve growth factor, comprising administering to the patient in need of such treatment a therapeutically effective amount of the polypeptide of claim 2 that binds nerve growth factor to inhibit binding of nerve growth factor to its receptor trkA to reduce hyperalgesia.

19. A method of promoting hypoalgesia in a patient, comprising administering to a patient in need of such treatment a therapeutically effective amount of the polypeptide of claim 2 that binds nerve growth factor to inhibit binding of nerve growth factor to its receptor trkA to promote hypoalgesia.