EP1984004A2 - Glucane permettant d'améliorer une thérapie - Google Patents

Glucane permettant d'améliorer une thérapie

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Publication number
EP1984004A2
EP1984004A2 EP07718218A EP07718218A EP1984004A2 EP 1984004 A2 EP1984004 A2 EP 1984004A2 EP 07718218 A EP07718218 A EP 07718218A EP 07718218 A EP07718218 A EP 07718218A EP 1984004 A2 EP1984004 A2 EP 1984004A2
Authority
EP
European Patent Office
Prior art keywords
cancer
glucan
antibody
subject
beta
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP07718218A
Other languages
German (de)
English (en)
Other versions
EP1984004A4 (fr
Inventor
Rolf Einar Engstad
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Arcticzymes Technologies ASA
Memorial Sloan Kettering Cancer Center
Original Assignee
Biotec Pharmacon ASA
Sloan Kettering Institute for Cancer Research
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US11/334,763 external-priority patent/US7906492B2/en
Application filed by Biotec Pharmacon ASA, Sloan Kettering Institute for Cancer Research filed Critical Biotec Pharmacon ASA
Publication of EP1984004A2 publication Critical patent/EP1984004A2/fr
Publication of EP1984004A4 publication Critical patent/EP1984004A4/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001103—Receptors for growth factors
    • A61K39/001106—Her-2/neu/ErbB2, Her-3/ErbB3 or Her 4/ErbB4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001111—Immunoglobulin superfamily
    • A61K39/001113—CD22, BL-CAM, siglec-2 or sialic acid- binding Ig-related lectin 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001124—CD20
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001102—Receptors, cell surface antigens or cell surface determinants
    • A61K39/001129—Molecules with a "CD" designation not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/0005—Vertebrate antigens
    • A61K39/0011—Cancer antigens
    • A61K39/001169—Tumor associated carbohydrates
    • A61K39/001171—Gangliosides, e.g. GM2, GD2 or GD3
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/39533—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals
    • A61K39/39558—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum against materials from animals against tumor tissues, cells, antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07K16/3076—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 against structure-related tumour-associated moieties
    • C07K16/3084—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 against structure-related tumour-associated moieties against tumour-associated gangliosides
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L5/00—Compositions of polysaccharides or of their derivatives not provided for in groups C08L1/00 or C08L3/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/54—Medicinal preparations containing antigens or antibodies characterised by the route of administration
    • A61K2039/541—Mucosal route
    • A61K2039/542—Mucosal route oral/gastrointestinal
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55583—Polysaccharides

Definitions

  • Glucans are a heterogeneous group of glucose polymers found in the cell walls of plants, bacteria and fungi.
  • the basic structure of branched glucan consists of a linear backbone of ⁇ -l,3-linked glucose with ⁇ -1, 6-linked side branches of ⁇ -l,3-glu ⁇ an, ⁇ -l,3-glucan is the component responsible for the majority of biological activities of zymosan, a commonly used leukocyte stimulant derived from the cell wall of Bakers yeast (Saccharomyces cerevisiae) .
  • Beta-glucans have been tested for tumor therapy in mice for nearly 40 years 1 ' 2 .
  • Several forms of mushroom- derived beta-glucans are used clinically to treat cancer in Japan, including PSK (from Coriolus versicolor) , Lentinan and Schizophyllan.
  • PSK has moderately improved survival rates in some cancer trials after gastrectomy 3 ' 4 , colorectal surgery 5 ' 5 , and esophagectomy 7 to remove primary tumors. Results have i>een less encouraging in breast cancer 8 ' 9 and leukemia 10 .
  • Schizophyllan also moderately improved survival of patients with operable gastric cancer 11 , inoperable gastric cancer 12 ' 13 , and cervical cancer 14 .
  • beta-glucans are not widely used by Western oncologists, beta-glucan containing botanical medicines such as Reishi and maitake 15 are widely used by U.S. cancer patients as alternative/complementary cancer therapies.
  • beta-glucans especially from Bakers' yeast have long been employed as feed additives for animals, as dietary supplement for humans 17 , in treatment of wounds 18 , and as an active ingredient in skin cream formulations.
  • the basic structural unit in beta-glucans is the ⁇ (l-»3) -linked glucosyl units.
  • beta-glucans have various degrees of branching and of linkages in the side chains. The frequency and hinge-structure of side chains determine its immunomodulatory effect.
  • Beta-glucans of fungal and yeast origin are normally insoluble in water, but can be made soluble either by acid hydrolysis or by derivatization introducing charged groups like -phosphate, -sulphate, amine, -carboxymethyl and so forth to the molecule 19"20 .
  • This invention provides a composition comprising an effective amount of yeast beta-glucan capable of enhancing immune responses in a subject or a host.
  • the enhanced immune responses are antitumor immune responses, which can be induced or initiated by various techniques or procedures generally known in the art.
  • antitumor immune responses can be induced by antitumor antibodies, cancer vaccines, or other compositions intended to induce immune responses against cancer.
  • the present invention provides a yeast beta-glucan composition capable of enhancing the efficacy of antitumor antibodies and/or their derivatives.
  • the present invention provides a yeast beta-glucan composition capable of enhancing the efficacy of cancer vaccines, or the efficacy of other compositions intended to induce immune responses against cancer.
  • Antibodies as used herein refer to any part of immunoglobulin molecules (e.g. a monoclonal antibody) having specific cancer cell binding affinity by which they are able to exercise anti-tumor activity. Examples are antigen binding fragments or derivatives of antibodies.
  • the antibody used in the present invention can be a single monoclonal antibody or a combination of antibodies .
  • the antibodies may be directed to at least one epitope or multiple epitopes of an antigen or multiple antigens. Accordingly, this invention encompasses at least one antibody.
  • the cancer recognized by antibodies includes, but not limited to, neuroblastoma, melanoma, non-Hodgkin 1 s lymphoma, Epstein-Barr related lymphoma, Hodgkin's lymphoma, retinoblastoma, small cell lung cancer, brain tumors, leukemia, epidermoid carcinoma, prostate cancer, renal cell carcinoma, transitional cell carcinoma, breast cancer, ovarian cancer, lung cancer colon cancer, liver cancer, stomach cancer, and other gastrointestinal cancers.
  • This invention further provides the above compositions and a pharmaceutically acceptable carrier, thereby forming pharmaceutical compositions.
  • This invention also provides a method for treating a subject with cancer, comprising administrating the above- described composition to the subject.
  • the present invention provides a method for enhancing tumoricidal activities of antitumor antibody in a subject having cancer.
  • cancer include, but are not limited to, neuroblastoma, melanoma, non-Hodgkin' s lymphoma, Epstein-Barr related lymphoma, Hodgkin's lymphoma, retinoblastoma, small cell lung cancer, brain tumors, leukemia, epidermoid carcinoma, prostate cancer, renal cell carcinoma, transitional cell carcinoma, breast cancer, ovarian cancer, lung cancer, colon cancer, liver cancer, stomach cancer, or other gastrointestinal cancers .
  • the above method comprises the steps of (a) administering to the subject antitumor antibody that binds to cancer cells in the subject; and (b) administering orally to the subject a composition comprising an effective amount of yeast glucan, wherein the orally administered glucan enhances tumoricidal activities of the antibody.
  • the antibody is a monoclonal antibody. More preferably, the antibody is capable of activating complement or activating antibody dependent cell-mediated cytotoxicity.
  • Representative examples of antitumor antibodies include, but are not limited to, antibodies that recognize CD20, CD22, HER-2/neu, CD25, epidermal growth factor receptor, or gangliosides .
  • the yeast glucan used in the above method has an average molecular weight of about 16,000 to about 17,000 daltons, with a range from about 6,000 to about 30,000 daltons, or from about 6,000 to about 25,000 daltons .
  • the yeast glucan can be administered at the same or different time as the administration of the antitumor antibody.
  • the yeast glucan is capable of priming or inducing secretion of cytokines, chemokines or growth factors by leukocytes .
  • the present invention also provides a therapeutic regimen for a subject having cancer, the regimen comprising a cooperative anti-cancer effect resulting from administering to a subject in need thereof: (i) antitumor antibody that binds to cancer cells in the subject, or a cancer vaccine composition intended to induce antitumor immune responses; and (ii) an effective amount of yeast glucan which is administered to the subject orally, wherein the orally administered glucan enhances tumoricidal activities of the antibody or the cancer vaccine composition.
  • the yeast glucan can be administered at the same or different time as the administration of the antitumor antibody or the cancer vaccine. Examples of antitumor antibodies and yeast glucan have been described above.
  • cancer vaccine examples include whole tumor cells, tumor cell lysates, tumor cell derived RNAs, tumor cell derived proteins, tumor cell derived peptides, tumor cell derived carbohydrates, tumor cell derived lipids, tumor cell derived DNA sequences and gene modified tumor cells, either clinically synthesized or recombinant products to serve as tumor anti-genes.
  • tumor cells could be derived from a patient's own tumor or tumor from an unrelated donor.
  • the present invention also provides uses of an effective amount of yeast glucan for preparing an anti-cancer pharmaceutical composition.
  • the glucan is administered to a subject orally to enhance tumoricidal activities in the subject.
  • the anti-cancer pharmaceutical composition may further comprise antitumor antibodies that bind to cancer cells in the subject, or a cancer vaccine composition intended to induce antitumor immune responses.
  • the yeast glucan can be administered to a subject at the same or different time as the administration of the antitumor antibody or the cancer vaccine . Representative examples of antitumor antibodies, cancer vaccine, and yeast glucan have been described above .
  • Figure 1 shows treatment of disseminating human lymphoma in SCID mice using Rituxan and barley or yeast ⁇ - glucan.
  • Five millions Daudi cells in 100 ⁇ l normal saline were injected intravenously (i.v.) into SCID mice. Tumors grew systemically and the mice became paralyzed when tumor cells infiltrated the spinal canal, resulting in hind-leg paralysis. The mice were sacrificed at the onset of paralysis or when the animals lost' 10% of their body weight. Therapy was initiated ten days after injection of tumor cells.
  • rituximab Genentech, San Francisco, CA
  • 400 ⁇ g glucan was administered orally via intragastric gavage daily for 29 days.
  • the mice were weighed weekly and observed clinically at least once daily.
  • Mice receiving rituxan plus barley glucan or rituxan plus yeast soluble glucan have a highly significant prolonged survival (p ⁇ 0.05) .
  • FIG. 2 shows 1 H NMR spectrum of a typical SBG (Soluble Beta Glucan) sample (Biotec Pharamacon ASA, Troms ⁇ , Norway) .
  • a SBG sample was dissolved in DMSO-d e at a concentration of approximately 20 mg/ml and with a few drops of TFA-d added.
  • the spectrum (cut-out from 2.7 to 5.5 ppm) was collected over 2 hours on a JEOL ECX 400 NMR spectrometer at 80 0 C. Chemical shifts were referenced to residual proton resonance from the DMSO-d 6 at 2.5 ppm, and the spectrum was baseline corrected.
  • Figure 3 shows viscosity profile of SBG. Profiles for a 2% solution of SBG at 20 or 30 0 C at different shear rates were shown. Glycerol (87%) was used as reference solution.
  • Figure 4 shows beta-glucan comprising a beta-1,3- linked backbone.
  • Figure 5 shows beta-1, 3-glucans isolated from yeast with beta-1, 3-linked side chains anchored to the main chain through beta-1, 6 -linkage .
  • the meaning of the expression "higher order conformation” defines the formation of a molecule by transformation of a collection of free atoms, which find themselves in a random spatial configuration, into a more stable non-random pattern of those same atoms. In other words, these atoms have connected themselves to each other, resulting in a new molecule, a new totality.
  • the connection in this case is chemical, i.e. by means of chemical bonds like hydrogen bonds .
  • Several of such molecules can in turn react with each other, resulting in other molecules, either of the same size, or possibly of a larger size. Both are new totalities again.
  • the larger molecules are higher-order totalities.
  • the expression “immunostimulating” refers to stimulating the immune system by inducing activation or increasing activity of any components of the immune system.
  • the expression “immunopotentiating” refers to the activities of one substance that enhance or increase the immunostimulating effects of another substance .
  • beta-glucan to have immunopotentiating activity is likely the result of its ability to present multiple epitopes for interaction with receptors on the target cells, thereby clustering beta-glucan receptors and mimicking the challenge by a pathogenic organism. Such multiple interactions with specific receptors on the cell are believed to depend partly on glucan's ability to form "higher order" structures presenting multiple binding epitopes in close vicinity. Soluble beta-glucan formulations which possess durable interchain associations, as expressed by a high viscosity profile, would thus be likely candidates for expressing "immunpotentiating" abilities .
  • cancer refers to pathological process that results in the formation and growth of a cancerous or malignant neoplasm.
  • the term "effective amount” is used to describe that amount of a compound, when administered to an animal or a human, would lead to suppression or eradication of tumor growth or spread of the cancer, or other desirable immune responses.
  • animal is used to describe an animal, preferably a mammal, more preferably a human, to whom treatment or method according to the present invention is provided.
  • pharmaceutically acceptable carrier, additive or excipient means a chemical composition with which an appropriate glucan or derivative may be combined and which, following the combination, can be used to administer the appropriate glucan to treat animals, preferable mammals, and most preferably humans.
  • beta-glucans of microbial origin like yeasts, are recognised by specific pattern recognition receptors on immune cells as a result of phylogenetic adaptation for detecting possible pathogens.
  • Beta-glucans in e.g. fungal cell walls are major structural element that secure the strength and integrity of the cell and are thus vital for the organism.
  • Beta-1, 3-glucans are present in almost all fungal cells and they are highly conserved 'structures, the latter being a prerequisite for the so-called Pathogen Associated Molecular Patterns (PAMPs) recognised by the immune system.
  • PAMPs Pathogen Associated Molecular Patterns
  • Immunologically active beta-glucans are likely to bind to beta-glucan receptor known as Dectin-1 when introduced to the organism through the gastrointestinal tract.
  • beta-1, 3-glucans having the structural elements and conformations mimicking its fungal origin as being recognised by the immune cells would thus be considered favourable with respect to achieving an immune activation, especially when administered orally. It is likely that beta- 1, 3 and 1 , 4 glucans, although not derived from a microbial organism, would interact with the immune cells based on its similarity to conserved structures on pathogenic organisms . Examples of useful beta-glucans include, but are not limited to, particulate and soluble yeast cell wall glucans as described in PCT/IB95/00265 and EP 0759089.
  • beta-1, 3- glucan compositions having the ability to form interchain associations, as exemplified in having a high viscosity profile as described for the barley beta-1, 3-1, 4-glucan preparations, would also be suitable candidates. Specific preparations of e.g. lentinan, scleroglucan and schizophyllan showing durable interchain interactions are likely to be effective.
  • beta-1, 3-glucan formulations solublized by deriatization like glucan phosphates, glucan sulphates, carboxymethyl-glucans, and retaining the immunopotentialting activity of the native molecule and interchain assosiation would be possible active products.
  • Beta-glucan formulations not presenting a pathogen- like feature could nevertheless be potent adjuvants for immunotherapy when administered directly into systemic distribution, like when given i.v. as described in Herlyn et al . (Monoclonal antibody-dependent murine macrophage-mediated cytotoxicity against human tumors is stimulated by lentinan. Jpn. J. Cancer Res. 16, 37-42 (1985)), or when given i.p. as described in U.S. Serial No ' . 60/261,911.
  • the present invention discloses a composition for achieving a synergistic therapeutic effect in an animal, preferably a mammal, most preferably a human in need thereof, comprising (i) a viscous and immunopotentiating yeast beta-glucan composition comprising a beta-1, 3-linked backbone as shown in Figure 4 and (ii) an antitumor antibody, wherein the synergistic therapeutic effect is the eradication or suppression of cancer or tumor cells .
  • the ability of yeast beta-glucans to have immunopotentiating activity is likely due to their ability to present multiple epitopes for interaction with receptors on the target cells, thereby clustering beta-glucan receptors and mimicking the challenge by a pathogenic organism.
  • the beta-glucan composition comprises yeast beta-glucans with beta-l, 3-linked main chain having a molecular weight (MW) >6000 Da, and has side chains attached thereto giving a soluble product with strong interchain assosiations .
  • Representative examples include, but are not limited to, beta-l, 3-glucans isolated from yeast with beta-l, 3-linked side chains anchored to the main chain through beta-l, 6-linkage (see Figure 5).
  • Suitable forms of yeast glucans include, but are not limited to, particulate, soluble, or gel form.
  • yeast beta-glucans is a mixture of soluble beta-glucan chains with molecular weight (MW) >6000 daltons that interact to give a higher order conformation which would exhibit immunostimulatory activity when administered orally to induce synergistic effect with the antibodies.
  • the mixture of soluble beta-glucans comprise linear beta-1, 3- glucan chains with MW >6000 Da, or more preferably, with MW ranging from 6000-30,000 Da, together with branched high molecular weight beta-1, 3-glucan (MW >15,000 Da) with beta- 1,3 linked side chain (s) extending from within the main chain as shown in Figure 5.
  • glucan As described above is SBG (Soluble Beta Glucan) produced by Biotec Pharamacon ASA
  • Bakers' yeast is an underivatized aqueous soluble ⁇ -1, 3/1, 6- glucan characterized by NMR and chemical analysis to consist of polymers of ⁇ -l,3-linked D-glucose containing side chains of ⁇ -1, 3 and ⁇ -l,6-linked D-glucose (see Figure 2) .
  • the yeast glucans have an average molecular weight of about 16,000 to about 17,000 daltons, with a range from about 6,000 to about 30,000 daltons, or from about 6,000 to about 25,000 daltons
  • SBG shows a complex beta- glucan composition with high molecular weight chains having beta-1, 3-linked side chains attached to the repeating beta- 1,3-linked main chain through a beta-1, 6-linked branching point, and medium molecular weight linear beta-1, 3-glucan chains in the range of 6 - 15 kDa.
  • SBG Soluble Beta Glucan
  • SBG has been shown to be a potent immunostimulating agent for activating human leukocytes in vitro, e.g. priming and inducing the production of cytokines (see Engstad et al .
  • yeast glucans of the present invention it is preferable for the yeast glucans of the present invention to have such functional properties of priming and inducing cytokine production by human leukocytes.
  • Products having the desired structural features giving a higher order conformation like SBG that facilitates the needed interaction with responding cells in the intestinal tract would be the preferred products when administered orally.
  • Their action as immunopotentiators in synergy with anti-cancer antibodies is likely to be at least as powerful when administered parenterally, e.g. when administered i.p., s.c, i.m. or i.v.
  • Functional dose range of the glucans can be readily determined by one of ordinary skill in the art. For example, when administered orally the functional dose range would be in the area of 1-500 mg/kg b.w. (body weight) /day, more preferable 10-200 mg/kg b.w./day, or most preferable 20-80 mg/kg/day. In another embodiment, when administered parenterally the functional dose range would be 0.1-10 mg/kg b.w./day.
  • dosages of the compound of the present invention administered to an animal will vary depending upon any number of factors, including but not limited to, the type of animal and type of cancer and disease state being treated, the age of the animal, the route of administration and the relative therapeutic index.
  • Formulations suitable for oral administration of the beta-glucan include, but are not limited to, an aqueous or oily suspension, an aqueous or oily solution, or an emulsion. Such formulations can be administered by any means including, but not limited to, soft gelatin capsules.
  • Liquid formulations of a pharmaceutical composition of the present invention which are suitable for oral administration may be prepared, packaged, and sold either in liquid form or in the form of a dry product intended for reconstitution with water or other suitable vehicle prior to use.
  • the beta-glucan can be administered to an animal as frequently as several times daily, or it may be administered less frequently, such as once a day.
  • the antibody treatment will for instance depend upon the type of antibody, the type of cancer, the severity of the cancer, and the condition of each patient.
  • the beta-glucan treatment is closely interrelated with the antibody treatment regimen, and could be ahead of, concurrent with, or after the antibody administration.
  • the frequency of the beta-glucan and antibody dose will be readily apparent to the skilled artisan and will depend upon any number of factors, such as, but not limited to, the type and severity of the disease being treated, and the type and age of the patients. Treatment with the substance of the present invention could happen at the same time or at different times. For example, the beta- glucan treatment could start a few days ahead of the i.v. antibody treatment, and then the beta-glucan is administered concurrently with the antibody. In another embodiment, beta- glucan treatment may continue for a few days after ending the antibody treatment.
  • the antibody treatment could include a cocktail of antibodies or antibody-formulations/ modified antibodies and/or derivatives thereof .
  • glucan When administered orally, glucan is taken up by macrophages and monocytes that carry these carbohydrates to the marrow and reticuloendothelial system from where they are released, in an appropriately processed form, onto myeloid cells including neutrophils and onto lymphoid cells including natural killer (NK) cells.
  • the processed glucan binds to CR3 on these neutrophils and NK cells, and activating their antitumor cytotoxicity in the presence of tumor-specific antibodies .
  • the present invention provides a composition comprising an effective amount of orally administered
  • Glucans derived from cell walls of yeasts such as Saccharomyces cervisiae, may be used in the above-described compositions .
  • glucans having ⁇ (l-3) and ⁇ (l-6) linkages such as SBG (Soluble Beta Glucan) produced by Biotec Pharamacon ASA (Troms ⁇ , Norway) , is used in the above-described compositions.
  • SBG Soluble Beta Glucan
  • the above mentioned pharmaceutical compositions may contain pharmaceutically acceptable carriers and other ingredients known to enhance and facilitate drug administration. The relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and condition of the subject treated.
  • Such a pharmaceutical composition may comprise the active ingredient alone, in a form suitable for administration to a subject, or the pharmaceutical composition may comprise the active ingredient and one or more pharmaceutically acceptable carriers, one or more additional ingredients, or some combination of these.
  • the active ingredient may be present in the pharmaceutical composition in forms which are generally well known in the art.
  • compositions described herein may be prepared by any method known or hereafter developed in the art of pharmacology.
  • preparatory methods include the step of bringing the active ingredient into association with a carrier or one or more other accessory ingredients, and then, if necessary or desirable, shaping or packaging the product into a desired single-or multi-dose unit.
  • Controlled- or sustained-release formulations of a pharmaceutical composition of the present invention may be made using conventional technology.
  • the above glucan composition may comprise a monoclonal antibody, or an antibody against cancer or tumor cells, which include but are not limited to anti-CEA antibody, anti-CD20 antibodies, anti-CD25 antibodies, anti- CD22 antibodies, anti-HER2 antibodies, anti-tenascin antibodies, MoAb M195, Dacluzimab, anti-TAG-72 antibodies, R24, Herceptin, Rituximab, 528, IgG, IgM, IgA, C225, Epratuzutnab, MoAb 3F8, and antibody directed at the epidermal growth factor receptor, or a ganglioside, such as GD3 or GD2.
  • the antibody is a tumor-binding antibody.
  • the antibody is capable of activating complement and/or activating antibody dependent cell-mediated cytotoxicity.
  • the antibody modulates T-cell or B-cell function.
  • the antibodies are effective against cancers which include neuroblastoma, melanoma, non-Hodgkin' s lymphoma, Epstein-Barr related lymphoma, Hodgkin's lymphoma, retinoblastoma, small cell lung cancer, brain tumors, leukemia, epidermoid carcinoma, prostate cancer, renal cell carcinoma, transitional cell carcinoma, breast cancer, ovarian cancer, lung cancer, colon cancer, liver cancer, stomach cancer, or other gastrointestinal cancers.
  • cancers which include neuroblastoma, melanoma, non-Hodgkin' s lymphoma, Epstein-Barr related lymphoma, Hodgkin's lymphoma, retinoblastoma, small cell lung cancer, brain tumors, leukemia, epidermoid carcinoma, prostate cancer, renal cell carcinoma, transitional cell carcinoma, breast cancer, ovarian cancer, lung cancer, colon cancer, liver cancer, stomach cancer, or other gastrointestinal cancers.
  • the present invention also provides a method for treating a subject comprising administrating the above- described composition to a subject.
  • the present invention also provides a composition comprising an effective amount of orally administered (1- ⁇ 3) , (l->6) beta-glucan capable of enhancing the efficacy of vaccines.
  • the " vaccine is against cancer or infectious agents, such as bacteria, viruses, fungi, or parasites .
  • the present invention also provides a composition comprising an effective amount of orally administered (l->3) , (l->6) beta-glucan capable of enhancing host immunity.
  • the host immunity includes, but is not limited to, antitumor immune responses.
  • the present invention provides a composition comprising an effective amount of orally administered (l->3), (1- ⁇ 6) beta-glucan capable of enhancing the action of an agent in preventing tissue rejection.
  • the tissue is transplanted tissue or transplanted organ or the host of graft-versus-host disease.
  • kits for inhibiting cancer cell growth and/or metastasis includes a kit or an administration device comprising a glucan as described herein and information material which describes administering the glucan or a composition comprising the glucan to a human.
  • the kit or administration device may have a compartment containing the glucan or the composition of the present invention.
  • the "Information material” includes, but is not limited to, a publication, a recording, a diagram, or any other medium of expression which can be used to communicate the usefulness of the composition of the invention for its designated use.
  • the EL4 syngeneic mouse model of lymphoma was used to study antibody response to whole tumor vaccine in the presence of ⁇ -glucan.
  • live EL4 tumor cells were planted subcutaneousIy or intravenously in immunocompetent C57B1/6 mice, they engrafted rapidly causing death from large tumor masses and metastases to distant organs.
  • EL4 tumor cells were planted subcutaneousIy or intravenously in the presence of anti-GD2 antibody 3F8, tumor cell engraftment diminished.
  • ⁇ -glucan is known to activate antigen-presenting cells
  • EL4 cells were administered in the presence of 3F8 as a tumor vaccine to test if ⁇ -glucan can provide adjuvant effect to induce protective immunity.
  • mice were vaccinated subcutaneously with EL4 lymphoma (as whole tumor vaccine) in the presence of anti-GD2 antibody 3F8 plus yeast ⁇ -glucan.
  • Mouse sera were obtained at week 2, 4, and 8 after vaccination.
  • Serum antibodies against surface antigens on EL4 cells were assayed by flow cytometry.
  • Antibodies against total cell antigens were assayed by flow cytometry.
  • Results from these experiments indicate that: (1) 3F8 was necessary to prevent subcutaneous EL4 tumor engraftment; (2) 3F8 enhanced antibody response to EL4 whole tumor vaccine; (3) live EL4 tumor vaccine stimulated a significantly higher immune response compared to irradiated EL4 tumor vaccine; (4) antibody titer against EL4 tumor increased with increasing dose of glucan as an adjuvant, with an optimal dose at 2 mg; and (5) the higher the dose of glucan, the longer the mice were protected when subsequently challenged with intravenous EL4 in a tumor prevention model.

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Abstract

L'invention concerne une composition thérapeutique pour traiter le cancer chez un mammifère. Cette composition comprend une quantité efficace d'une composition de bêta-glucane de levure appropriée pour être administrée oralement ou pour être absorbée par voie gastro-intestinale, chez le mammifère. La composition thérapeutique sus-mentionnée peut également comprendre des anticorps antitumoraux ou une composition de vaccin contre le cancer. Le glucane de levure permet d'intensifier les activités antitumorales des anticorps antitumoraux ou de la composition de vaccin contre le cancer.
EP07718218A 2006-01-17 2007-01-17 Glucane permettant d'améliorer une thérapie Withdrawn EP1984004A4 (fr)

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US11/334,763 US7906492B2 (en) 2001-01-16 2006-01-17 Therapy-enhancing glucan
PCT/US2007/001427 WO2007084661A2 (fr) 2006-01-17 2007-01-17 Glucane permettant d'améliorer une thérapie

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US7906492B2 (en) 2001-01-16 2011-03-15 Sloan-Kettering Institute For Cancer Research Therapy-enhancing glucan
US7507724B2 (en) 2001-01-16 2009-03-24 Sloan-Kettering Institute For Cancer Research Therapy-enhancing glucan
JP5153188B2 (ja) * 2007-03-30 2013-02-27 小林製薬株式会社 Ｔｈ１／Ｔｈ２バランス改善剤
AU2008322737A1 (en) * 2007-11-13 2009-05-22 Biotec Pharmacon Asa Methods of treating or preventing inflammatory diseases of the intestinal tract
JP5242855B2 (ja) * 2010-07-29 2013-07-24 国立大学法人北海道大学 免疫アジュバント
JP5990752B2 (ja) * 2011-01-31 2016-09-14 オリンパス株式会社 抗体療法の効果増強剤
US11229701B2 (en) * 2012-04-30 2022-01-25 Hibercell, Inc. Methods for identifying beta-glucan binding to immune cells
EP2832360A1 (fr) 2013-07-30 2015-02-04 Fresenius Kabi Deutschland GmbH Polysaccharide pour utilisation dans la prévention de la formation de métastases et/ou de rechute
EP3851111A1 (fr) * 2014-07-10 2021-07-21 Biothera, Inc. Bêta-glucane en combinaison avec des agents anticancéreux affectant le microenvironnement de la tumeur
US11815435B2 (en) 2017-02-24 2023-11-14 Hibercell, Inc. Beta glucan immunopharmacodynamics
BR112020018761A2 (pt) * 2018-03-13 2020-12-29 Hibercell, Inc. Imunoterapia combinada com beta-glucano e agonista de cd40
EP3784250A4 (fr) * 2018-04-24 2022-04-06 Memorial Sloan-Kettering Cancer Center Procédés d'amélioration de l'immunogénicité de vaccins spécifiques d'un antigène faiblement immunogènes à l'aide de bêta-glucanes de levure oraux
US20210290708A1 (en) * 2018-09-21 2021-09-23 Nantcell, Inc. Methods and compositions for modulating myeloid-derived suppressor cells
JP7048102B2 (ja) 2019-05-23 2022-04-05 国立研究開発法人医薬基盤・健康・栄養研究所 免疫賦活活性を有する核酸多糖複合体の抗腫瘍薬としての応用

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AU2008207369B2 (en) 2009-12-17
EP1984004A4 (fr) 2010-03-03
AU2008207369A1 (en) 2008-09-11
WO2007084661B1 (fr) 2008-01-10
WO2007084661A3 (fr) 2007-11-08
JP2009528267A (ja) 2009-08-06

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