WO2012153186A2 - Anticorps monoclonaux dirigés contre epcam-icd et méthodes de détection de cellules d'un cancer épithélial - Google Patents

Anticorps monoclonaux dirigés contre epcam-icd et méthodes de détection de cellules d'un cancer épithélial Download PDF

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Publication number
WO2012153186A2
WO2012153186A2 PCT/IB2012/001017 IB2012001017W WO2012153186A2 WO 2012153186 A2 WO2012153186 A2 WO 2012153186A2 IB 2012001017 W IB2012001017 W IB 2012001017W WO 2012153186 A2 WO2012153186 A2 WO 2012153186A2
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Prior art keywords
cancer
antibody
epcam
icd
subject
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PCT/IB2012/001017
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English (en)
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WO2012153186A3 (fr
Inventor
Thillainathan Yoganathan
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Kalgene Pharmaceuticals Inc.
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Publication of WO2012153186A2 publication Critical patent/WO2012153186A2/fr
Publication of WO2012153186A3 publication Critical patent/WO2012153186A3/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Epithelial cell-derived cancers comprise approximately 80-85% of all cancers, and include, amongst others, breast, bladder, lung, pancreatic, thyroid and prostate cancers (1-4).
  • breast cancer is the most common cancer among women worldwide
  • thyroid cancer is the most common epithelial cell-derived malignancy of the endocrine glands (4, 5).
  • EpCAM Epithelial cell adhesion molecule
  • EpCAM serves important roles in cell adhesion, proliferation, differentiation, migration, cell cycle regulation (2, 7-9). It has been shown that EpCAM upregulates c-myc, cyclin A and E, promotes cell cycling and enhances proliferation (8). In addition to its potential role in proliferation, EpCAM can antagonize epithelium- specific, calcium-independent homotypic cadherin-mediated cell-cell adhesions (9). Formation of EpCam-mediated adhesion has a negative regulatory effect on adhesions mediated by classic cadherins, which may have strong effects on the differentiation and growth of epithelial cells. In vivo expression of EpCam is related to increased epithelial proliferation and negatively correlates with cell differentiation (6, 10).
  • EpCAM EpCAM-associated cytoplasmic kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase kinase
  • EpCAM has gained interest as a potential therapeutic target. Negative side effects were mostly mild and concerned the gastrointestinal tract, although new high-affinity antibodies may cause more serious damage to normal EpCAM-expressing normal tissue.
  • Chimeric and humanized monoclonal antibodies have been generated, such as chimeric mAb 323/A3 and 17-1 A or humanized mAb huNR-LU-1317 and MT201 (2).
  • Immunotherapy with the monoclonal antibody 17-1 A decreased the frequency of distant metastasis in patients with colorectal cancer and eliminated disseminated breast cancer tumor cells in the bone marrow (13-16).
  • EpCAM ectodomain
  • TACE proteases ADAM 17
  • Presenilin-2 a 5 kDa intracellular domain of the protein that translocates to the nucleus (10).
  • Ep-ICD was detected in the cytoplasm and nucleus of experimental cells, but not when protease inhibitors were present.
  • Ep-ICD Ep-ICD with FHL2 and Wnt pathway components ⁇ -catenin and Lef-1 was reported to form a nuclear complex that binds DNA at Lef-1 consensus sites, and to induce gene transcription in the nucleus and, as a result, increased cell proliferation and tumor formation in immunodeficient mice (10).
  • Ep-ICD The oncogenic potential of Ep-ICD was demonstrated using a mouse xenograft model, in which HEK293 cells stably expressing EpCAM or Ep-ICD produced nearly equivalent tumors (10). Gastrointestinal tumor sections frequently exhibit nuclear Ep-ICD, while normal tissue sections do not. These data provide substantial evidence that the positive impudence of EpCAM on cell proliferation can be accounted for by liberation of its Ep-ICD from the plasma membrane. In view of the novel role of EpCAM as an oncogenic signal transducer and cancer stem cell marker, it is important to establish the clinical significance of nuclear Ep-ICD in human cancers.
  • the present invention provides for four novel mouse monoclonal antibodies that have been generated against a unique immunogen that has been designed and synthesized based upon a segment of the human epithelial cell adhesion molecule (EpCAM) intracellular domain (Ep- ICD), namely, the peptide sequence: SRKKRMAKYEKAEIKEMGEMHRELNA (SEQ ID NO: l) which corresponds to amino acids 289-314 of the carboxy terminus of the full-length protein.
  • EpCAM human epithelial cell adhesion molecule
  • the present invention is thus directed in a first aspect to antibodies with binding specificity for human epithelial cell adhesion molecule (EpCAM) or a portion thereof.
  • EpCAM human epithelial cell adhesion molecule
  • present invention is directed to antibodies with binding specificity for the intracellular domain of EpCAM (Ep-ICD) or a portion thereof.
  • EpCAM human epithelial cell adhesion molecule
  • present invention is directed to antibodies with binding specificity for the intracellular domain of EpCAM (Ep-ICD) or a portion thereof.
  • EpCAM human epithelial cell adhesion molecule
  • Ep-ICD intracellular domain of EpCAM
  • the present invention is directed to anti-Ep-ICD antibodies.
  • the antibodies of the present invention have binding specificity for the amino acid sequence
  • Antibodies of the present invention may be polyclonal antibodies or monoclonal antibodies. Preferably, the antibodies are IgG antibodies.
  • the antibodies of the present invention include humanized antibodies, chimeric antibodies and antibody fragments selected from the group consisting of Fab, Fab', (Fab')2, and Fv fragments, and single chain antibodies (scFv). In particular,
  • the present invention is directed in a second aspect to a method of screening a test sample for EpCAM or Ep-ICD, comprising: (a) contacting a test sample with an antibody having binding specificity for Ep-ICD under conditions promoting binding of the antibody to EpCAM or Ep-ICD, and (b) detecting binding of the antibody to EpCAM or Ep-ICD, thereby screening a test sample for a EpCAM or Ep-ICD.
  • the antibody may be labeled with a detectable marker or a conjugate, or the antibody may be detected using a labeled secondary antibody.
  • the test sample may be a biological sample isolated from a subject.
  • the biological sample may be an epithelial cell cancer, including a cancer selected from the group consisting of squamous cell carcinoma, adenocarcinoma, and transitional cell carcinoma.
  • the antibody may be KalEpCAMl,
  • KalEpCAMl KalEpCAM2, KalEpCAM3, or KalEpCAM4, or antigen-binding fragments thereof.
  • the subject may be a mammal, such as a human.
  • the present invention is directed in a fourth aspect to a method of treating cancer in a subject comprising, administering a therapeutically effective amount of a pharmaceutical composition comprising one or more of antibodies KalEpCAMl, KalEpCAM2, KalEpCAM3, and KalEpCAM4, and antigen-binding fragments thereof, to the subject, thereby treating cancer in a subject.
  • the cancer may be an epithelial cell cancer, including a cancer selected from the group consisting of squamous cell carcinoma, adenocarcinoma, and transitional cell carcinoma.
  • the one or more antibodies or fragments may be conjugated to an anti-cancer agent.
  • the anticancer agent may be an agent selected from the group consisting of a drug, a chemotherapeutic agent, a radioisotope, a pro-apoptotic agent, an anti-angiogenic agent, a hormone, a cytokine, a cytotoxic agent, a cytocidal agent, a cytostatic agent, a peptide, a protein, an antibiotic, an antibody, a Fab fragment of an antibody, a hormone antagonist, a nucleic acid or an antigen.
  • a drug a chemotherapeutic agent, a radioisotope, a pro-apoptotic agent, an anti-angiogenic agent, a hormone, a cytokine, a cytotoxic agent, a cytocidal agent, a cytostatic agent, a peptide, a protein, an antibiotic, an antibody, a Fab fragment of an antibody, a hormone antagonist, a nucleic acid or an antigen.
  • the chemotherapeutic drug may be selected from the group consisting of cyclophosphamide, etoposide, vincristine, procarbazine, prednisone, carmustine, doxorubicin, methotrexate, bleomycin, dexamethasone, phenyl butyrate, bryostatin-1, leucovorin, adriamycin, cisplatin, taxol, topotecan, fluoropyrimidine, oxaliplatin, and irinotecan.
  • the subject may be a mammal, such as a human.
  • hybridoma cell line KalEpcaml hybridoma cell line KalEpcam2
  • hybridoma cell line KalEpcam3 hybridoma cell line KalEpcam4.
  • Hybridoma cell line KalEpcaml produces monoclonal antibody KalEpCAMl.
  • Hybridoma cell line KalEpcam2 produces monoclonal antibody KalEpCAM2.
  • Hybridoma cell line KalEpcam3 produces monoclonal antibody KalEpCAM3.
  • Hybridoma cell line KalEpcam4 produces monoclonal antibody KalEpCAM4.
  • Figure 1 shows ELISA data from serum of mouse #4 tested against four concentrations of Ep-ICD protein.
  • Figure 2 shows Western blot screening of various mouse anti-Ep-ICD hybridoma tissue culture supernatants against Ep-ICD protein.
  • Figure 3 shows Western blot screening of supernatants from four mouse anti-Ep-ICD hybridomas, namely, KalEpcaml, KalEpcam2, KalEpcam3 and KalEpcam4 against full-length EpCAM protein.
  • Figure 4 shows Western blot screening of supernatants from hybridomas KalEpcaml, KalEpcam2 and KalEpcam3 against mouse cell lysate.
  • Figure 5 shows Western blot screening of supernatants from mouse anti-Ep-ICD hybridomas KalEpcaml, KalEpcam2, KalEpcam3 and KalEpcam4 against full-length EpCAM protein.
  • Figure 6 shows Western blot screening of supernatants from hybridomas KalEpcam2 against two mouse 4T1 cell lysates.
  • Figure 7 shows Western blot screening of protein G-purified monoclonal antibody KalEpCAM2 against full-length EpCAM protein.
  • Figure 8 shows Western blot screening of protein G-purified monoclonal antibody KalEpCAM2 against mouse 4T1 cell lysate.
  • Figure 9 shows immunohistochemistry screening using KalEpCAM2 mAb against epithelial cancer samples (thyroid, colon, prostate).
  • a monoclonal antibody is regarded as an antibody of unique specificity, derived from the immortalization of a single plasma B cell in vitro, through hybridoma technology.
  • Hybrid cell lines (called hybridomas) are formed by fusing a specific antibody-producing B cell with a myeloma (B cell cancer) cell, resulting in a population of cells with the ability to grow in tissue culture and its absence of antibody chain synthesis.
  • Antibodies produced by a hybridoma are all of a single specificity and are therefore monoclonal antibodies.
  • the antibodies that comprise the anti-Ep-ICD antibodies of the present invention should be broadly interpreted and understood to include monoclonal and polyclonal antibodies; IgG, IgM, IgA, IgD and IgE; naturally occurring, semi-synthetic and fully synthetic antibodies, including humanized and chimeric antibodies; antibody fragments, such as Fab, Fab', (Fab')2, and Fv fragments, and single chain antibodies (scFv); antibodies with known affinities and those with unknown affinities.
  • each of the antibodies of the present invention demonstrates binding specificity for the amino acid sequence: S RKKRM AKYEKAEIKEMGEMHRELN A (SEQ ID NO: l) or a fragment thereof, or both.
  • the antibodies of the present invention may be constructed by first producing an antibody with binding specificity to EpCAM, or a specific portion thereof, such as Ep-ICD.
  • the anti-Ep-ICD antibodies of the present invention also include the monoclonal antibodies (KalEpCAMl, KalEpCAM2, KalEpCAM3, and KalEpCAM4) produced by the following four hybridoma cell lines: KalEpCAM2, KalEpCAM2, KalEpCAM3, and
  • KalEpCAM4 Antibody fragments described herein may be produced from such monoclonal antibodies.
  • the anti-Ep-ICD antibodies of the present invention can be utilized as diagnostics and research tools, as well as agents of medical treatment.
  • the antibodies can be used in the detection and/or treatment of: (i) epithelial cells of normal epithelial, such as normal stem and progenitor cells, (ii) cancer-initiating cells of various origins, head and neck cancer, thyroid cancer, lung cancer, esophagus cancer, liver cancer, breast cancer, pancreatic cancer, bladder cancer, colon cancer, rectal cancer and prostate cancer, and (iii) cells of epithelial cancers, such as squamous cell carcinoma, adenocarcinoma, transitional cell carcinoma, including head and neck cancer, thyroid cancer, lung cancer, esophagus cancer, liver cancer, breast cancer, pancreatic cancer, bladder cancer, colon cancer, rectal cancer and prostate cancer.
  • epithelial cells of normal epithelial such as normal stem and progenitor cells
  • cancer-initiating cells of various origins head and neck
  • the antibodies can be used in such techniques as immunohistology, immunofluorescence, immunoblots, immunoprecipitation, electron microscopy, ELISAs, polypeptide microarrays, and in in vivo diagnostic applications.
  • test samples such as a biological sample from a subject, may be screened for the presence of EpCAM or Ep-ICD.
  • EpCAM EpCAM
  • Ep-ICD Ep-ICD
  • the presence of the protein or domain may be used as a diagnostic for cancer, or to track the efficacy of anti-cancer treatment in a patient previously diagnosed as having cancer.
  • the antibodies can also be used to grade the particular stage of a cancer through the diagnostic methods, including Stages 0-IV; Primary Tumor (T) stages TX, TO, Tis, Tl, T2, T3, and T4; Regional Lymph Nodes (N) stages NX, NO, Nl, N2, and N3; Distant Metastasis (M) stages MX, MO, and Ml; tumor grading; and estrogen receptor positive (ER+) or negative (ER-) grading.
  • the antibodies can be detectably labeled or they may be indirectly detected by using a second (or third) antibody that is labeled and that specifically recognizes the anti-EpCAM-ICD antibody.
  • the antibodies of the invention can be detectably labeled with a detectable marker or a conjugate. Suitable detectable markers include, but are not limited, to a metal (e.g., gold for electron microscopy applications), fluorescent markers (e.g., for
  • the pharmaceutical compositions optionally comprise a pharmaceutically acceptable diluent, carrier, and/or excipient, such as buffers, surfactants, dispersing agents, preservatives, solubilizing agents, and isotonicity agents, or any other pharmacologically inert vehicle for delivering an antibody of the invention to a subject.
  • a pharmaceutically acceptable diluent, carrier, and/or excipient such as buffers, surfactants, dispersing agents, preservatives, solubilizing agents, and isotonicity agents, or any other pharmacologically inert vehicle for delivering an antibody of the invention to a subject.
  • Conventional techniques for preparing pharmaceutical compositions are disclosed, for example in: Remington, The Science and Practice of Pharmacy, 19th ed., Gennaro, Ed., Mack Publishing Co., Easton, PA 1995.
  • the antibodies of the present invention may be used in the treatment of a disease or condition in a subject. Such methods include administering a therapeutically effective amount
  • EpCAM EpCAM-associated antigen
  • Ep-CAM Epithelial cell adhesion molecule
  • This therapeutic goal maybe achieved by developing robust high throughput assays on clinical tumor tissue samples for these two EpCAM components to serve as a guide to target monoclonal antibody therapy.
  • identifying the nuclear and cytoplasmic localization of Ep-ICD using the antibodies of the present invention should provide additional information about the signaling pathway modulated in the cancer samples.
  • This strategy offers unique tests for epithelial cancers by determining the appropriate EpCAM target or other w/ii-mediated signaling molecules as a therapeutic target.
  • the subject is a human or non-human animal, e.g., a non-human primate, bird, horse, cow, goat, sheep, a companion animal, such as a dog, cat or rodent, or other mammal.
  • the ameliorating, blocking, reducing, decreasing or inhibiting is about 100%, 99%, 98%, 97%, 96%, 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 10%, 5% or 1% versus a subject to which the composition has not been administered.
  • mice sera were taken seven days after the second boost.
  • ELISA data demonstrated that serum from mouse #4 (serum 4) had the best reactivity to the EpCam protein ( Figure 1).
  • Utilization of the monoclonal antibodies of the present invention furthermore allows for the practicing of a multi-protein assay to identify aggressive epithelial cancers including thyroid cancers.
  • mouse 4T1 cell lysates were separated by reducing SDS-PAGE (10% gel, 200v for half hour), transferred to 0.2 um PVDF membrane (lOOv for one hour), blocked and incubated overnight in a cold room with anti human-EpCAM mouse monoclonal antibody KalEpcam (dilution 1: 1000). After washing, blots were incubated with 1: 10000 HRP-conjugated goat anti-mouse IgG (Jackson Immuno Research) for one hour. The signal was detected using chemiluminescent detection with ImmunoStar (Bio-Rad).
  • Ep-ICD protein was separated by reducing SDS-PAGE, transferred to 0.2 um PVDF membrane, blocked and incubated overnight at 4 degrees Celsius with neat mouse anti-Ep-ICD hybridoma tissue culture supernatants. After washing, blots were incubated with 1:5000 diluted goat anti-mouse IgG (Jacksonlmmun, cat# 115-035-164) for one hour. The signal was detected using chemilumine scent detection with ImmunoStar (Bio-Rad). Eight hybridomas cell culture supernatants demonstrated good reactivity to the EpCam-ICD proteins, and one supernatant (7G4) also showed some reactivity to the EpCam-ICD-BSA protein.
  • the KalEpCAM2-producing hybridoma colony was further clonally expanded and the ascites produced thereby were purified using protein G affinity.
  • the protein G purified mAb was characterized using Western Blot based on the titration with ELISA, the results of which are presented below in Figure 7 and Figure 8.
  • KalEpCAM antibodies will also be evaluated in clinical studies in order to further evaluate the role of the EpCam-ICD in breast, prostate and colon cancer, with the objective of being able to clearly detect, at the early stage of tumor development, the presence of cells of these aggressive cancer types in patients through the use of the KalEpCam antibodies as a diagnostic tool.
  • EpCAM expression is an indicator of recurrence in basal-like breast

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Abstract

Cette invention concerne des anticorps ayant une spécificité de liaison au domaine intracellulaire (Ep-ICD) de la molécule d'adhésion des cellules épithéliales (EpCAM), notamment les anticorps KalEpCAMl, Kal-EpCAM2, Kal-EpCAM3 ou Kal-EpCAM4. L'invention concerne par ailleurs l'utilisation des anticorps dans des méthodes de dépistage, des méthodes de diagnostic du cancer et des méthodes de traitement du cancer.
PCT/IB2012/001017 2011-05-06 2012-05-04 Anticorps monoclonaux dirigés contre epcam-icd et méthodes de détection de cellules d'un cancer épithélial WO2012153186A2 (fr)

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US61/483,143 2011-05-06

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WO2012153186A2 true WO2012153186A2 (fr) 2012-11-15
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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2567235A1 (fr) * 2010-05-04 2013-03-13 Paul Walfish Procédé pour le diagnostic de cancers épithéliaux par détection de polypeptide epicd
WO2018019772A1 (fr) 2016-07-26 2018-02-01 Tessa Therapeutics Pte. Ltd. Récepteur d'antigènes chimérique
WO2022272050A1 (fr) * 2021-06-25 2022-12-29 Academia Sinica Polythérapie anticancéreuse avec un inhibiteur de molécule d'adhésion de cellules épithéliales (epcam) et un inhibiteur de wnt

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011032296A1 (fr) * 2009-09-21 2011-03-24 Mount Sinai Hospital Méthodes et compositions pour le diagnostic et le traitement du cancer de la thyroïde
WO2011137513A1 (fr) * 2010-05-04 2011-11-10 Paul Walfish Procédé pour le diagnostic de cancers épithéliaux par détection de polypeptide epicd

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011032296A1 (fr) * 2009-09-21 2011-03-24 Mount Sinai Hospital Méthodes et compositions pour le diagnostic et le traitement du cancer de la thyroïde
WO2011137513A1 (fr) * 2010-05-04 2011-11-10 Paul Walfish Procédé pour le diagnostic de cancers épithéliaux par détection de polypeptide epicd

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
BAEUERLE, P. A. ET AL.: 'EpCAM (CD326) finding its role in cancer.' BRITISH JOURNAL OF CANCER vol. 96, no. 3, 12 February 2007, ISSN 0007-0920 pages 417 - 423 *
MAETZEL, D. ET AL.: 'Nuclear signalling by tumour-associated antigen EpCAM.' NATURE CELL BIOLOGY. vol. 11, no. 2, February 2009, ISSN 1465-7392 pages 162 - 171 *
RALHAN, R. ET AL.: 'EpCAM nuclear localization identifies aggressive Thyroid Cancer and is a marker for poor prognosis.' BMC CANCER. vol. 10, 25 June 2010, ISSN 1471-2407 page 331 *
RALHAN, R. ET AL.: 'Nuclear and Cytoplasmic Accumulation of Ep-ICD Is Frequently Detected in Human Epithelial Cancers.' PLOS ONE. vol. 5, no. 10, 30 November 2010, ISSN 1932-6203 page E14130 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2567235A1 (fr) * 2010-05-04 2013-03-13 Paul Walfish Procédé pour le diagnostic de cancers épithéliaux par détection de polypeptide epicd
EP2567235A4 (fr) * 2010-05-04 2013-09-25 Paul Walfish Procédé pour le diagnostic de cancers épithéliaux par détection de polypeptide epicd
WO2018019772A1 (fr) 2016-07-26 2018-02-01 Tessa Therapeutics Pte. Ltd. Récepteur d'antigènes chimérique
WO2022272050A1 (fr) * 2021-06-25 2022-12-29 Academia Sinica Polythérapie anticancéreuse avec un inhibiteur de molécule d'adhésion de cellules épithéliales (epcam) et un inhibiteur de wnt

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