Use of GLP for the treatment, prevention, diagnosis, and prognosis of bone-related and nutrition-related disorders

• US 20020037836A1
• Filed: 09/18/2001
• Published: 03/28/2002
• Est. Priority Date: 09/18/2000
• Status: Active Grant

• Current Assignee: Sanos Bioscience A/S (C.C. Consulting A/S)
• Original Assignee: Sanos Bioscience A/S (C.C. Consulting A/S)
• Inventors: Henriksen, Dennis Bang
• Granted Patent: US 6,770,620 B2
• Time in Patent Office: Days
• US Class Current: 514/2
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/26 Glucagons
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 38/30 Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2 insulin-like growth factor binding protein A61K38/1754
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• 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 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 5/14 of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/18 : of the parathyroid hormones
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/12 : Antihypertensives

Abstract

The present invention relates to methods for prevention and treatment of bone-related or nutrition-related disorders using a GLP molecule or GLP activator either alone or in combination with another therapeutic. The present invention also encompasses methods of diagnosing or monitoring the progression of a disorder. The invention also encompasses methods of monitoring the effectiveness of treatment of the invention.

Claims

1. A pharmaceutical composition comprising an effective amount of:

(a) a GLP-2 molecule or GLP-2 activator; and

(b) another therapeutic agent.

2. The pharmaceutical composition of claim 1, wherein said other therapeutic agent is an anti-osteoporosis agent.

3. The pharmaceutical composition of claim 2, wherein the anti-osteoporosis agent is alendronate sodium, clodronate, etidronate, gallium nitrate, mithramycin, norethindrone acetate, pamidronate, or risedronate sodium.

4. The pharmaceutical composition of claim 1, wherein said other therapeutic agent is an insulin-releasing agent.

5. The pharmaceutical composition of claim 1, wherein said other therapeutic agent is a glucagon-inhibiting agent.

6. The pharmaceutical composition of claim 1, wherein said other therapeutic agent is an epinephrine-inhibiting agent.

7. The pharmaceutical composition of claim 1, wherein said other therapeutic agent is a circadian-rhythm-modulating agent.

8. The pharmaceutical composition of claim 1, wherein said other therapeutic agent is a steroid hormone.

9. The pharmaceutical composition of claim 8, wherein said steroid hormone is an estrogen, androgen, progestin, or glucocorticoid.

10. The pharmaceutical composition of claim 1, wherein said other therapeutic agent is a non-steroid hormone.

11. The pharmaceutical composition of claim 10, wherein said non-steroid hormone is parathyroid hormone, calcitonin, calcitriol, melatonin, thyroid hormone, growth hormone, or an osteoclast-activating factor.

12. The pharmaceutical composition of claim 1, wherein said other therapeutic agent is an immunotherapeutic agent.

13. The pharmaceutical composition of claim 12, wherein said immunotherapeutic agent is an antibody or an immunomodulator.

14. The pharmaceutical composition of claim 1, wherein said other therapeutic agent is a cytokine.

15. The pharmaceutical composition of claim 14, wherein said cytokine is an interferon, growth factor, lymphokine, tumor necrosis factor, tumor necrosis-factor-like cytokine, lymphotoxin-α

, lymphotoxin-β

, macrophage inflammatory protein, granulocyte monocyte colony stimulating factor, interleukin, an OX40 ligand, a CD27 ligand, a CD30 ligand, CD40 ligand, a CD137 ligand, a Fas ligand, 4-1BBL, or endothelial monocyte activating protein.

16. The pharmaceutical composition of claim 14, wherein said cytokine is interleukin-1, tumor necrosis factor-β

, or type 1 insulin-like growth factor.

17. The pharmaceutical composition of claim 1, wherein said other therapeutic agent is an anti-obesity agent.

18. The pharmaceutical composition of claim 17, wherein said anti-obesity agent is benzphetamine, benzylisopropylamine, bupropion, dexfenfluramine, dextroamphetamine, diethylpropion, dimethylphenethylamine, evodamine, fenfluramine, fluoxetine, mazindol, methamphetamine, naltrexone, orlistat, phendimetrazine, phentermine, or sibutramine.

20. The method of claim 19 further comprising administering an effective amount of another therapeutic agent.

21. The method of claim 19 or 20, wherein said bone-related disorder is osteoporosis, hypercalcemia of malignancy, osteopenia due to bone metastases, periodontal disease, hyperparathyroidism, periarticular erosions in rheumatoid arthritis, Paget'"'"'s disease, osteodystrophy, myositis ossificans, Bechterew'"'"'s disease, malignant hypercalcemia, osteolytic lesions produced by bone metastasis, bone loss due to immobilization, bone loss due to sex steroid hormone deficiency, bone abnormalities due to steroid hormone treatment, bone abnormalities caused by cancer therapeutics, osteomalacia, Bechet'"'"'s disease, osteomalacia, hyperostosis, osteopetrosis, metastatic bone disease, immobilization-induced osteopenia, or glucocorticoid-induced osteoporosis.

22. The method of claim 20, wherein said other therapeutic agent is an anti-osteoporosis agent.

23. The method of claim 22, wherein the anti-osteoporosis agent is alendronate sodium, clodronate, etidronate, gallium nitrate, mithramycin, norethindrone acetate, pamidronate, or risedronate sodium.

24. The method of claim 20, wherein said other therapeutic agent is an insulin-releasing agent.

25. The method of claim 20, wherein said other therapeutic agent is a glucagon-inhibiting agent.

26. The method of claim 20, wherein said other therapeutic agent is a epinephrine-inhibiting agent.

27. The method of claim 20, wherein said other therapeutic agent is a circadian-rhythm-modulating agent.

28. The method of claim 20, wherein said other therapeutic agent is a steroid hormone.

29. The method of claim 28, wherein said steroid hormone is an estrogen, androgen, progestin, or glucocorticoid.

30. The method of claim 20, wherein said other therapeutic agent is a non-steroid hormone.

31. The method of claim 30, wherein said non-steroid hormone is calcitonin, calcitriol, growth hormone, melatonin, parathyroid hormone, prostaglandin, or thyroid hormone.

32. The method of claim 20, wherein said other therapeutic agent is an immunotherapeutic agent.

33. The method of claim 32, wherein said immunotherapeutic agent is an antibody or an immunomodulator.

34. The method of claim 20, wherein said other therapeutic agent is a cytokine.

35. The method of claim 34, wherein said cytokine is an endothelial monocyte activating protein, granulocyte colony stimulating factor, interferon, interleukin, lymphokine, lymphotoxin-α

, lymphotoxin-β

, tumor necrosis factor, tumor necrosis-factor-like cytokine, macrophage inflammatory protein, monocyte colony stimulating factor, 4-1BBL, CD27 ligand, CD30 ligand, CD40 ligand, CD137 ligand, Fas ligand, or OX40 ligand.

36. The method of claim 35, wherein said cytokine is interleukin-1, tumor necrosis factorβ

, or type 1 insulin-like growth factor.

37. The method of claim 20, wherein said other therapeutic agent is a nutrient.

38. The method of claim 37, wherein said nutrient is a sugar, dietary fatty acid, triglyceride, protein, vitamin or mineral.

40. The method of claim 39 further comprising administering an effective amount of another therapeutic agent.

41. The method of claim 39 or 40, wherein said nutrition-related disorder is obesity, anorexia, bulimia, cachexia, insulin resistance, diabetes mellitus, hypertension, cardiovascular disease, pseudotumor, cerebri, hyperlipidemia, sleep apnea, cancer, pulmonary hypertension, cardiovascular disease, cholecystitis, and osteoarthritis.

42. The method of claim 40, wherein said other therapeutic agent is an anti-obesity agent.

43. The method of claim 42, wherein said anti-obesity agent is benzphetamine, benzylisopropylamine, bupropion, dexfenfluramine, dextroamphetamine, diethylpropion, dimethylphenethylamine, evodamine, fenfluramine, fluoxetine, mazindol, methamphetamine, naltrexone, orlistat, phendimetrazine, phentermine, or sibutramine.

44. The method of claim 19, 20, 39 or 40 wherein the administering is performed via oral, intravenous infusion, subcutaneous injection, intramuscular injection, topical, depo injection, implantation, time-release mode, controlled-release mode, intracavitary, intranasal, inhalation, intratumor, intraocular intraperitoneal, intraorbital, intracapsular, intraspinal, intrasternal, intra-arterial, intradermal parenteral, transmucosal, nasal, rectal, intravaginal, sublingual, submucosal, transdernal, or transdermal patch route.

45. The method of claim 20 or 40, wherein said other therapeutic agent is administered before administering the GLP-2 molecule or GLP-2 activator.

46. The method of claim 20 or 40, wherein said other therapeutic agent is administered after administering the GLP-2 molecule or GLP-2 activator.

47. The method of claim 20 or 40, wherein said other therapeutic agent is administered concurrently with the GLP-2 molecule or GLP-2 activator.

52. The composition of claim 1, further comprising a pharmaceutically acceptable carrier.

19. A method for treating or preventing a bone-related disorder, comprising administering to a patient in need thereof an effective amount of a GLP-2 molecule or GLP-2 activator.

39. A method for treating or preventing a nutrition-related disorder, comprising administering to a patient in need thereof, an effective amount of a GLP-2 molecule or GLP-2 activator.

48. A method for diagnosing a bone-related disorder in a patient comprising:

(a) determining the level of GLP-2 molecule expressed in a normal tissue and a test tissue;

(b) comparing said levels of GLP-2 molecule expression in said tissues, wherein a decrease said level of GLP-2 molecule expression in said test tissue indicates a bone-related disorder.

49. A method of monitoring the progression of a bone-related disorder in a patient comprising:

(a) determining the level of GLP-2 molecule expressed in a first diseased tissue;

(b) determining the level of GLP-2 molecule expressed in a second diseased tissue, wherein said second diseased tissue is taken from the same patient as said first diseased tissue but at a later date; and

(c) comparing said levels of GLP-2 molecule expression in said first and second diseased tissues, wherein a decrease said level of GLP-2 molecule expression in said second diseased tissue indicates progression of said bone-related disorder.

50. A method for treating or preventing a bone-related disorder, comprising administering to a patient in need thereof an effective amount of a mammalian expression vector comprising a nucleic acid encoding GLP-2.

51. A method for treating or preventing a nutrition-related disorder, comprising administering to a patient in need thereof an effective amount of a mammalian expression vector comprising a nucleic acid encoding GLP-2.

53. A method of determining the effectiveness of treatment with a GLP molecule or GLP activator in a patient comprising:

(a) determining the level of one or more markers of bone resorption from a first patient tissue samples prior to said treatment and a second patient tissue sample after said treatment;

(b) comparing said levels of one or more markers in said tissue samples, wherein a decrease in said level in said second tissue sample indicates effective treatment.

54. The method of claim 53, wherein said marker is S-CTX.

55. The method of claim 54, wherein the level of S-CTX is decreased.

57. The pharmaceutical composition of claim 56, further comprising another therapeutic agent.

56. A pharmaceutical composition comprising an effective amount of GLP-2 nucleic acid or variant thereof.