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1. (EP2447372) Anti alpha v beta 6 antibodies and uses thereof
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Claims

1. A humanized antibody that specifically binds to αvβ6 comprising a heavy chain variable domain sequence of SEQ ID NO: 3 and a light chain variable domain of SEQ ID NO: 4.
  2. A humanized antibody that specifically binds αvβ6, wherein said humanized antibody comprises a heavy chain variable domain sequence selected from the group consisting of SEQ ID NO:78, SEQ ID NO:79, or SEQ ID NO:80 and a light chain variable domain sequence selected from the group consisting of SEQ ID NO: 75, SEQ ID NO:76, and SEQ ID NO:77.
  3. A humanized antibody that specifically binds αvβ6, wherein said humanized antibody comprises a heavy chain variable domain sequence of SEQ ID NO:78, 79 or 80 and a light chain variable domain sequence of SEQ ID NO:75.
  4. The humanized antibody of claim 3, wherein said antibody comprises a heavy chain variable domain sequence of SEQ ID NO:78 and a light chain variable domain sequence of SEQ ID NO:75.
  5. A humanized antibody that specifically binds αvβ6, wherein said humanized antibody comprises a heavy chain variable domain sequence of SEQ ID NO:79 and a light chain variable domain of SEQ ID NO:75, 76 or 77.
  6. An isolated nucleic acid molecule comprising a coding sequence for any one of SEQ ID NOs: 3, 4, 75, 76, 77, 78, 79, and 80.
  7. An isolated polypeptide comprising an amino acid sequence of any one of SEQ ID NOs: 3, 4, 75, 76, 77, 78, 79, and 80.
  8. A recombinant vector comprising the nucleic acid molecule of claim 7.
  9. A host cell comprising the recombinant vector of claim 8.
  10. A composition comprising the antibody of any one of claims 1 to 5, and a pharmaceutically acceptable carrier.
  11. The composition of claim 10, wherein the antibody is conjugated to a cytotoxic agent.
  12. A method of preparing a humanized antibody comprising culturing the host cell of claim 9 under conditions appropriate for expression of a humanized antibody, wherein humanized antibody chains are expressed and a humanized antibody is produced.
  13. The method of claim 12, further comprising isolating the humanized antibody.
  14. The method of claim 12, wherein the host cell is a CHO cell.
  15. Use of the antibody of any of claims 1 to 5 for treating a subject having or at risk of having a disease mediated by αvβ6, wherein said disease is selected from the group consisting of fibrosis, psoriasis, cancer or Alport's syndrome thereby alleviating or postponing the onset of the disease.
  16. The use of claim 15, wherein the subject to be treated is human.
  17. The use of claim 15, wherein the fibrosis is scleroderma, scarring, liver fibrosis, kidney fibrosis, lung fibrosis, gut fibrosis, scleroderma, radiation-induced fibrosis, head and neck fibrosis, corneal scarring, LASIX, corneal transplant, trabeculectomy, hypertrophic scarring, burn induced fibrosis, surgical fibrosis, sarcoidosis, psoriasis or spinal cord injury fibrosis.
  18. The use of claim 17 wherein said lung fibrosis is selected from the group consisting of idiopathic pulmonary fibrosis, radiation induced fibrosis, chronic obstructive pulmonary disease (COPD), scleroderma, bleomycin induced fibrosis, chronic asthma, silicosis, asbestos induced fibrosis, acute lung injury and acute respiratory distress.
  19. The use of 18 wherein said acute respiratory distress is selected from the group consisting of bacterial pneumonia induced acute respiratory distress, trauma induced acute respiratory distress, viral pneumonia induced acute respiratory distress, ventilator induced acute respiratory distress, non-pulmonary sepsis induced acute respiratory distress and aspiration induced acute respiratory distress.
  20. The use of claim 17 wherein said kidney fibrosis is a chronic nephropathy associated with injury or fibrosis and is selected from the group consisting of lupus, diabetes, scleroderma, glomerular nephritis, focal segmental glomerular sclerosis, IgA nephropathy, hypertension, allograft and Alport's disease.
  21. The composition of claim 15, wherein the cancer is epithelial, oral, skin, cervical, ovarian, pharyngeal, laryngeal, oesophageal, lung, breast, kidney, or colorectal cancer.
  22. The composition of claim 10 or 11, wherein said composition is for use in the treatment of a disease wherein the disease is fibrosis, psoriasis, cancer or Alport's syndrome.
  23. The composition of claim 20, wherein the fibrosis is scleroderma, scarring, liver fibrosis, kidney fibrosis, or lung fibrosis.
  24. The composition of claim 20, wherein the cancer is epithelial, oral, skin, cervical, ovarian, pharyngeal, laryngeal, oesophageal, lung, breast, kidney, or colorectal cancer.
  25. Use of an antibody of any of claims 1 to 5 for reducing or preventing the metastasis of a primary tumor to a secondary location in a patient, wherein said antibody binding to one or more subunits of integrin αvβ6 on the cells of said tumor results in the death, chemosensitivity or decreased invasiveness of said tumor cells.
  26. Use of an antibody of any of claims 1 to 5 for eliminating αvβ6-positive metastatic tumor cells in a patient, wherein the antibody binds to one or more subunits of integrin αvβ6 on αvβ6-positive metastatic tumor cells, wherein the binding of said antibody to said integrin results in the death, chemosensitization or decreased invasiveness of said metastatic tumor cell.
  27. Use of an antibody of claims 1 to 5 for eliminating residual αvβ6-positive tumor cells from a patient following surgical excision of a tumor from a tissue or organ of said patient, wherein the binding of said antibody to one or more subunits of integrin αvβ6 on αvβ6-positive tumor cells results in the death, chemosensitization or decreased invasiveness of residual tumor cells remaining following surgical excision of a tumor from a tissue or organ of said patient.
  28. Use of an antibody of any of claims 1 to 5 for reducing or preventing the progression of a primary pre-metastatic or pre-invasive tumor to a metastatic or invasive tumor in a patient, wherein the binding of said antibody to one or more subunits of integrin αvβ6 on αvβ6-positive tumor cells results in the reduction or prevention of invasion of cells of said primary pre-metastatic or pre-invasive tumor to tissue areas surrounding said primary pre-metastatic or pre-invasive tumor.
  29. The use of claim 28, wherein said pre-metastatic or pre-invansive tumor is a carcinoma.
  30. An in vitro method of diagnosing a carcinoma that is more likely to progress to an invasive carcinoma, comprising:

(a) contacting a cancerous epithelial tissue sample comprising a tumor or portion thereof obtained from a patient, and a non-cancerous epithelial tissue sample obtained from a patient with an antibody of claims t to 6 that binds to one or more subunits of integrin αvβ6; and

(b) determining the level of expression of integrin αvβ6 in said tissue samples, wherein an increase in the level of expression of integrin αvβ6 in said cancerous tissue sample relative to the level of expression of integrin αvβ6 in said non-cancerous tissue sample indicates the presence in said patient of a carcinoma that is more likely to progress to an invasive carcinoma.


  31. The use of any of claims 25 through 29, wherein said carcinoma or tumor is selected from the group consisting of a breast, endometrial, pancreatic, colorectal, a lung, ovarian, cervical, prostatic, liver, oesophagus, head and neck, stomach, splenic and adenocarcinoma carcinoma or tumor.
  32. The use of claim 31, wherein said breast carcinoma is in situ breast carcinoma.
  33. The use of claim 32, wherein said in situ breast carcinoma is selected from the group consisting of a ductal carcinoma in situ (DCIS) and a lobular carcinoma in situ (LCIS).
  34. The use of any of claims 25 through 29, wherein said antibody is conjugated with at least one cytotoxic compound.
  35. The use of any of claims 25 through 29, wherein said antibody is to be administered to said patient in conjunction with the administration to said patient of at least one cytotoxic compound.
  36. The use of claim 34 or claim 35, wherein said cytotoxic compound is selected from the group consisting of cisplatin, carboplatin, oxaplatin, paclitaxel, melphalan, doxorubicin, methotrexate, 5-fluorouracil, etoposide, mechlorethamine, cyclophosphamide, bleomycin, a calicheamicin, a maytansine, a trichothene, CC 1065, diphtheria A chain, Pseudomonas aeruginosa exotoxin A chain, ricin A chain, abrin A chain, modeccin A chain, alpha-sarcin, an Aleuritesfordii protein, a dianthin protein, a Phytolaca americana protein, momordica charantia inhibitor, curcin, crotin, saponaria officinalis inhibitor, gelonin, mitogellin, restrictocin, phenomycin, enomycin, atricothecene, a ribonuclease, a deoxyribonuclease, a radioisotope and a prodrug-activating enzyme.
  37. The use of any of claims 25 to 29, wherein said antibody is to be administered to said patient in the form of a pharmaceutical composition comprising said antibody and one or more pharmaceutically acceptable carriers or excipients.
  38. The use of claim 37, wherein said antibody or composition is to be administered to said patient via a route selected from the group consisting of oral administration, parenteral administration, intracranial administration, intrapulmonary administration and intranasal administration.
  39. The use of claim 37, wherein said antibody or composition is administered to said patient via a parenteral route selected from the group consisting of intramuscular administration, intravenous administration, intraarterial administration and subcutaneous administration.
  40. The use of claim 39, wherein said parenteral route comprises administering said antibody or composition to said patient via injection.
  41. The method of claim 30, wherein said antibody is conjugated with at least one detectable label.
  42. The method of claim 41, wherein said detectable label is selected from the group consisting of a chromogenic label, an enzyme label, a radioisotopic label, a non-radioactive isotopic label, a fluorescent label, a toxic label, a chemiluminescent label, an X-radiographic label, a spin label and a nuclear magnetic resonance contrast agent label.
  43. The method of claim 30, wherein said tumor cells are from a metastatic carcinoma.
  44. The method of claim 30, wherein said tumor is a carcinoma.
  45. The method of claim 44, wherein said carcinoma is selected from the group consisting of a breast carcinoma, and endometrial carcinoma, a pancreatic carcinoma, a colorectal carcinoma, a lung carcinoma, an ovarian carcinoma, a cervical carcinoma, a prostatic carcinoma, a liver carcinoma, an oesophagus carcinoma, a head and neck carcinoma, a stomach carcinoma, a splenic carcinoma and an adenocarcinoma.
  46. The method of claim 45, wherein said breast carcinoma is in situ breast carcinoma.
  47. The method of claim 46, wherein said in situ breast carcinoma is selected from the group consisting of a ductal carcinoma in situ (DCIS) and a lobular carcinoma in situ (LCIS).