Monoclonal antibodies to progastrin and their uses

{
  "publication_number": "US2011117086A1",
  "country": "US",
  "kind": "A1",
  "title": "Monoclonal antibodies to progastrin and their uses",
  "abstract": "The present disclosure is directed to progastrin monoclonal antibodies, fragments thereof, compositions comprising progastrin monoclonal antibodies, and methods of making and using progastrin monoclonal antibodies and compositions thereof. The present disclosure is directed to methods of treating colorectal cancer with progastrin monoclonal antibodies and compositions comprising progastrin monoclonal antibodies or fragments thereof. The present disclosure is further directed to methods comprising detection of progastrin, including methods of diagnosing colorectal cancer and methods of monitoring efficacy of anti-cancer therapy in subjects suffering from colorectal cancer.",
  "claims": [
    "1. A monoclonal antibody that specifically binds human progastrin (hPG). 2. The monoclonal antibody of claim 1 which specifically binds an N-terminal region of hPG. 3. The monoclonal antibody of claim 2 which is obtainable using an immunogen comprising a peptide antigen having an amino acid sequence corresponding to SEQ ID NO:25. 4. The monoclonal antibody of claim 2 that competes for binding hPG with a reference anti-hPG monoclonal antibody obtainable from a hybridoma selected from the group consisting of 43B9G11, WE5H2G7, 6B5B11C10, 20D2C3G2, 1E9A4A4, 1E9D9B6, 1C8D10F5, 1A7C3F11, 1B3B4F11, and 1C11F5E8. 5. The monoclonal antibody of claim 2 which comprises V L and V H CDRs corresponding in sequence to the V L and V H CDRs of the monoclonal antibodies obtainable from a hybridoma selected from the group consisting of: 43B9G11, WE5H2G7, 6B5B11C10, 20D2C3G2, 1E9A4A4, 1E9D9B6, 1C8D10F5, 1A7C3F11, 1B3B4F11, and 1C11F5E8. 6. The monoclonal antibody of claim 2 which comprises V L and V H CDRs having sequences selected from one of the following groups of V L and V H CDR sequences: (i) V H CDR1.3, V H CDR 2.3, V H CDR 3.3, V L CDR 1.3, V L CDR 2.3, and V L CDR 3.3; (ii) V H CDR 1.4, V H CDR 2.4, V H CDR 3.4, V L CDR 1.4, V L CDR 2.4, and V L CDR 3.4; (iii) V H CDR 1.16, V H CDR 2.16, V H CDR 3.16, V L CDR 1.16, V L CDR 2.16, and, V L CDR 3.16; and (iv) V H CDR 1.19, V H CDR 2.19, V H CDR 3.19, V L CDR 1.19, V L CDR 2.19, and V L CDR 3.19. 7. The monoclonal antibody of claim 1, which is humanized. 8. The monoclonal antibody of claim 7 which comprises V H and V L chains having sequences selected from one of the following groups of V H and V L sequences: (i) hV H 3 (SEQ ID NO:21) and hV L 3 (SEQ ID NO:22); (ii) hV H 4 (SEQ ID NO:23) and hV L 4 (SEQ ID NO:24); (iii) hV H 16a (SEQ ID NO:84) and hV L 16a (SEQ ID NO:85); (iv) hV H 16b (SEQ ID NO:86) and hV L 16b (SEQ ID NO:87); (v) hV H 16c (SEQ ID NO:88) and hV L 16c (SEQ ID NO:89); (vi) hV H 19a (SEQ ID NO:90) and hV L 19a (SEQ ID NO:91); (vii) hV H 19b (SEQ ID NO:92) and hV L 19b (SEQ ID NO:93); and (viii) hV H 19c (SEQ ID NO:94) and hV L 19c (SEQ ID NO:95). 9. The monoclonal antibody of claim 1 which specifically binds a C-terminal region of hPG. 10. The monoclonal antibody of claim 9 which is obtainable using an immunogen comprising a peptide antigen having an amino acid sequence corresponding to SEQ ID NO:27. 11. The monoclonal antibody of claim 9 which competes for binding hPG with a reference anti-hPG monoclonal antibody obtainable from a hybridoma selected from the group consisting of 1B4A11D11, 1B6A11F2, 1B11E4B11, 1C10D3B9, 1D8F5B3, 1E1C7B4, 2B4C8C8, 2B11E6G4, 2C6C3C7, 2H9F4B7, 1F11F5E10, 1F11F5G9, and 1A11F2C9. 12. The monoclonal antibody of claim 9 which comprises V L and V H CDRs corresponding in sequence to the V L and V H CDRs of the monoclonal antibodies obtainable from a hybridoma selected from the group consisting of: 1B4A11D11, 1B6A11F2, 1B11E4B11, 1C10D3B9, 1D8F5B3, 1E1C7B4, 2B4C8C8, 2B11E6G4, 2C6C3C7, 2H9F4B7, 1F11F5E10, 1F11F5G9, and 1A11F2C9. 13. The monoclonal antibody of claim 9 which comprises V H and V L CDRs having sequences selected from one of the following groups of V H and V L CDR sequences: (i) V H CDR 1.8, V H CDR 2.8, V H CDR 3.8, V L CDR 1.8, V L CDR 2.8, and V L CDR 3.8; and (ii) V H CDR 1.13, V H CDR 2.13, V H CDR 3.13, V L CDR 1.13, V L CDR 2.13, and V L CDR 3.13. 14. The monoclonal antibody of claim 9, which is humanized. 15. The monoclonal antibody of claim 14 which comprises V H and V L chains having sequences selected from one of the following groups of V H and V L sequences: (i) hV H 8a (SEQ ID NO:75) and hV L 8a (SEQ ID NO:76); (ii) hV H 8b (SEQ ID NO:77) and hV L 8b (SEQ ID NO:78); (iii) hV H 8c (SEQ ID NO:79) and hV L 8c (SEQ ID NO:76); (iv) hV H 13a (SEQ ID NO:80) and hV L 13a (SEQ ID NO:81); and (v) hV H 13b (SEQ ID NO:82) and hV L 13b (SEQ ID NO:83). 16. The monoclonal antibody of claim 1 which has an affinity for hPG in the range of about 1 pM to about 7 nM. 17. The monoclonal antibody of claim 1 that binds to an epitope comprising an amino acid sequence corresponding to a sequence selected from the group consisting of SEQ ID NOs:28, 29, 30, 31, and 32. 18. The monoclonal antibody of claim 1 that binds to an epitope comprising an amino acid sequence corresponding to a sequence selected from the group consisting of SEQ ID NOs:33, 34, 35, and 36. 19. The monoclonal antibody of claim 1 which competes for binding hPG with a reference antibody selected from the group consisting of: anti-hPG MAb1, anti-hPG MAb2, anti-hPG MAb3, anti-hPG MAb4, anti-hPG MAb15, anti-hPG MAb16, anti-hPG MAb17, anti-hPG MAb18, anti-hPG MAb19, and anti-hPG MAb20. 20. The monoclonal antibody of claim 1 which competes for binding hPG with a reference antibody selected from the group consisting of: anti-hPG MAb5, anti-hPG MAb6, anti-hPG MAb7, anti-hPG MAb8, anti-hPG MAb9, anti-hPG MAb10, anti-hPG MAb11, anti-hPG MAb12, anti-hPG MAb13, anti-hPG MAb14, anti-hPG MAb21, anti-hPG MAb22, and anti-hPG MAb23. 21. The monoclonal antibody of claim 1 which neutralizes hPG activity in an in vitro assay carried out with LS174T cells. 22. A composition comprising a monoclonal antibody according to claim 1 and an excipient, carrier, and/or diluent. 23. The composition of claim 22 which is formulated for pharmaceutical use. 24. A polynucleotide encoding a variable light chain for an anti-hPG monoclonal antibody according to claim 1. 25. A polynucleotide encoding a variable heavy chain for an anti-hPG monoclonal antibody according to claim 1. 26. An expression vector comprising a polynucleotide encoding a variable light chain for an anti-hPG monoclonal antibody according to claim 1. 27. An expression vector comprising a polynucleotide encoding a variable heavy chain for an anti-hPG monoclonal antibody according to claim 1. 28. A host cell transformed with pairs of polynucleotides suitable for expressing an anti-hPG monoclonal antibody according to claim 1. 29. A hybridoma capable of secreting an anti-hPG monoclonal antibody according to claim 1. 30. The hybridoma of claim 29 selected from the group consisting of: 43B9G11, WE5H2G7, 6B5B11C10, 20D2C3G2, 1B4A11D11, 1B6A11F2, 1B11E4B11, 1C10D3B9, 1D8F5B3, 1E1C7B4, 2B4C8C8, 2B11E6G4, 2C6C3C7, 2H9F4B7, 1E9A4A4, 1E9D9B6, 1C8D10F5, 1A7C3F11, 1B3B4F11, 1C11F5E8, 1F11F5E10, 1F11F5G9, and 1A11F2C9. 31. The hybridoma of claim 29, which is selected from the group consisting of: 43B9G11, WE5H2G7, 1B4A11D11, 1B6A11F2, 1B11E4B11, 1D8F5B3, 1E1C7B4, 2B4C8C8, 2B11E6G4, 2H9F 4 B7, 1E9A4A4, 1C8D10F5, 1A7C3F11, 1C11F5E8, 1F11F5E10, 1F11F5G9, and 1A11F2C9. 32. The hybridoma of claim 29, which is selected from the group consisting of: 1B4A11D11, 1B6A11F2, 1B11E4B11, 2B4C8C8, 2B11E6G4, and 1E9A4A4. 33. A method of obtaining an anti-hPG monoclonal antibody comprising: (a) culturing a hybridoma of claim 21 under suitable conditions; and (b) recovering the anti-hPG monoclonal antibody from the culture medium or the hybridoma cells. 34. A method of treating colorectal cancer comprising administering to a subject an amount of a humanized neutralizing anti-hPG monoclonal antibody effective to treat the colorectal cancer. 35. The method of claim 34 in which the neutralizing anti-hPG monoclonal antibody competes for binding with an anti-hPG monoclonal antibody obtainable from a hybridoma selected from the group of consisting of: 43B9G11, WE5H2G7, 6B5B11C10, 20D2C3G2, 1B4A11D11, 1B6A11F2, 1B11E4B11, 1C10D3B9, 1D8F5B3, 1E1C7B4, 2B4C8C8, 2B11E6G4, 2C6C3C7, 2H9F4B7, 1E9A4A4, 1E9D9B6, 1C8D10F5, 1A7C3F11, 1B3B4F11, 1C11F5E8, 1F11F5E10, 1F11F5G9, and 1A11F2C9. 36. The method of claim 34 in which the neutralizing anti-hPG monoclonal antibody has CDRs corresponding in sequence to the CDRs of an anti-hPG monoclonal antibody selected from the group consisting of: anti-hPG MAb1, anti-hPG MAb2, anti-hPG MAb3, anti-hPG MAb4, anti-hPG MAb5, anti-hPG MAb6, anti-hPG MAb7, anti-hPG MAb8, anti-hPG MAb9, anti-hPG MAb10, anti-hPG MAb11, anti-hPG MAb12, anti-hPG MAb13, anti-hPG MAb15, anti-hPG MAb16, anti-hPG MAb17, anti-hPG MAb18, anti-hPG MAb19, anti-hPG MAb20, anti-hPG MAb21, anti-hPG MAb22, or anti-hPG MAb23. 37. A method of inhibiting proliferation of colorectal tumor cells, comprising exposing the colorectal tumor cells to a neutralizing anti-hPG monoclonal antibody. 38. The method of claim 37 in which the neutralizing anti-hPG monoclonal antibody competes for binding with an anti-hPG monoclonal antibody obtainable from a hybridoma selected from the group of consisting of: 43B9G11, WE5H2G7, 6B5B11C10, 20D2C3G2, 1B4A11D 11, 1B6A11F2, 1B11E4B11, 1C10D3B9, 1D8F5B3, 1E1C7B4, 2B4C8C8, 2B11E6G4, 2C6C3C7, 1E9A4A4, 1E9D9B6, 1C8D10F5, 1A7C3F11, 1B3B4F11, 1C11F5E8, 1F11F5E10, 1F11F5G9, and 1A11F2C9. 39. The method of claim 37 in which the neutralizing anti-hPG monoclonal antibody has CDRs corresponding in sequence to the CDRs of an anti-hPG monoclonal antibody selected from the group consisting of anti-hPG MAb1, anti-hPG MAb2, anti-hPG MAb3, anti-hPG MAb4, anti-hPG MAb5, anti-hPG MAb6, anti-hPG MAb7, anti-hPG MAb8, anti-hPG MAb9, anti-hPG MAb10, anti-hPG MAb11, anti-hPG MAb12, anti-hPG MAb13, anti-hPG MAb15, anti-hPG MAb16, anti-hPG MAb17, anti-hPG MAb18, anti-hPG MAb19, anti-hPG MAb20, anti-hPG MAb21, anti-hPG MAb22, or anti-hPG MAb23. 40. The method of claim 37 which is carried out in vitro. 41. The method of claim 37 which is carried out in vivo. 42. A kit useful for detecting hPG, comprising an N-terminal anti-hPG monoclonal antibody according to claim 2 and an antibody that specifically binds a C-terminal region of hPG. 43. The kit of claim 42, wherein the antibody that specifically binds a C-terminal region of hPG is a polyclonal antibody. 44. A kit useful for detecting hPG, comprising a C-terminal anti-hPG monoclonal antibody according to claim 9 and an antibody that specifically binds an N-terminal region of hPG. 45. The kit of claim 44, wherein the antibody that specifically binds an N-terminal region of hPG is a polyclonal antibody. 46. A method of diagnosing colorectal cancer in a subject, comprising quantifying the amount of progastrin in a serum sample from the subject using at least one monoclonal antibody according to claim 1, wherein a quantity of progastrin in a range of about 20 to 400 pM is indicative of colorectal cancer. 47. A method of selecting a patient suitable for anti-hPG therapy, comprising quantifying the amount of progastrin in a serum sample from a patient with colorectal cancer using at least one monoclonal antibody according to claim 1, wherein a quantity of progastrin in a range of about 20 to 400 pM is indicative of suitability for anti-hPG therapy. 48. A method of monitoring the effectiveness of a colorectal cancer treatment, comprising quantifying the amount of progastrin in a serum sample from a subject who is being treated for colorectal cancer, as a function of time, using at least one monoclonal antibody according to claim 1, where a time-dependent decrease in the subject's serum progastrin level indicates the treatment is effective. 49. A method of inhibiting a progastrin-dependent signal transduction cascade in a cell, comprising exposing cells that secretes hPG to an amount of a neutralizing anti-hPG monoclonal antibody effective to inhibit progastrin-dependent signal transduction."
  ],
  "description_excerpt": "None.\n\nNone.\n\nThe present disclosure is directed to, among other things, monoclonal antibodies to progastrin, compositions and methods for making such antibodies, and methods of using such antibodies, for example in the diagnosis and/or treatment of colorectal cancer.\n\nColorectal Cancer (CRC) is a major public health issue, affecting more than 1,000,000 people each year and accounting for more than 500,000 deaths each year. CRC is the second leading cause of death due to cancer. In the United States alone, for 2009, approximately 147,000 new cases and over 49,900 deaths due to CRC were reported. There are three forms of CRC: sporadic CRC; hereditary non-polyposis colon cancer (HNPCC), caused by germline mutations in DNA mismatch repair genes; and familial adenomatous polyposis (FAP), due to germline mutations in the APC gene. Sporadic CRC accounts for nearly 85% of cases, while HNPCC accounts for about 5% and FAP accounts for about 1% (Heyer et al., 1999, Oncogene 18:5325-5333).\n\nClinical management of CRC typically involves surgical resection of tumors often accompanied by chemotherapy. Presently, about 50% of CRC patients die within five years of diagnosis. The lack of reliable screening tests and the ineffectiveness of currently available therapies are major causes of the high mortality rate. There is an urgent need for new clinical approaches for diagnosing CRC, as well as for treatments effective against colorectal cancer tumors that have minimal adverse effects on otherwise healthy tissue.",
  "cpc": [
    "C07K 16/26",
    "A61K 2039/505",
    "A61K 39/395",
    "A61P 1/00",
    "A61P 35/00",
    "C07K 2317/24",
    "C07K 2317/33",
    "C07K 2317/34",
    "C07K 2317/565",
    "C07K 2317/567",
    "C07K 2317/73",
    "C07K 2317/76",
    "C07K 2317/92",
    "G01N 2333/595",
    "G01N 33/57535",
    "G01N 33/57585"
  ],
  "ipc": [
    "A61P 35/00",
    "C07H 21/00",
    "C12N 15/63",
    "C12N 5/071",
    "C12N 5/09",
    "C12N 5/10",
    "C12N 5/16",
    "C12P 21/08",
    "G01N 33/566",
    "A61K 39/395",
    "C07K 16/26"
  ],
  "assignees": [
    "Centre National de la Recherche Scientifique CNRS",
    "Institut National de la Sante et de la Recherche Medicale INSERM",
    "Biorealites SAS"
  ],
  "inventors": [
    "Julie Pannequin",
    "Laure Boudier",
    "Dominique Joubert",
    "Frédéric Hollande"
  ],
  "filing_date": "2010-10-15",
  "publication_date": "2011-05-19",
  "priority_date": "2009-10-16",
  "application_number": "US-90604110-A",
  "family_id": "43086711",
  "cited_by_count": 27,
  "citations": [
    "US7854932B2"
  ]
}