WO1998010783A1 - Le muc-1, agent therapeutique immunosuppresseur traitant les etats inflammatoires et auto-immunitaires - Google Patents

Le muc-1, agent therapeutique immunosuppresseur traitant les etats inflammatoires et auto-immunitaires Download PDF

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WO1998010783A1
WO1998010783A1 PCT/US1997/015928 US9715928W WO9810783A1 WO 1998010783 A1 WO1998010783 A1 WO 1998010783A1 US 9715928 W US9715928 W US 9715928W WO 9810783 A1 WO9810783 A1 WO 9810783A1
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muc
derivative
repeats
cells
icam
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B. Michael Longenecker
Judith C. Hugh
Lyle H. Regimbald
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Biomira Inc.
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Priority to EP97940948A priority Critical patent/EP0925071A4/fr
Priority to AU42613/97A priority patent/AU741258B2/en
Priority to JP10513781A priority patent/JP2001501599A/ja
Priority to CA002264748A priority patent/CA2264748A1/fr
Publication of WO1998010783A1 publication Critical patent/WO1998010783A1/fr

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Definitions

  • an object of the present invention to provide new methods for treating autoimmune disorders, inflammatory disorders, organ transplant rejection and graft versus host disease.
  • methods are provided which comprise administering a pharmaceutically effective amount of MUC-l, a MUC-1 derivative or a MUC-1 carbohydrate derivative to a patient in need of said treatment.
  • novel pharmaceutical compositions of new and effective medicaments to implement methods for treating autoimmune disorders, inflammatory disorders, organ transplant rejection and graft versus host disease.
  • compositions which comprise an amount of MUC-1, a MUC-1 derivative or a MUC-1 carbohydrate derivative effective for treating an autoimmune disorder, inflammatory disorder, organ transplant rejection or graft versus host disease, in combination with a pharmaceutically effective vehicle.
  • the MUC-1 derivative comprises multiple tandem repeats of the MUC-1 core sequence.
  • FIG. 1 shows expression of MUC-l at the surface of cultured murine (410.4) breast carcinoma cells transfected with the human MUC-1 gene as ascertained by flow cyto etry using the antibody B27.29. Note the high MUC-1 expression (fluorescence intensity) of MUC-lHi, which is approximately 2.5-fold higher than that of MUC-1 Lo, whereas the wild-type 410.4 cell line does not express MUC-1.
  • Figure 2 shows binding of MCF-7 cells to 4 hr stimulated HUVEC is inhibited most efficiently by anti-E selectin (Serotec 1.2B6) when endothelial monolayers are preincubated with monoclonal antibodies, and by anti-sLe ⁇ " (CSLEX & B67.4 sLe*) when MCF-7 cells are pretreated with monoclonal antibodies ( Figure 2a) .
  • Binding of MCF-7 cells to 24 hr stimulated HUVEC is inhibited by anti- ICAM-1 (Serotec 84H10) (endothelial pretreatment) and by anti-MUC-1 (B27.29) (MCF-7 pretreatment) ( Figure 2b).
  • Adhesion was assessed by a standard static endothelial adhesion assay described in Berry, et al . Br . J . Cancer 51:179 (1985). Results are expressed as a percentage of fluorescence signal from the total number of cells added to each well; each value represents the mean of three replicates +/- SD (error bars) ; " denotes wells coated with stimulated monolayers. The experiments shown are the best of three independent experiments of each type.
  • FIG. 3 shows high MUC-1 expressing transfectant
  • Figure 4a shows determination of serum MUC-1 levels by sandwich radioimmunoassay.
  • Figure 4b shows that lower serum MUC-1 levels correlate with longer survival time.
  • Figure 5 shows high MUC-1 expressing cells (GZHi) , which bind to immobilized recombinant soluble ICAM-1-Ig fusion protein and are inhibited by anti-MUC-1 (B27.29), anti- ICAM-1 (18E3D) , and soluble MUC-1.
  • Adhesion was measured as described in Ta ada, et al . Cancer Res . 53:354 (1993) . The values shown are the means of three replicates +/- SD; " denotes ICAM-1 coated wells. The experiment shown is the best of four independent experiments.
  • FIG. 6 shows high MUC-1-expressing cells (MUC-1 Hi) bind optimally to recombinant ICAM-1 (rhICAM-1) at 37°Ca. This adhesion mechanism is susceptible to almost complete inhibition at 4°C. Adhesion was measured and the results are expressed as described in the description to Figure
  • Figure 7 shows that addition of purified human MUC-l to the in vitro human T cell culture inhibits T cell proliferative response against strong allogenic stimulus.
  • FIG 8 panel a, shows the inhibition of T cell proliferation by the addition of 10 ug/ml of MUC-1 or a MUC-1 derivative, as compared to OSM or culture medium controls.
  • Panels b and c show the abrogation of mucin- mediated T cell inhibition by anti CD28 Mab and IL-2, respectively.
  • Figure 9 shows the direct relationship between the number of MUC-1 tandem core repeats and the inhibition of T cell proliferation.
  • the present invention relates to the use of MUC-1 and its derivatives to treat inflammatory or autoimmune disorders, based on the ability of MUC-1 to bind to ICAM- 1 and on evidence suggesting that MUC-1 has immunosuppressive effects in tumor models.
  • the present invention also relates to use of MUC-1 and its derivatives to suppress or prevent transplant rejection and graft versus host reactions. It is known that both inflammatory and autoimmune disorders are associated with a hyperreactive, or overreactive, immune response.
  • MUC-1 and its derivatives may be employed as immunosuppressive agents to treat these disorders by suppressing the overreactive immune response.
  • Mucins are a family of glycoproteins, greater than 200kDa. Some mucins, such as MUC-1, are membrane bound molecules with an extended extracellular domain composed of tandem repeats of amino acid (aa) sequences which contain numerous potential O-glycosylation sites.
  • mucinous tumor antigens both expressed on the cell surface of tumor cells and shed from the surface of tumor cells, are associated with a poor prognosis of a variety of cancer types. See, for example Itzkowitz, et al . Cancer 66: 1960 (1990).
  • MUC-1 Epithelial Membrane Antigen
  • MUC-1 is a well-characterized tumor cell surface mucin which is shed into the serum and carries repeating sialyl-Tn epitopes. See Cancer Research 47:5476 (1987) and Reddish, et al . Glycocon jugate Journal 13:1 (1996).
  • MUC- 1 is a highly glycosylated mucin type glycoprotein present on the luminal surface of most glandular epithelia and is often found increased over the entire surface of many carcinoma cells. This mucin extends far above the cell surface making it easily available for interactions with other cells.
  • MUC-1 is expressed in normal breast and in approximately 90% of breast cancers. MUC-1 is present as both a transmembrane form as well as in a secreted form. It is not known if both show similar patterns of glycosylation.
  • Mucins are known to lubricate mucosal surfaces providing protection, and cell surface mucins are thought to participate in cell-cell interactions. See Samuel and Longenecker J_n Vaccine Design : The Subunit and Adjuvant Approach , Powell, et al . , eds. (Plenum Press, N.Y. pp. 875-890 (1995)). Some investigators support an anti- adhesive function for MUC-1 through steric hindrance and negatively charged O-linked sialic acid residues. Ligtenberg, et al . Cancer Res . 52:2318 (1992).
  • the extracellular and cytoplasmic domains can support intercellular adhesion.
  • the extracellular domain is composed of 30 to 90 tandem repeats of a highly glycosylated twenty aa sequence.
  • the presence of numerous highly glycosylated tandem repeats allows MUC-1 to extend 200-500 run above the cell surface far beyond the surrounding 10-30 nm glycocalyx. This places it in an ideal position to enhance adhesion with those cells possessing the appropriate receptor(s).
  • Sialylated Lewis ⁇ / ⁇ residues which are also carried by MUC-1, mediate the adhesion of malignant colonic cells to E-Selectin. Sawada, et al . Int . J. Cancer 57: 901 (1994), Zhang, et al . Int .
  • ICAM-1 Intracellular Adhesion Molecule
  • B cells and T-cells and antigen presenting cells (APCs) where it participates in cell-cell interactions important for the induction of an immune response. It is also present in high levels on endothelial cells.
  • ICAM-1 CD 54 is found on most cells of the immune system, particularly on cytokine-activated cells, of both hemolytic and non-hemolytic origin fibroblasts and keratinocytes.
  • CD43 a highly glycosylated mucin type glycoprotein with no structural resemblance to the beta 2 integrins (CD lla/b with CD18) has been reported to bind ICAM-1. Rosenstein, et al . Nature 354: 233 (1991). This suggests that there is pliancy in the receptor- ligand recognition so that members of different receptor classes could interact. Thus, it is possible that MUC-1 mediates adverse effects through an interaction with adhesion molecules, such as ICAM-1. Support for an ICAM-l/MUC-1 interaction can be drawn from studies of cytotoxic T lymphocytes and MUC-1 transfected cells.
  • MUC-1 membrane-bound MUC-1
  • the mucin is also altered with fewer carbohydrate residues, thereby exposing usually cryptic epitopes on the protein core and interior carbohydrates.
  • This cancer-associated configuration forms the basis for anticancer immunotherapy. Longenecker, et al . The Immunologist 1:89 (1993), Agrawal, et al . Cancer Res . 55:2257 (1995).
  • MUC-1 is shed from tumor cells and is thus elevated in the serum, where it correlates with an unfavorable prognosis and possibly immunosuppression through the induction of T-cell anergy. Reddish et al . Cancer Immunol Immunother. 42:303-09 (1996).
  • soluble MUC-1 can competitively inhibit adhesive interactions of MUC-1-positive cells with ICAM-1 ( Figure 5) , it is possible that serum MUC-1 is inducing the anergic state by occupying ICAM-l receptors on cytotoxic T-cells (CTLs) .
  • CTLs cytotoxic T-cells
  • serum MUC-1 could also inhibit adhesive interactions of migrating cells with the endothelium and thus (a) cause decreased recruitment of inflammatory cells to the tumor site and (b) facilitate tumor cell escape and metastasis from the primary mass.
  • the MUC-1 used in the compositions and methods of this invention may be purified from sources such as cancer cell lines secreting MUC-1 and pleural effusions or ascites fluid from cancer patients. See Example 8.
  • the MUC-1 used in the methods of this invention may also be obtained by recombinant DNA techniques that are well known to those of skill in the art. See, for example Gendler, et al . , J . Biol Chem . 265:15286 (1990).
  • MUC-1 derivative is used to refer to a peptide that is structurally and/or functionally related to MUC-1. Such derivatives may retain some or all of the functional characteristics of MUC-1, in particular, the immunosuppressive function of MUC-1. The immunosuppressive function easily may be measured using the assays set for below in the Examples.
  • a MUC-1 derivative may be partially deglycosylated or completely unglycosylated MUC-1 protein. Deglycosylation of MUC-1 protein can be carried out using techniques that are well known to the skilled artisan.
  • a MUC-1 derivative may be a fragment of the MUC-1 protein. Such fragments may be glycosylated or unglycosylated.
  • fragments within the invention can be obtained from purified MUC-1 or MUC-1 produced by recombinant DNA methodology by methods that include digestion with enzymes such as pepsin or papain.
  • MUC-1 fragments encompassed by the present invention can be synthesized using an automated peptide synthesizer such as those supplied commercially by Applied Biosystems, Multiple Peptide Systems and others, or they may be produced manually, using techniques well known in the art. See Geysen et al . , J . Immunol . Methods 102: 259 (1978) .
  • MUC-1 derivatives also include glycosylated or non- glycosylated synthetic peptides.
  • MUC-1 derivatives within the present invention include proteolytic cleavage-resistant MUC-1 fragments or MUC-1 fragments containing one or more non-natural amino acids, such as D-amino acids.
  • the MUC-1 derivative would include the extracellular tandem repeat region of MUC-1, which includes repeats of the amino acid sequence DTRP (Asp-Thr-Arg-Pro) .
  • these tandem repeats include the sequence SAPDTRP (Ser-Ala-Pro-Asp-Thr-Arg- Pro) .
  • Some preferred MUC-1 derivatives comprise at least one peptide core repeat of the MUC-1 mucin.
  • a MUC-1 peptide core repeat in the native MUC-1 molecule comprises the 20 amino acid sequence PDTRPAPGSTAPPAHGVTSA (Pro-Asp-Arg-Thr-Pro-Ala-Pro-Gly-Ser-Thr-Ala-Pro-Pro-Ala- His-Gly-Val-Thr-Ser-Ala) .
  • Useful synthetic derivatives include permutations of this sequence, for example, GVTSAPDTRPAPGSTAPPAH, where the repeat merely begins with GVTS rather than PDTR. Other, similar permutations are also possible.
  • MUC-1 derivatives comprise at least one truncated peptide core repeat of the MUC-1 mucin, for example, GVTSAPDTRPAPGSTA.
  • GVTSAPDTRPAPGSTA truncated peptide core repeat of the MUC-1 mucin
  • Examples 8 and 9 demonstrate that fewer than 1 core repeat fails to exhibit the MUC-1 immunosuppressive function. But, where more than 1 repeat is present, it is observed that the degree of immunosuppression increases linearly with the number of repeats present. Thus, although an upper limit to the number of repeats that effectively can be employed is likely, MUC-1 derivatives containing very large numbers of repeats are contemplated. For example, the native MUC-1 contains 60-100 of such repeats.
  • MUC-1 derivatives contemplate from about 2 to about 100 core repeats.
  • more preferred MUC-1 derivatives comprise from 2-20 repeats of the MUC-1 core.
  • Most preferred MUC-1 derivatives comprise from 3-6 repeats of the MUC-1 core and the repeats preferably are arranged in tandem.
  • these preferred MUC-1 derivatives may be glycosylated or partially glycolysated according to methods known in the art.
  • MUC-1 and MUC-1 derivatives can be modified with large molecular weight polymers, such as polyethylene glycols.
  • an MUC-1 derivative within the present invention is a non-peptide "mimetic," i . e . , a compound that mimics one or more functional characteristics of the MUC-1 protein.
  • Mimetics are generally water-soluble, resistant to proteolysis, and non-immunogenic. Conformationally restricted, cyclic organic peptides which mimic MUC-1 can be produced in accordance with known methods described, for example, by Saragovi, et al . , Science 253: 792 (1991).
  • MUC-1 carbohydrate derivatives are also contemplated.
  • Such a derivative refers to a glycopeptide which retains at least one functional characteristic of MUC-1, such as immunosuppression.
  • Such a carbohydrate derivative may include all or part of the carbohydrate that is attached to the MUC-1 protein. Mimetics that mimic at least one property of MUC-1 carbohydrate may also be used.
  • MUC-1 derivatives may be designed to block ICAM-1-mediated cell interactions to effect immunosuppression.
  • T-cells interact via T-cell receptors (TCRs) , with antigen-presenting cells (APCs) .
  • APCs antigen-presenting cells
  • TCRs T-cell receptors
  • APCs antigen-presenting cells
  • a number of other interactions between APCs and TCR are required, using various accessory molecules (co-receptors) . Interaction of accessory molecules is important in a T-cell response because these interactions (1) increase the avidity of interaction between the APC and the T-cell and (2) induce various intracellular signal pathways in the T-cells.
  • MUC-1 or its derivatives can be used as immunosuppressive agents: when MUC-1 or its derivatives interacts with and cross-links ICAM-1 molecules in the absence of an antigenic stimulus, this results in nonresponsiveness (immunosuppression) of the
  • MUC-1 derivatives may be designed to block MUC-l/ICAM-1 interactions which will reduce the ICAM-1-mediated cellular immune response.
  • such blocking MUC-1 derivatives may be designed by using MUC-1 derivative binding to recombinant human (rh) ICAM-1-immunoglobulin (Ig) fusion protein. In this method, the fusion protein is immobilized in the solid phase. Libraries of synthetic MUC-1 peptides, glycopeptides and glycoconjugates based on the MUC-1 tandem repeat can be screened for blocking activity. Those compounds that partially or completely block MUC-1 binding to ICAM-1 may be screened for therapeutic effectiveness.
  • the multiple copies of the MUC-1 tandem repeat contained in the MUC-1 protein may be able to cross-link several ICAM-1 molecules, leading to immune suppression.
  • the "libraries" of synthetic peptides containing a single copy of the tandem repeat should not produce this effect. Similarly, those peptides that contain less than an entire tandem repeat should not produce this effect.
  • the data presented below in Examples 8 and 9 support this view.
  • the derivatives can be further evaluated using a T-cell based immune suppression system.
  • T-cell based immune suppression system determines the ability of a derivative to prevent in vitro T-cell induction.
  • MUC-1 interacts with ICAM-1, and is expected to react with other adhesion molecules such as ICAM-3 , various MUC-1 derivatives should be useful as drugs that block the MUC-1/adhesion molecule interaction.
  • adhesion inhibitors could be used to treat cancer patients who are immunosuppressed by MUC-1 mucin.
  • compositions of the invention generally contain a pharmaceutically effective amount of MUC-1, a MUC-1 derivative or a MUC-1 carbohydrate derivative.
  • MUC-1, a MUC-1 derivative or a MUC-1 carbohydrate derivative is admixed with a pharmaceutically effective vehicle (excipient) .
  • a suitable formulation will depend on the nature of the disorder to be treated, the nature of the medicament chosen, the route of administration desired and the judgment of the attending physician. Suitable formulations and pharmaceutically effective vehicles, can be found, for example, in REMINGTON'S PHARMACEUTICAL SCIENCES, chapters 83-92, pages 1519-1714 (Mack Publishing Company 1990) (Remington's), which are hereby incorporated by reference.
  • MUC-1, a MUC-1 derivative or a MUC-1 carbohydrate derivative may be used to treat autoimmune disorders and inflammatory disorders. MUC-1 may also be used to prevent or suppress organ transplantation rejection and graft versus host disease in bone marrow transplantation.
  • the methods of the invention typically comprise administering a pharmaceutically effective amount of MUC- 1, a MUC-1 derivative or a MUC-1 carbohydrate derivative to a patient in need of treatment.
  • the patient may be a human or non-human animal.
  • an "inflammatory disorder” refers to any of the many inflammatory disorders that are well known to those of skill in the art. These disorders include, but are not limited to, the following disorders: inflammatory arthritis such as rheumatoid arthritis, psoriasis, allergies such as allergic contact dermatitis, and ankylosing spondylitis.
  • an "autoimmune disorder” refers to any of the many autoimmune disorders that are well known to those of skill in the art. These disorders include, but are not limited to, the following disorders: myasthenia gravis, systemic lupus erythematosus, polyarteritis nodosa, Goodpastures syndrome, isopathic thro bocytopenic purpura, autoimmune hemolytic anemia, Grave's disease, rheumatic fever, pernicious anemia, insulin-resistant diabetes mellitus, bullous pemphigold, pemphigus vulgaris, viral myocarditis (Cocksakie B virus response), autoimmune thyroiditis (Hashimoto's disease) , male infertility (autoimmune) , sarcoidosis, allergic encephalomyelitis, multiple sclerosis, Sjorgens disease, Reiter's disease, Celiac disease, sympathetic ophthalmia, and primary biliary cirrhosis.
  • Intracapsular, intravenous, intrathecal, and intraperitoneal routes of administration of MUC-1 and its derivatives may be employed.
  • the skilled artisan will recognize that the route of administration will vary depending on the disorder to be treated.
  • intracapsular administration may be used when treating arthritis.
  • Injection into the hepatic portal vein may be employed when treating inflammatory hepatitis.
  • Intra- organ injection of the thyroid may be used when treating thyroiditis.
  • Either intravenous or intraperitoneal administration may be used when treating autoimmune diseases of the gastrointestinal tract, such as pancreatitis or colitis.
  • Intrathecal administration may be appropriate when treating autoimmune encephalitis.
  • Intravenous or intra-organ injections may be employed to prevent or suppress transplant rejections, such as kidney transplants.
  • treating in its various grammatical forms in relation to the present invention refers to preventing, curing, reversing, attenuating, alleviating, minimizing, suppressing or halting the deleterious effects of a disease state, disease progression, disease causative agent (e.g., bacteria or viruses) or other abnormal condition.
  • disease causative agent e.g., bacteria or viruses
  • MUC-1 a pharmaceutically effective amount of MUC-1, a MUC-1 derivative or a MUC-1 carbohydrate derivative
  • a pharmaceutically effective amount of MUC-1, a MUC-1 derivative or a MUC-1 carbohydrate derivative is well within the purview of the skilled clinician and largely will depend on the exact identity of the inventive compound, particular patient characteristics, route of administration and the nature of the disorder being treated. General guidance can be found, for example, in the publications of the International Conference on Harmonisation and in REMINGTON'S PHARMACEUTICAL SCIENCES, chapters 27 and 28, pp. 484-528 (Mack Publishing Company 1990) .
  • Determining a pharmaceutically effective amount specifically will depend on such factors as toxicity and efficacy of the medicament. Toxicity may be determined using methods well known in the art and found in the foregoing references. Efficacy may be determined utilizing the same guidance in conjunction with the methods described below, for example, in Examples 8 and 9. A pharmaceutically effective amount, therefore, is an amount that is deemed by the clinician to be toxicologically tolerable, yet efficacious.
  • mice bearing MUC-1 transfected tumor cells (which secrete MUC-1 into the serum) who develop the highest serum MUC-1 levels following tumor transplantation are the mice showing the shortest survival time compared to mice who had non- detectable levels of serum MUC-1 following tumor transplantation.
  • MUC-1 Hi cells were transplanted subcutaneously and tumors developed in over 90% of the mice within 6-8 weeks. Mice were followed for survival and serum MUC-1 levels were measured at various times following tumor transplant.
  • Figure 4a shows that the 8 mice that died before day 63 had higher serum MUC-1 levels than those that survived to day 63.
  • Figure 4b shows that of the 8 mice who died before day 63, there was a significant direct association between MUC-1 level and survival time.
  • Example 2 This example shows that intravenous injection of
  • MUC-1 mucin made mice more susceptible to the tumor transplant of human MUC-1 transfected tumor cells.
  • the procedures employed in this example are similar to those described in Fung, et al . Cancer Research 51: 1170-1176 (1991) , which is hereby incorporated by reference.
  • the human MUC-1 system was used instead of the epiglycanin system.
  • CB6 mice were injected intravenously with MAb B27.29 affinity purified MUC-1 mucin (20 micrograms each treatment or approximately 400 units) prior to (day-2) and after (days +2 and +6) an attempted tumor challenge.
  • Affinity purified mucin had been prepared by affinity adsorption on a B 27.29 CnBr-Sepharose matrix from a pleural effusion fluid obtained from a patient with adenocarcinoma of the ovaries.
  • MUC-1 mucin treated and control mice were challenged with lxlO 6 GZ-Hi tumor cells injected into the subcutaneous space along the flank. Mice were observed by palpation and visual inspection at the injection site for the occurrence of tumors over a period of 8 weeks.
  • This example shows that adding purified human MUC-1 mucin to human T-cell cultures strongly inhibits T-cell proliferation against a strong allo-antigenic stimulus in vitro.
  • the mixed lymphocyte reaction is conducted by mixing the lymphocytes of HLA disparate individuals in in vitro tissue cultures.
  • the "responder population” in this experiment is purified T-cells from one population, while the “stimulator” population in this experiment is the adherent antigen presenting cells obtained from an HLA mismatched individual donor.
  • the two cell populations were mixed and cultured either in the presence or absence of various doses of B27.29 affinity purified MUC-1 mucin that was purified from a pleural effusion fluid. The results of this experiment are presented in Figure 7.
  • MUC-1 mucin binds to ICAM-1.
  • ICAM-1-Ig fusion protein binds to the peptide core of the tandem repeat sequence of the MUC-1 molecule thereby implicating MUC-1 in breast cancer metastases and immune suppression.
  • MUC-1 preferentially localizes to free membrane surfaces including a peripheral ensheathing pattern of staining on the surface of intravascular tumor emboli.
  • Tumor emboli stained for MUC-1 using the DAB immunoperoxidase technique showed intense peripheral staining in contrast to solid tumor nests which show a diffuse cytoplasmic staining pattern. There was uneven staining along the endothelial surface, which probably represents shed antigen.
  • Tumor cell - endothelial cell adhesion assay Endothelial cell monolayers were grown in 24 well tissue culture plates and stimulated with 20 U/mL TNF ⁇ + 20 U/mL IL-l ⁇ (Phariningen) for 4 or 24 hr. To these plates BCECF AM ester (Molecular Probes) fluorescent dye labeled tumor cells (1.5 x 10 5 /5OOuL/well) were added and incubated for 25 in. at 37 C. Non - specifically adherent cells were removed by vigorous agitation (shaker at 175 rp ) and peripheral aspiration. Remaining adherent cells were then lysed with detergent (NP-40) for
  • Tumor cell - immobilized ICAM-1 adhesion assay 96 well tissue culture plates were coated with 50 uL of a solution with 20 ug/mL recombinant soluble ICAM-1 in PBS for 1 hr at room temperature. Wells were then blocked with 1% BSA for 2 hr at 37 C and washed four times with PBS. Antibodies (10 ug/mL) (anti-ICAM-1 164B, 18E3D, 84H10, anti-E selectin 1.2B6) and soluble MUC-1 (10 ug/mL) were added to the wells for 90 min. at room temperature. Wells were then washed again before addition of cells.
  • BCECF labeled tumor cells were pretreated +/- 20 ug/mL of anti-MUC-1 (B27.29, or DF3P) and were then added to the appropriate wells for 40 min. at 37 C. Wells were then washed and percent adhesion was then determined as described in the tumor cell - endothelial cell adhesion assay.
  • results A series of monoclonal antibodies were screened for their ability to inhibit the binding of a human breast carcinoma cell line (MCF-7) to human umbilical vein endothelial cell (HUVEC) monolayers which had been stimulated with IL-I ⁇ and TNF- ⁇ . Consistent with other studies of epithelial cancer cell lines, following four hour cytokine stimulation of the HUVECs, antibodies to E selectin or its ligands (SLe ⁇ ) showed the greatest inhibition of adhesion of the MCF-7' s to the HUVECs (Fig. 2a) . Antibody to ICAM-1 (84H10) also showed inhibition but much less than that obtained by anti-E selectin (1.2B6). An antibody to MUC-1 (B27.29), had no effect.
  • MCF-7 human breast carcinoma cell line
  • HUVEC human umbilical vein endothelial cell
  • Fig. 3a shows an increase in adhesion with increasing MUC-1 expression with GZHi showing a two fold increase in adhesion over GZLo and a four fold increase over the wild type (410.4) .
  • This adhesion was inhibited by antibodies to MUC-1 (B27.29) and ICAM-1 (18E3D) while anti-E selectin and control antibodies (CD31) showed no effect (Fig. 3b).
  • the adhesion of the MUC-1 transfectants was studied using immobilized recombinant human ICAM-1-Ig fusion protein.
  • MUC-1 expressing cells to a collagen type I control in subsequent experiments.
  • Pretreatment of the ICAM-1 coated wells with soluble MUC-1 was equally effective at blocking adhesion of GZHi to ICAM-1.
  • ICAM-1 immunoglobulin superfamily member
  • a possible binding site on MUC-1 for ICAM-1 is suggested by the inhibition of the interaction by B27.29.
  • This antibody recognizes a limited sequence of the MUC-1 core peptide tandem repeat which encompasses that recognized by SM3. Reddish, et al . Tumor Marker One 7: 19 (1992). This implicates the core peptide sequence of the tandem repeat as the binding site for ICAM-1.
  • ICAM-3 A molecule with considerable sequence homology to ICAM-1 is ICAM-3. This adhesion molecule shows a unique pattern of expression and is found typically only in the new vasculature of solid tumors and in certain vascular hyperplasias. Patey, et al . Am . J. Pathol . 148: 465-472 (1996) .
  • Example 4 Using the procedures described in Example 4 , the ability of MUC-1 to bind to ICAM-3 is assessed. Once it has been determined that ICAM-3 binds to MUC-1, various treatment regimens can be developed based on the ICAM-
  • Example 4 Using the procedures described in Example 4 , the ability of MUC-1 to bind to other adhesion molecules is assessed. Once adhesion molecules have been identified that bind to MUC-1, various treatment regimens can be developed.
  • autoimmune disease is myasthenia gravis.
  • a patient produces antibodies to the acetylcholine receptor at the neuromuscular junction. This production of antibodies is dependant upon the active participation of CD+helper T cells.
  • CD+helper T cells These T cells are activated by antigen presenting cells that express ICAM-1 which interacts with T cell LFA-1 forming an adhesion between APC and T cells. Blocking of this interaction will prevent T cell activation and the subsequent T cell help needed for the disease manifesting antibody response.
  • CD4+T cell population In the case of inflammatory arthritis a CD4+T cell population is known to invade the synovium of effected joints and to produce the pro-inflammatory cytokines TNF and interferon gamma. These cytokines then induce resident synovial cells to produce collagenase and other hydrolytic enzymes that degrade of collagen and destroy tendons cartilage and ligaments. The activation of these CD4 T cells requires ICAM-1 interaction with antigen presenting cells. This interaction could be blocked by the intrasynovial (or systemic) administration of a pharmaceutically effective amount of MUC-1, a MUC-1 derivative or a MUC-1 carbohydrate derivative, thereby blocking the T cell activation and subsequent production of the pro-inflammatory cytokine mediators of this crippling disease.
  • This example demonstrates the ability of synthetic peptides, having multiple tandem repeats of the MUC-1 core, to inhibit T cell proliferation.
  • MUC-1 was purified from ascites fluid obtained from ovarian cancer patients. 2M sodium acetate at pH 5 was added to the ascites fluids and centrifuged for 30 minutes at 20krpm. After filtration through a 0.45 micron cellulose acetate filter, the solution was mixed with B27.29 Mab (Reddish et al . , J. Tumor Marker Oncol. 7:19-27 (1992)) CNBr coupled to sepharose 4B overnight, followed by washing with 1M NaCl/PBS. The affinity bound MUC-1 mucin was eluted with 50 mM diethanola ine (Fisher purified) in 150 mM NaCl at pHll.
  • the eluant was neutralized with 2M sodium acetate at pH 5.
  • the affinity purified material was dialyzed against PBS and then sterile filtered with Nalgene 0.2 micron cellulose acetate syringe filter.
  • the affinity purified MUC-1 mucin was quantitated by using Truquant BR RIA assay (Biomira Diagnostics Inc., Roxdale, ON, Canada). For the calculation of amount of MUC-1 mucin, the conversion formula 1 BR unit as approximately 50 ng of MUC-1 mucin, was used.
  • Synthetic MUC-l derivatives contained l, 3, 4, 5 or 6 tandem repeats of the MUC-1 core and were approximately 16, 60, 80, 100 and 120 amino acids in length.
  • the 16- mer contained the sequence GVTSAPDTRPAPGSTA.
  • the other derivatives contained tandem repeats of the sequence
  • Ovine submaxillary mucin was employed as a control.
  • Enriched T cell populations were purified from buffy coats obtained from normal red cross donors using nylon wool columns by previously reported procedures. See, e.g., Agrawal et al . , J. Immunol. 157: 2089-95 (1996) and
  • mito ycin C treated allogeneic PBLs were cocultured with purified T cells in the presence or absence of affinity purified MUC-1 mucin or control OSM.
  • the T cells were cultured 6-7 days in AIM V medium in the absence or presence of MUC-1, MUC-1 derivative or OSM at the indicated concentration. After this time, the T cells were harvested, washed and cultured as indicated.
  • T cells (10 6 /ml) were cultured in AIM V medium with allo PBLs in the absence or presence of MUC- 1, MUC-1 derivative or OSM 10 ug/ml for 6-7 days. T cells were harvested and plated in 96 well flat bottom plates at 10 5 / ell with allo PBLs (l0 5 /well) , in the presence or absence of affinity purified MUC-1, MUC-l derivative or OSM. Control cultures were treated with either 50 U/ml IL-2 or 1 ug/ml anti-CD28 Mab. After 4 days of culture, 3 H-thymidine (1 uCi/well) was added.
  • the cells were harvested on the fifth day and 3 H- thy idine incorporation was measured by liquid scintillation.
  • Table 2 demonstrates the statistical significance of these data compared to the OSM control.
  • Example 2 illustrates the direct correlation of number of tandem repeats with the inhibit T cell proliferation. The methods used are described in Example
  • Synthetic peptides as described in Example 8, corresponding to 3, 4, 5 or 6 MUC-1 repeats, were added at 10 ug/ml to allo cultures and T cell proliferation was measured at 14 days from the start of culture. Because the same amount of each peptide was present in each well, all samples contained the same total number of individual repeats. Thus, the only difference was the number of repeats tandemly joined in the peptide. In other words, any effect observed is a result of the oligomeric nature of the repeats, not the absolute number of them.

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Abstract

L'invention porte sur de nouveaux modes de traitement et de nouvelles préparations pharmaceutiques à base de mucine MUC-1 et de ses dérivés. Les dérivés préférés comportent de multiples unités répétées en tandem de la séquence coeur du MUC-1. La figure montre que de faibles taux sériques de MUC-1 sont en relation avec une survie plus longue. Les préparations pharmaceutiques et procédés de l'invention sont particulièrement intéressants pour traiter les troubles de nature auto-immunitaire et inflammatoires, le rejet des greffes et les problèmes greffon/organisme récepteur.
PCT/US1997/015928 1996-09-10 1997-09-10 Le muc-1, agent therapeutique immunosuppresseur traitant les etats inflammatoires et auto-immunitaires WO1998010783A1 (fr)

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EP97940948A EP0925071A4 (fr) 1996-09-10 1997-09-10 Le muc-1, agent therapeutique immunosuppresseur traitant les etats inflammatoires et auto-immunitaires
AU42613/97A AU741258B2 (en) 1996-09-10 1997-09-10 MUC-1 as an immunosuppressive therapeutic agent for the treatment of inflammatory and autoimmune conditions
JP10513781A JP2001501599A (ja) 1996-09-10 1997-09-10 炎症性疾患および自己免疫疾患の治療のための免疫抑制治療薬としてのｍｕｃ―１
CA002264748A CA2264748A1 (fr) 1996-09-10 1997-09-10 Le muc-1, agent therapeutique immunosuppresseur traitant les etats inflammatoires et auto-immunitaires

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0964694A1 (fr) * 1996-10-25 1999-12-22 Dana-Farber Cancer Institute, Inc. Immunomodulation induite par la mucine
WO2000034468A2 (fr) * 1998-12-11 2000-06-15 Biomira Inc. Antagonistes de la muc-1 et methodes de traitement de troubles immunitaires
WO2002038168A2 (fr) * 2000-11-07 2002-05-16 Nemod Immuntherapie Ag Utilisation de proteines produites pendant la grossesse, fixant la selectine, de liposomes, de fragments de mucine natifs et de composes mimetiques pour traiter et prevenir des maladies infectieuses, pour empecher la metastatisation et pour prevenir des maladies tumorales
WO2002062319A2 (fr) * 2001-01-19 2002-08-15 Corixa Corporation Administration sous forme de microspheres de peptides de mucine
WO2004009632A2 (fr) 2002-07-22 2004-01-29 Nemod Immuntherapie Ag Procede de production d'une mucine immunostimulatrice (muc1)
US9095551B2 (en) 2009-01-29 2015-08-04 Riken Combined preparation for treating joint diseases

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995003825A1 (fr) * 1993-07-30 1995-02-09 Finn Olivera J Peptides synthetiques a repetitions en tandem multiples, a base de mucine et d'analogues, et utilisations

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* Cited by examiner, † Cited by third party
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JP2001502907A (ja) * 1996-10-25 2001-03-06 ダナ―ファーバー キャンサー インスティテュート インク． ムチンが介在した免疫調節

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995003825A1 (fr) * 1993-07-30 1995-02-09 Finn Olivera J Peptides synthetiques a repetitions en tandem multiples, a base de mucine et d'analogues, et utilisations

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP0925071A4 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0964694A1 (fr) * 1996-10-25 1999-12-22 Dana-Farber Cancer Institute, Inc. Immunomodulation induite par la mucine
EP0964694A4 (fr) * 1996-10-25 2000-09-13 Dana Farber Cancer Inst Inc Immunomodulation induite par la mucine
WO2000034468A2 (fr) * 1998-12-11 2000-06-15 Biomira Inc. Antagonistes de la muc-1 et methodes de traitement de troubles immunitaires
WO2000034468A3 (fr) * 1998-12-11 2000-11-16 Biomira Inc Antagonistes de la muc-1 et methodes de traitement de troubles immunitaires
WO2002038168A2 (fr) * 2000-11-07 2002-05-16 Nemod Immuntherapie Ag Utilisation de proteines produites pendant la grossesse, fixant la selectine, de liposomes, de fragments de mucine natifs et de composes mimetiques pour traiter et prevenir des maladies infectieuses, pour empecher la metastatisation et pour prevenir des maladies tumorales
WO2002038168A3 (fr) * 2000-11-07 2004-06-10 Nemod Immuntherapie Ag Utilisation de proteines produites pendant la grossesse, fixant la selectine, de liposomes, de fragments de mucine natifs et de composes mimetiques pour traiter et prevenir des maladies infectieuses, pour empecher la metastatisation et pour prevenir des maladies tumorales
WO2002062319A2 (fr) * 2001-01-19 2002-08-15 Corixa Corporation Administration sous forme de microspheres de peptides de mucine
WO2002062319A3 (fr) * 2001-01-19 2003-03-27 Corixa Corp Administration sous forme de microspheres de peptides de mucine
WO2004009632A2 (fr) 2002-07-22 2004-01-29 Nemod Immuntherapie Ag Procede de production d'une mucine immunostimulatrice (muc1)
US9095551B2 (en) 2009-01-29 2015-08-04 Riken Combined preparation for treating joint diseases

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