[go: up one dir, main page]
More Web Proxy on the site http://driver.im/

WO2012171077A1 - Procédé et composition pour traiter ou inhiber une mucosite associée à une chimiothérapie ou à une lésion causée par un rayonnement - Google Patents

Procédé et composition pour traiter ou inhiber une mucosite associée à une chimiothérapie ou à une lésion causée par un rayonnement Download PDF

Info

Publication number
WO2012171077A1
WO2012171077A1 PCT/AU2012/000700 AU2012000700W WO2012171077A1 WO 2012171077 A1 WO2012171077 A1 WO 2012171077A1 AU 2012000700 W AU2012000700 W AU 2012000700W WO 2012171077 A1 WO2012171077 A1 WO 2012171077A1
Authority
WO
WIPO (PCT)
Prior art keywords
lps
hyperimmune
radiation
colostrum
composition
Prior art date
Application number
PCT/AU2012/000700
Other languages
English (en)
Inventor
Grant Thomas Rawlin
Roy Michael Robins-Browne
Yaron Ilan
Original Assignee
Immuron Limited
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
Application filed by Immuron Limited filed Critical Immuron Limited
Priority to AU2012269740A priority Critical patent/AU2012269740A1/en
Publication of WO2012171077A1 publication Critical patent/WO2012171077A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/12—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria
    • C07K16/1203—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from bacteria from Gram-negative bacteria
    • 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
    • A61K39/02—Bacterial 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
    • A61K39/02—Bacterial antigens
    • A61K39/025—Enterobacteriales, e.g. Enterobacter
    • 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
    • A61K39/40—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum bacterial
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/10—Immunoglobulins specific features characterized by their source of isolation or production
    • C07K2317/12—Immunoglobulins specific features characterized by their source of isolation or production isolated from milk

Definitions

  • This invention relates to a method of treatment or inhibition of the development of alimentary mucositis arising from chemotherapy or radiation damage, to a composition for use in such treatment, to the use of such composition in manufacture of a medicament for treatment or inhibition of the development of alimentary mucositis arising from chemotherapy or radiation damage, in particular the invention is directed to treatment of alimentary mucositis arising from chemotherapy or exposure to radiation, including cancer therapy.
  • ARS acute radiation syndrome
  • hematopoietic syndrome contributes to mortality as demonstrated by the success of bone marrow shielding, hematopoietic cell transplant (HCT), and G-CSF administration in supporting recovery. At higher doses, death occurs earlier and even HCT does not reduce mortality. Concomitant thermal and skin injuries compromise survival at all doses.
  • Damage from radiation exposure can include fibrosis, vascular damage, aberrant angiogenesis, pneumonitis, atherogenesis, osteonecrosis, immunosuppression and functional impairment of the gastrointestinal tract, lungs, kidneys, and other organs.
  • Epithelial cells in the upper and low gastrointestinal tract are especially vulnerable to damage by radiation and chemotherapeutics agents used in cancer, and by analogy to radiation in the form of environmental exposure to radionuclides or high dose radiation from accidental or purposeful exposure. Damage to the epithelial tissue, directly and indirectly can lead to gastrointestinal symptoms and chronic conditions including mucositis, enteritis, and proctitis.
  • the epithelial tissue of the mouth and oesophagus are particularly sensitive to radiation and chemotherapeutic agents.
  • chemotherapeutic agent for head and neck cancers
  • oral ulcerations characteristic of mucositis are a major clinical problem causing considerable pain, increased susceptibility to infection and inability to eat.
  • Treatment of abdominal or pelvic cancers with radiation causes radiation enteritis, damage to the intestinal lining occurring typically in the small bowel, and less frequently in the large bowel.
  • Mucositis is the major clinical side-effect of exposure to radiation (e.g. radiation associated with cancer therapies) and treatment with chemotherapeutic agents, causing pain, weight loss, diarrhoea and in some cases patients suffer serious infections and may even elect to withdraw from cancer treatment, (Keefe, 2007, Current Opinion in Oncology 19:323-327).
  • radiation e.g. radiation associated with cancer therapies
  • chemotherapeutic agents causing pain, weight loss, diarrhoea and in some cases patients suffer serious infections and may even elect to withdraw from cancer treatment, (Keefe, 2007, Current Opinion in Oncology 19:323-327).
  • Clinically mucositis is seen as oral mucositis, called stomatitis, and as intestinal mucositis.
  • the symptoms are caused by the cytotoxic effects associated radiation, and with cancer chemotherapy and radiation.
  • These therapies are particularly damaging to epithelial cells because those cells are rapidly dividing.
  • Epithelial cells border the lumen of the gastro-intestinal tract from the lips to the anus.
  • Symptoms of alimentary mucositis include pain, discomfort, inability to tolerate food or liquid and diarrhoea. Mucositis can be limiting in the ability of a patient to undergo necessary cancer therapy. Mucositis of the intestinal lining will start to manifest 3-7 days after radiation exposure or chemotherapy while oral mucositis will appear 7-10 days after radiation exposure or chemotherapy.
  • Post-radiation bacteraemia contributes to total body irradiation (TBI) toxicity.
  • Mouthwashes are used relief of oral symptoms.
  • denzydamine hydrochloride has been used as a gargle in particular to relieve symptoms associated with head and neck cancer, but has less effectiveness in chemotherapy-induced mucositis, nor does it help counter intestinal mucositis.
  • Topical anaesthetics have been used to some effect, but while they temporarily relieve pain, they do not change the course of the tissue damage.
  • Antiseptic gargles such as chlorhexidine, hydrogen peroxide and povidone iodine are used; however they appear to be of limited effectiveness in the mouth and of no use in the intestine.
  • Antibacterial agents such as antibiotic lozenges are used and release low amounts of antibiotic into the mouth. While these seem to have effectiveness in chemotherapeutic patients, they have little effectiveness in radiotherapy patients and have the added risk of selecting for antibiotic resistant strains of microorganisms.
  • Monoclonal antibodies have the disadvantages when used as oral treatments that (a) they are more difficult to make at large scale leading to high expense on a per patient basis, (b) they have narrow specificity which prevents the capture of a broad spectrum of toxic agents, (c) they are generally more susceptible to degradation in the harsh gastric environment, (d) monoclonals present a limited ability to cross-link to form agglutinations which facilitate excretion from the body.
  • SNS Strategic National Stockpile
  • the agents in the SNS that could be used for medical problems related to radiological/nuclear events are calcium and zinc DTPA (diethylenetriamine pentaacetic acid) which are chelating agents for the transuranium elements plutonium, americium, and curium), Prussian Blue which is an oral ion- exchange drug is indicated for decorporation of cesium and thallium), and the growth factors G-CSF and GM-CSF which are to minimise the severity of neutropenia-associated complications and shorten the duration of severe neutropenia.
  • calcium and zinc DTPA diethylenetriamine pentaacetic acid
  • Prussian Blue which is an oral ion- exchange drug is indicated for decorporation of cesium and thallium
  • G-CSF and GM-CSF which are to minimise the severity of neutropenia-associated complications and shorten the duration of severe neutropenia.
  • compositions that treat the damage associated with exposure to chemotherapeutic agents or radiation, for example the radiation associated with cancer therapy or radiological/nuclear events.
  • a method for treating or inhibiting the development of alimentary mucositis arising from chemotherapy or radiation damage in a subject comprising: providing a hyperimmune dairy material or egg derived material comprising anti-lipopolysaccharide (anti-LPS) antibody raised against a vaccine comprising LPS; and administering to the subject a composition comprising the anti-LPS antibody or fragment thereof which antibody or fragment binds LPS associated with commensal bacteria.
  • anti-LPS anti-lipopolysaccharide
  • the subject is a patient suffering cancer. In another aspect, the subject is a person exposed to radiation.
  • the LPS in the vaccine is derived from gram negative bacteria.
  • the LPS in the vaccine is at least partly separated from bacterial cell walls.
  • the LPS in the vaccine has been separated by mechanical means.
  • the radiation damage is associated with cancer therapy.
  • the present invention provides a method of treatment of a subject exposed to radiation to reduce the effects of radiation damage comprising: forming hyperimmune colostrum by vaccinating cows; and administering the hyperimmune material to said patient wherein the step / of vaccinating cows to produce hyperimmune material comprises vaccination with a vaccine comprising LPS.
  • the present invention provides a method of treatment of a patient suffering cancer to reduce the effects of cancer therapy comprising: forming hyperimmune colostrum by vaccinating cows; and administering the hyperimmune material to said patient wherein the step of vaccinating cows to produce hyperimmune material comprises vaccination with a vaccine comprising LPS.
  • the hyperimmune colostrum formed comprises material selected from the group consisting of anti-LPS antibodies and fragments thereof wherein the material binds commensal bacteria.
  • the present invention provides a medicament composition for treatment of a subject exposed to radiation to . reduce the effects of radiation damage comprising anti-LPS antibodies which bind commensal bacteria.
  • the present invention provides a medicament composition for treatment of a patient suffering cancer to reduce the effects of cancer therapy comprising anti-LPS antibodies which bind commensal bacteria.
  • the present invention provides a use of a hyperimmune colostrum in manufacture of a medicament for treatment or inhibition of alimentary mucositis arising from radiation damage in a subject exposed to radiation wherein the hyperimmune material is raised by vaccination with an antigen comprising LPS and the medicament comprises material selected from the group consisting of anti-LPS antibodies and fragments thereof wherein the material binds commensal bacteria.
  • the present invention provides a use a hyperimmune colostrum in manufacture of a medicament for treatment or inhibition of alimentary mucositis arising from cancer therapy in a patient suffering cancer wherein the hyperimmune material is raised by vaccination with an antigen comprising LPS and the medicament comprises material selected from the group consisting of anti-LPS antibodies and fragments thereof wherein the material binds commensal bacteria.
  • the present invention provides a use of LPS in manufacture of a medicament for treatment or inhibition of alimentary mucositis arising from radiation damage in a subject exposed to radiation by administration of a composition comprising one or more of anti-LPS antibodies and fragments thereof obtained from hyperimmune colostrum raised by vaccination of cows with LPS wherein the anti-LPS antibodies and fragments thereof bind commensal bacteria.
  • the present invention provides a use of LPS in manufacture of a medicament for treatment or inhibition of alimentary mucositis arising from cancer therapy in a patient suffering cancer by administration of a composition comprising one or more of anti-LPS antibodies and fragments thereof obtained from hyperimmune colostrum raised by vaccination of cows with LPS and wherein the anti-LPS antibodies and fragments thereof bind commensal bacteria.
  • the present invention provides a method of cancer radiotherapy which comprises administering to a subject in need of such therapy an amount of a composition comprising anti-LPS antibodies which bind commensal bacteria effective to minimise damage to subject to radiation.
  • the subject is a patient suffering cancer.
  • the radiation damage is associated with cancer therapy.
  • the radiation damage is alimentary mucositis.
  • Figure 1 Western Blot with anti-LPS antibodies (dairy derived) made as described in Example 3.
  • B is a Western Blot with antibodies contained in non-hyperimmune colostrum. This data demonstrates colostrum containing polyclonal anti-LPS antibodies of the present invention binds LPS of commensal bacteria.
  • mice receiving oral antibiotic show significantly increased time to death, with 100% mortality b day 23.
  • Mice receiving both antibiotic and colostrum containing polyclonal anti-LPS antibodies demonstrate survival to Day 30. These data indicate colostrum containing polyclonal anti-LPS antibodies decrease the morbidity mortality and mortality associated with exposure to radiation.
  • compositions comprising anti-LPS antibodies protect against damage caused by exposure to radiation or chemotherapeutic agents.
  • LPS increased both endogenous intestinal prostaglandin (which increases I EC proliferation and decreases I EC apoptosis) production and intestinal crypt survival in mice exposed to 14 Gray radiation when injected parenteral ⁇ 2-24 hours prior to exposure (Riehl T, Cohn S, Tessner T, et al. Lipopolysaccharide is radioprotective in the mouse intestine through a prostaglandin-mediated mechanism. Gastroenterology 2000; 1 18:1106— 11 16).
  • the present invention provides a method for treating or inhibiting the development of alimentary mucositis arising from chemotherapy or radiation damage in a subject comprising: providing a hyperimmune dairy material or egg derived material comprising anti- lipopolysaccharide (anti-LPS) antibody raised against a vaccine comprising LPS; and administering to the subject a composition comprising the anti-LPS antibody or fragment thereof which antibody or fragment binds LPS associated with commensal bacteria.
  • anti-LPS anti- lipopolysaccharide
  • the subject is may be a patient suffering cancer and/or a person exposed to radiation.
  • the hyperimmune material is raised against LPS.
  • the "hyperimmune material” in one embodiment is hyperimmune dairy derived material such as milk particularly colostral milk (colostrum) and the like which is enriched in antibodies or fragments thereof and which is derived from an animal source.
  • the hyperimmune dairy material is preferably hyperimmune colostrum.
  • the hyperimmune material is derived from bird eggs. The hyperimmune material is enriched when compared with corresponding material in which the animal has not been challenged with the antigen in question namely LPS.
  • colostrum where used herein includes colostral milk; processed colostral milk such as colostral milk processed to partly or completely remove one or more of fat, cellular debris, lactose and casein; and colostral milk or processed colostral milk which has been dried by for example, freeze drying, spray drying or other methods of drying known in the art.
  • Colostral milk is generally taken from a mammal such as a cow within five days after parturition.
  • the mammalian colostrum is bovine colostrum retained from the first 4 days post parturition, more preferably bovine colostrum retained from the first 2 days post parturition, even more preferably bovine colostrum retained from the first day post parturition, and most preferably bovine colostrum retained from the first milking post parturition.
  • the colostrum collected from the cow comprises at least 4% total protein (weight %), more preferably 5%, more preferably at least 8%, more preferably at least 10%.
  • the ratio of IgG to total protein of the colostrum collected from the cow is at least 10%, more preferably 20%.
  • LPS Lipopolysaccharide
  • Carbohydrate a polysaccharide joined by a covalent bond.
  • LPS is a major component, for example, of the outer membrane of Gram-negative bacteria, contributing greatly to the structural integrity of the bacteria, and protecting the membrane from certain kinds of chemical attack.
  • the only Gram-positive bacteria that possesses LPS is Listeria monocytogenes, the common infective agent in unpasteurized milk.
  • the term "radiation” includes a radiation source, such as, ionising radiation, radiation therapy, accidental radiation exposure, and exposure to individuals at risk for radiation exposure. Accordingly, the methods can benefit individuals who are exposed to radiation inadvertently or who are exposed to radiation as part of their work, including, for example, individuals working in nuclear power plants or nuclear fuel and/or nuclear waste processing facilities, individuals transporting nuclear material, researchers working with radioactive materials, individuals responsible for handling hazardous materials, members of the military, medical care workers, and the like.
  • the subject is a patient receiving X-rays for purposes of medical monitoring and/or diagnosis.
  • the subject is a patient radiation purposes cancer therapy. >
  • ionising radiation refers to photons having enough energy to ionise a bond, such as, ⁇ , ⁇ and ⁇ rays from radioactive nuclei and x-rays.
  • ionizing subatomic particles include alpha particles, beta particles and neutrons.
  • Exposure to a significant dose of ionizing radiation can also result in systemic effects.
  • high doses of radiation can induce radiation sickness, also referred to as Acute Radiation Syndrome (ARS).
  • ARS is induced as a result of the effect of radiation on various systems of the body, including the hematopoietic system, digestive system, cardiovascular system, reproductive system, and the like.
  • Bone marrow and circulating immune cells, such as leukocytes, are particularly sensitive to the effects of ionizing radiation. Radiation results in immunosuppression leading to opportunistic 1$ infection, including bacterial translocation from a damaged gastrointestinal system.
  • neutropenia and thrombocytopenia are characteristics of exposure to high but acute dose of whole body.
  • the mean lethal dose of radiation required to kill 50% of humans 60 days after whole-body irradiation is between 3.25 and 4Gy without supportive care, and 6-7Gy when antibiotics and transfusion support are provided.
  • the mortality is largely attributed to the haematopoietic syndrome, a consequence of hypoplasia or aplasia of the bone marrow. Cytopenias develop as a result of radiation-induced and normal attrition of mature functional cells, combined with the failure of replacement because of radiation-induced depletion of haematopoietic stem cells and progenitors.
  • cytopenia generally correlate with radiation dose and prognosis, but the kinetics of depletion and recovery of blood cells also varies between the erythropoiesis, myelopoiesis and thrombopoiesis lineages, thrombopoiesis being the slowest.
  • the gastrointestinal syndrome arising from chemotherapy or radiation damage with radiation damage may result from ablation of stem cells in intestinal crypts, which in turn leads to denudation of the intestinal mucosa.
  • this injury occurs after whole-body doses in the range of 3-15Gy and in rodents doses at the upper end of this range usually result in death within about 1 week after irradiation.
  • radiation damage includes damage at the molecular level (e.g., DNA mutagenesis or alteration, or chromosomal damage), the cellular level (e.g., apoptosis, or uncontrolled cell proliferation, including tumour formation and metastasis), the tissue level (e.g., tissue damage, including degeneration, atrophy, fibrosis, and necrosis), the organ level (e.g., organ failure), and/or the system or organism level (e.g., mortality).
  • the molecular level e.g., DNA mutagenesis or alteration, or chromosomal damage
  • the cellular level e.g., apoptosis, or uncontrolled cell proliferation, including tumour formation and metastasis
  • the tissue level e.g., tissue damage, including degeneration, atrophy, fibrosis, and necrosis
  • the organ level e.g., organ failure
  • system or organism level e.g., mortality
  • chemotherapeutic agent refers to agents that have the property of inhibiting the growth or proliferation (e.g., a cytostatic agent), or inducing the killing, of tumour cells (and interchangeable terms as discussed above).
  • the chemotherapeutic agent inhibits or reverses the development or progression of a cancer, such as for example, solid tumour, or a soft tissue tumour.
  • a chemotherapeutic agent may reduce, prevent, mitigate, limit, and/or delay the growth of metastases or neoplasms, or kill neoplastic cells directly by necrosis or apoptosis of neoplasms or any other mechanism, or that can be otherwise used, in a pharmaceutically-effective amount, to reduce, prevent, mitigate, limit, and/or delay the growth of metastases or neoplasms in a subject with neoplastic disease.
  • Chemotherapeutic agents include, for example, fluoropyrimidines; pyrimidine nucleosides; purine nucleosides; anti-folates, platinum agents; anthracyclines/anthracenediones; epipodophyllotoxins; camptothecins; hormones; hormonal complexes; antihormonals; enzymes, proteins, peptides and polyclonal and/or monoclonal antibodies; vinca alkaloids; taxanes; epothilones; antimicrotubule agents; alkylating agents; antimetabolites; topoisomerase inhibitors; antivirals; and various other cytotoxic and cytostatic agents.
  • the skilled person would be familiar with a variety of chemotherapeutic agents available for treatment of cancer.
  • chemotherapy refers to administration of at least one chemotherapeutic agent to a patient having a cancer.
  • a composition described herein provides a clinically significant decrease in tissue damage.
  • the nature, extent, time course, and/or other aspects of chemotherapy or radiation-induced tissue damage can be measured using various methods and clinical indicators known in the art.
  • the protective effect of a composition described herein is assessed by measuring levels and/or recovery of haematological endpoints, such as lymphocyte, neutrophil, and/or platelet counts.
  • a protective effect can be assessed at the organ or system level by, for example, measuring the occurrence of opportunistic infection and/or bacterial translocation.
  • a protective effect can be assessed at the organism level by measuring survival rates, such as the thirty day survival in mice, which is a robust measurement of recovery from radiation, as exemplified in Example 4, below.
  • composition of the present invention is administered to a subject following inadvertent exposure to radiation.
  • Cancer therapy including cancer radiotherapy, is a very significant public health activity. Given the incidence of cancer in the population and the international assessment that more than 50% of cancer patients benefit from inclusion of radiotherapy in their treatment, more than 10% of the population are likely to experience cancer radiotherapy in their lifetime.
  • the subject is a patient suffering cancer.
  • the radiation damage is associated with cancer therapy.
  • the radiation damage is alimentary mucositis.
  • the present invention provides a method of treatment of a subject exposed to radiation to reduce the effects of radiation damage comprising forming hyperimmune colostrum by vaccinating cows; and administering the hyperimmune material to said patient wherein the step of vaccinating cows to produce hyperimmune material comprises vaccination with a vaccine comprising LPS.
  • the present invention provides a method of treatment of a patient suffering cancer to reduce the effects of cancer therapy comprising: forming hyperimmune colostrum by vaccinating cows; and administering the hyperimmune material to said patient wherein the step of vaccinating cows to produce hyperimmune material comprises vaccination with a vaccine comprising LPS.
  • the hyperimmune colostrum formed comprises material selected from the group consisting of anti-LPS antibodies and fragments thereof wherein the material binds commensal bacteria.
  • the present invention provides a medicament composition for treatment of a subject exposed to radiation to reduce the effects of radiation damage comprising anti-LPS antibodies which bind commensal bacteria.
  • the present invention provides a medicament composition for treatment of a patient suffering cancer to reduce the effects of cancer therapy comprising anti-LPS antibodies which bind commensal bacteria.
  • the present invention provides a use of a hyperimmune colostrum in manufacture of a medicament for treatment or inhibition of alimentary mucositis arising from radiation damage in a subject exposed to radiation wherein, the hyperimmune material is raised by vaccination with an antigen comprising LPS and the medicament comprises material selected from the group consisting of anti-LPS antibodies and fragments thereof wherein the material binds commensal bacteria.
  • the present invention provides a use a hyperimmune colostrum in manufacture of a medicament for treatment or inhibition of alimentary mucositis arising from cancer therapy in a patient suffering cancer wherein the hyperimmune material is raised by vaccination with an antigen comprising LPS and the medicament comprises material selected from the group consisting of anti-LPS antibodies and fragments thereof wherein the material binds commensal bacteria.
  • the present invention provides a use of LPS in manufacture of a medicament for treatment or inhibition of alimentary mucositis arising from radiation damage in a subject exposed to radiation by administration of a composition comprising one or more of anti-LPS antibodies and fragments thereof obtained from hyperimmune colostrum raised by vaccination of cows with LPS wherein the anti-LPS antibodies and fragments thereof bind commensal bacteria.
  • the present invention provides a use of LPS in manufacture of a medicament for treatment or inhibition of alimentary mucositis arising from cancer therapy in a patient suffering cancer by administration of a composition comprising one or more of anti-LPS antibodies and fragments thereof obtained from hyperimmune colostrum raised by vaccination of cows with LPS and wherein the anti-LPS antibodies and fragments thereof bind commensal bacteria.
  • the present invention provides a method of cancer radiotherapy which comprises administering to a subject in need of such therapy an amount of a composition comprising anti-LPS antibodies which bind commensal bacteria effective to minimise damage to subject to radiation.
  • the subject is a patient suffering cancer.
  • the radiation damage is associated with cancer therapy.
  • the radiation damage is alimentary mucositis.
  • a composition of the present invention can be administered in single or multiple doses within a few hours after exposure to chemotherapy or radiation. In some embodiments, the composition is administered within 24 hours of exposure to chemotherapy or radiation. In further embodiments, the composition is administered within 48 hours, 72 hours, or 96 hours or more following exposure to chemotherapy or radiation.
  • the medicament composition for administration in treatment of a patient suffering cancer to reduce the effects of chemotherapy or radiation damage comprises anti-LPS antibodies which bind commensal bacteria.
  • the term "commensal” refers to non-pathogenic bacteria which form part of the normal flora of a healthy human alimentary tract.
  • Examples of commensal gram negative genera may be selected from the group of genera consisting of Enterobacter, Escherichia, Klebsiella, Bacteroides, Proteus, Salmonella, Serratia, Veillonella and Fusobacteria.
  • the determination of anti-LPS antibodies which bind LPS may be determined by conducting an appropriate assay.
  • the binding of LPS associated with commensal bacteria will generally result from the use of LPS from commensal bacteria in the vaccine used to prepare the anti-LPS.
  • LPS from non-commensal bacteria may produce antibodies which bind LPS associated with commensal bacteria and the above referenced test may be used to determine whether such anti-LPS antibodies have the requisite binding ability of LPS associated with commensal bacteria.
  • the LPS antigen used vaccination to produce anti-LPS antibodies may and preferably is derived from gram negative bacteria. Further as described above it is particularly preferred to use an antigen comprising LPS from gram negative commensal bacteria.
  • the antigen may comprise LPS in any of a range of forms. It may be in the form of whole live, attenuated or killed bacteria or may be in the form at least partly separated from bacterial cell walls.
  • the anti-LPS immunoglobulin preparation may be prepared by immunizing a mammal with LPS from multiple E. coli strains.
  • the mammal or avian may be immunized with LPS selected from the group consisting of 06, 08, 015, 025, 027, 063, 078, 0114, 0115, 0128, 0148, 0153, 0159, and other LPS associated with enterotoxigenic E. coli.
  • the mammal or avian may be immunized with LPS selected from the group consisting of 078, 06, 08, 0129 and 0153 LPS.
  • LPS may comprise 078 LPS.
  • the mammal is immunised with 06, 08, 015, 025, 027, 063, 078, 0114, 0115, 0128, 0148, 0153, and 0159 LPS.
  • the bacteria from which each type of 0 antigen is isolated are grown in separate bacterial culture systems, and after separation of the O antigen from the bacteria, the component antigens are added together to form a component of the vaccine.
  • LPS may be separated, at least in part, by a range of methods using for example heat, detergents, lysis or mechanical means.
  • Methods of separating LPS from cell walls of bacteria are described in our application WO/2004/078209 (with reference to separation of O-antigen) the contents of which are herein incorporated by reference.
  • the preferred method of separating LPS from cell walls is by application of shear.
  • the LPS antigen used in vaccination can be separated from the bacterial cell walls by application of an effective amount of shear, homogenisation or heat or by effective combinations thereof.
  • Methods of preparing hyperimmune bovine colostrum (HIBC) are also described in WO/2004/078209.
  • the method involves the use of colostrum or a colostrum extract, further characterised in that the colostrum is enriched in anti-LPS antibodies when compared with colostrum obtained without vaccination.
  • the anti-LPS antibodies are polyclonal immunoglobulins or chimeric antibodies or dendrimer presented immunoactive fragments or immunoactive fragments such as F(ab) and F(ab)2 fragments or recombinant immunoactive fragments, or affinity purified immunoglobulins or immunoactive fragments thereof. Fragments thereof which bind LPS associated with commensal bacteria may be identified by methods known in the art.
  • the hyperimmune dairy material preferably contains at least 3 g per kilogram of product which is IgG anti-LPS antibody, or an equivalent molar concentration of other anti-LPS antibody.
  • the hyperimmune material may contain at least 5g, at least 10g or at least 15g anti-LPS antibody per kg of hyperimmune material on the basis of the dry weight of components.
  • the upper end of the range of antibody concentration will depend on factors such as the dose, the disease state and the health of the patient.
  • the hyperimmune material may, for example contain no more than 80g such as no more than 60g, no more than 50g or no more than 40g anti-LPS antibody per kg of hyperimmune material on the basis of the dry weight of components.
  • the composition to be administered to the patient preferably contains at least 3 g per kilogram of product which is IgG anti-LPS antibody or fragment which binds LPS of commensal bacteria (based on the dry weight of components).
  • the composition may contain at least 5g, at least 10g or at least 15g anti-LPS antibody and fragments thereof per kg of composition on the basis of the dry weight of components.
  • the upper end of the range of antibody concentration will depend on factors such as the dose, the disease state, and the health of the patient.
  • the hyperimmune material may, for example contain no more than 80g such as no more than 60g, no more than 50g or no more than 40g anti-LPS antibody and fragments thereof which bind LPS of commensal bacteria per kg of composition on the basis of the dry weight of components.
  • the effective amount of a composition to be administered can be dependent oh any number of variables, including without limitation, the species, breed, size, height, weight, age, overall health of the subject, the type of formulation, the dose of radiation received or anticipated, or the amount of time before or the amount of time elapsed since exposure to radiation.
  • the appropriate effective amount can be routinely determined by those of skill in the art using routine optimization techniques, the skilled and informed judgment of the practitioner, and other factors evident to those skilled in the art.
  • a therapeutically effective dose of the compounds described herein will provide therapeutic benefit without causing substantial toxicity to the subject.
  • the anti-LPS immunoglobulin preparation is administered at a dose of about 5 mg to about 25000 mg per day, 10 mg to about 20000 mg per day, 25 mg to about 15000 mg per day, or about 100 mg to about 2000 mg per day.
  • the anti-LPS immunoglobulin preparation is administered at a dose of about 200 mg to about 2000 mg per day. In another embodiment, the anti-LPS " immunoglobulin preparation is administered at a dose of about 50 mg to about 500 mg one to four times per day.
  • the anti-LPS immunoglobulin preparation is administered at a dose of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg per day.
  • the anti-LPS immunoglobulin preparation is formulated for administration at a dose of about 5 mg to about 25000 mg per day, about 10 mg to about 20000 mg per day, about 25 mg to about 15000 mg per day, or about 100 mg to about 2000 mg per day.
  • the anti-LPS immunoglobulin preparation is formulated for administration at a dose of about 200 mg to about 2000 mg per day. In another embodiment, the anti-LPS immunoglobulin preparation is formulated for administration at a dose of about 50 mg to about 500 mg one to four times per day.
  • the anti-LPS immunoglobulin preparation is formulated for administration at a dose of 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg, 1600 mg, 1700 mg, 1800 mg, 1900 mg, or 2000 mg per day.
  • Toxicity and therapeutic efficacy of agents or compounds can be assayed using standard pharmaceutical procedures in a variety of systems and environments, including cell-free environments, cellular environments (e.g., cell culture assays), multicellular environments (e.g., in tissues or other multicellular structures), and/or in vivo (e.g., in experimental animals), e.g., by determining the LD50 (the dose lethal to 50% of the population) and/or the ED50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index and it can be expressed as the ratio LD50/ED50.
  • Data obtained from cell culture assays and animal studies can be used in formulating a range of dosage for use in the subject.
  • the dosage of such agents or compositions lies preferably within a range of circulating concentrations that include the ED50 with little or no toxicity.
  • the dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.
  • composition used in the treatment of mucositis may in one embodiment comprise a carrier admixed with the anti-LPS antibody prior to administration, for example, by mixing a composition of hyperimmune colostrum from immunised cows or one or more processed components thereof with conventional foods and/or pharmaceutically acceptable excipients.
  • the ratio of enriched product relative to conventional dairy material from unvaccinated animals may, for example, be at least 4, such as at least 0 in a comparative ELISA assay.
  • the hyperimmune material binds LPS taken from at least one Gram negative organism selected from the group of genera consisting of Enterobacter, Escherichia, Klebsiella, Bacteroides, Proteus, Salmonella, Serratia, Veillonella and Fusobacteria.
  • the hyperimmune material binds at least two of the above family, more preferably at least 3, even more preferably at least 4.
  • the degree of enrichment in material selected from anti-LPS antibodies and fragments thereof which bind LPS may be at least 4 times, for example at least 10 times the level found in corresponding unvaccinated animals with respect each of 2 bacterial LPS, each of 3 bacterial LPS or each of 4 bacterial LPS as determined by standard ELISA.
  • low molecular weight moieties have been substantially removed from the colostrum or the colostrum extract.
  • substantially removed is meant that at least 75% and preferably 90% of the low molecular weight moieties are removed.
  • At least 75% (such as at least 90% or substantially complete removal) of, moieties of molecular weight less than 30kDa have been removed from the colostrum or the colostrum extract.
  • molecular weight moieties less than 60kDa have been substantially removed from the colostrum or colostrum extract.
  • the hyperimmune material comprises immunogenic material selected from antibody and antibody fragments which bind LPS associated with commensal bacteria.
  • the antibody or antibody fragment is a polyclonal antibody or a polyclonal antibody fragment of bovine origin.
  • the antibody or antibody fragment is generated by vaccinating a dairy cow, wherein the vaccine comprises LPS moieties substantially separated from bacterial wall fragments as a result of the application of shear. This process is described in our co-pending application PCT/AU2004/00027, which is incorporated herein by reference.
  • the LPS ligands are provided in an oral formulation, and treatment of the patient by oral administration commences 3 to 6 days before cancer therapy takes place.
  • the LPS ligands are provided in an oral formulation, and treatment by oral administration commences within 1 to 48 hours after cancer therapy takes place.
  • the vaccination regimen leading to the production of hyperimmune colostrum preferably involves the injection of an animal with 0.3 to 15 mL of vaccine on 2 to 8 occasions prior to parturition.
  • the time period between successive vaccinations is 1 to 4 weeks, more preferably 2 to 3 weeks.
  • the processed hyperimmune colostrum can be formulated as a tablet or as a powder within a capsule or as an additive to a drink mix as described in US Patent 5,780, 028.
  • the composition is formulated for sequential, separate or co-administration with an antibiotic.
  • the present invention provides for concurrent administration of a composition of the present invention with an antibiotic or combination of antibiotics.
  • the antibiotics may include B-lactam antibiotics with and without B-lactamase inhibitors, aminoglycosides, tetracyclines, sulfonamides and trimethoprim, vancomycin, macrolides, fluoroquinolones and quinolones, polymyxins and other antibiotics.
  • the antibiotic is ciprofloxacin.
  • Ciprofloxacin the human-use equivalent of the veterinary fluoroquinolone ENR, was Food and Drug Administration-approved in 1987. Fluoroquinolones have excellent oral bioavailability, are well tolerated, and have been extensively used after myeloablative chemoradiotherapy.
  • compositions of the present invention have an advantage in that they are unlikely to produce toxicity in either minimally affected or critically ill populations. Furthermore, the compositions of the present invention have an advantage in that they are stable and may be stored and stockpiled for the treatment of populations of individuals. For example, the compositions of the present may be stored and stockpiled for the treatment of populations of individuals inadvertently exposed to radiation or chemical agents.
  • composition for administration to the patient further comprises a food-grade antimicrobial moiety, such as citrus extracts and iodine based antiseptics.
  • a food-grade antimicrobial moiety such as citrus extracts and iodine based antiseptics.
  • the antimicrobial moiety is the grapefruit seed extract of the chemical family diphenol hydroxybenzene sold under the product name Citricidal by NutriBiotics of Ripton, Vermont, USA.
  • composition for administration to the patient may be the hyperimmune material but may and may be derived from the hyperimmune material.
  • the composition for administration to the patient may have been processed using a detailing operation, more preferably using a defatting operation and an operation to remove cellular debris, more preferably a defatting operation, an operation to remove cellular debris and an operation to remove salts, sugars, other low molecular weight entities and some water.
  • the composition for administration to the patient comprises colostrum components which contain the anti-LPS in dried form.
  • Other components such as selected from the group consisting of adjutants, carriers , drugs, and other actives may be present in the composition and may be intimately mixed before, during or after the drying process.
  • the composition comprising colostrum may be dried by lyophilisation or other method known in the art for drying colostrum.
  • the composition for administration to the patient comprises at least three quarters of the lyophilised material by dry weight of the composition based on the dry weight of lypholized hyperimmune colostrum.
  • the bovine colostrum collected from the cow comprises at least 4% total protein (weight %), more preferably 5%, more preferably at least 8%, more preferably at least 10%.
  • the ratio of IgG to total protein of the colostrum collected from the cow is at least 10%, more preferably 20%.
  • composition for administration to the patient maybe in the form of preparations such as food additives, aqueous solutions, oily preparations, emulsions, gels, etc. , and these preparations may be administered orally, topically, rectally, nasally, bucally, or vaginally.
  • the preparations may be administered in dosage formulations containing conventional non-toxic acceptable carriers and may also include one or more acceptable additives, including acceptable salts, polymers, solvents, buffers, excipients, bulking agents, diluents, excipients, suspending agents, lubricating agents, adjuvants, vehicles, delivery systems, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants or sweeteners.
  • a preferred dosage form of the present invention is a powder for incorporation into beverages, pills, syrup, capsules, tablets, granules, beads, chewable lozenges or food additives, using techniques known in the art.
  • compositions for administration to the patient may, for example, contain additives such as described in our co-pending application WO/2006/053383 the contents of which are herein incorporated by reference.
  • the composition may be administered to the patient in a range of forms depending on the area of the Gl tract which is subject to mucositis (or likely to be subject to mucositis), the type of cancer treatment and condition of the patient. Examples of forms include mouth washes gargles, suppositories, tablets, caplets, pastes, syrups, or in powder or water dispensable powder or granular forms. Where the composition is administered in tablet form the tablet may be made by compressing or moulding the active ingredient, with one or more accessory ingredients optionally included.
  • Compressed tablets may be prepared by compressing, in a suitable machine, the active ingredient in a free- flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active, or dispersing agent.
  • Moulded tablets may be made in a suitable machine, by moulding together a mixture of the powdered active ingredient and a suitable carrier, moistened with an inert liquid diluent.
  • the treatment may be used in inhibiting and/or relieving mucositis in a range of cancer treatments.
  • the patient is being treated for at least one cancer selected from the group consisting of bone marrow, neck, head, stomach/oesophagus, liver, pancreas and the chemotherapeutic agent is selected from the set of Alkylating agents (such as Cyclophosphamide), Anthrocyclines (such as Doxorubicin), Cytoskeletal disrupters (such as Paclitaxel), Epothilones, Nucleotide analogs and precursor analogs (such as Fluorouracil), peptide antibiotics (such as Bleomycin), Platinum based agents (such as Cisplatin), Retinoids and Alkyloids.
  • Alkylating agents such as Cyclophosphamide
  • Anthrocyclines such as Doxorubicin
  • Cytoskeletal disrupters such as Paclitaxel
  • Epothilones such as Paclitaxel
  • Epothilones such as
  • the patient may be treated using the composition comprising anti-LPS antibodies or fragments prior to or during treatment for at least one of cancer of bone marrow, neck, head, stomach/oesophagus, liver, pancreas and the anti-cancer radioisotope agent is selected from the set teletherapy (external beam radiotherapy) including proton therapy, brachytherapy - sealed source radiotherapy, brachytherapy -unsealed source radiotherapy (this includes injection or ingestion of radioisotopes).
  • the composition is administered to the patient in a combination therapy with sucralfate paste.
  • sucralfate is freshly prepared prior to administration.
  • composition and sucralfate are coadministered in one or more medicament formulations.
  • the composition and sucralfate are separately administered.
  • the composition may be administered to the patient in a dose of anti-LPS antibody (and /or fragment) suitable to relieve or inhibit mucositis.
  • the dose will typically be repeated at intervals during and/or prior to cancer treatment which are effective to limit the effects of mucositis.
  • the composition is dosed 1 to 4 times per day at a dose of between 50 to 5000 mg of antibody such as from 200 to 3500 mg of antibody or fragment on an IgG equivalent basis.
  • the IgG equivalent of an antibody fragment is the original IgG moiety from which the fragment is taken.
  • the antibody may be delivered in a liquid, paste or solid and in one embodiment the antibody is in a liquid formulation and each dose comprises 20 to 200 ml total liquid volume such as from 50 to 150 ml total volume.
  • Such a liquid formulation may comprise a thickening agent such as xantham gum and / or a flavouring agent such as vanilla.
  • Example 1 [0144] In this example procedures are provided for confirming that hyperimmune sample material comprising anti - LPS antibody binds with LPS derived from commensal bacteria.
  • Enterobacter aerogenes was cultured on horse blood agar (HBA) plates in 37°C incubator for 16 hours
  • Klebsiella pneumoniae was cultured on Luria agar (LA) plates in37°C incubator for 6 hours
  • Pseudomonas aeruginosa was cultured on horse blood agar (HBA) plates in 37°C incubator for 16 hours
  • Salmonella typhimurium was cultured on Luria agar (LA) plates in37°C incubator for 16 hours.
  • Bacteria are collected from the plate the following day using a sterile cotton swab and suspended in phosphate buffered saline (PBS), to an optical density of 2.0 measured at 600 nm.
  • PBS phosphate buffered saline
  • PVDF polyvinylidene difluorite
  • Figure A is a Western Blot with anti-LPS antibodies (dairy derived) made as described in Example 3, and
  • Figure B is a Western Blot with antibodies contained in non- hyperimmune colostrum.
  • Wild-type C57BL/6 mice may be treated with 5-fluorouracil (450mg/kg) by intra-peritoneal injection.
  • 30 control mice may be treated similarly but with saline.
  • 0 mice may be placed in cages with ad lib access to drinking bottles containing 10% solution of anti-LPS colostrum, or 10 with ad lib access 10% solution of colostrum from non-vaccinated cattle, 10 may be given water in the drinking bottles.
  • the animals may be sacrificed and pieces of duodenum, jejunum and ileum harvested for assessment of epithelial damage by morphometry.
  • 5-FU may be found to induce significant epithelial intestinal damage (reduction of villus height/crypts depth ratio).
  • Animals with access to anti-LPS colostrum may have significantly less epithelial damage than animals in the other groups.
  • Step 1 Production of vaccine for dairy cattle.
  • cows were immunised with a vaccine comprising 06, 08, 015, 025, 027, 063, 078, 0114, 0115, 0128, 0148, 0153, and 0159 LPS, and the antibodies prepared according to the methods referred to below at Step 2.
  • Step 2 The procedures for preparing anti-LPS antibodies from vaccinated cattle reported in Pub. No. WO/2004/078209 International Application No. PCT/AU2004/000277 (the contents of which are herein incorporated by reference) were used.
  • Example 4 Effect of colostrum containing polyclonal anti-LPS antibodies in combination with oral antibiotic enrofioxacin on survival of mice after 7 gray Total Body Irradiation ⁇ TBI).
  • mice Were exposed to radiation and treated as follows.
  • Powdered skim milk powder (Carnation Skim Milk Powder; Nestle) and colostrum containing polyclonal anti-LPS antibodies produced by the methods described in Example 3 ("ETEC") (Immuron; Melbourne, Australia) were reconstituted at a low (4mg/mouse/day) and high (40mg/mouse/day) dose in autoclaved tap water.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Immunology (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Mycology (AREA)
  • Organic Chemistry (AREA)
  • Microbiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une méthode pour traiter ou inhiber le développement d'une mucosite alimentaire due à une chimiothérapie ou à une lésion causée par un rayonnement, une composition utilisée pour le traitement, l'utilisation de cette composition pour préparer un médicament destiné à traiter ou inhiber le développement d'une mucosite alimentaire due à une chimiothérapie ou à une lésion causée par un rayonnement. L'invention concerne en particulier le traitement d'une mucosite alimentaire due à une chimiothérapie ou à une exposition aux rayonnements, notamment une thérapie anticancéreuse.
PCT/AU2012/000700 2011-06-17 2012-06-18 Procédé et composition pour traiter ou inhiber une mucosite associée à une chimiothérapie ou à une lésion causée par un rayonnement WO2012171077A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2012269740A AU2012269740A1 (en) 2011-06-17 2012-06-18 Method and composition for treatment or inhibition of mucositis associated with chemotherapy or radiation damage

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201161498019P 2011-06-17 2011-06-17
US61/498,019 2011-06-17

Publications (1)

Publication Number Publication Date
WO2012171077A1 true WO2012171077A1 (fr) 2012-12-20

Family

ID=47356439

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/AU2012/000700 WO2012171077A1 (fr) 2011-06-17 2012-06-18 Procédé et composition pour traiter ou inhiber une mucosite associée à une chimiothérapie ou à une lésion causée par un rayonnement

Country Status (2)

Country Link
AU (1) AU2012269740A1 (fr)
WO (1) WO2012171077A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020227263A1 (fr) * 2019-05-06 2020-11-12 Synthetic Biologics, Inc. Traitements oncologiques à base de phosphate alcalin
CN114302729A (zh) * 2019-08-29 2022-04-08 生物医学研究集团有限公司 癌化学疗法支持剂、食品及药品

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004273A1 (fr) * 1996-07-30 1998-02-05 Dcv Biologics L.P. Procede servant a traiter les lesions gastro-intestinales
WO1998051217A1 (fr) * 1997-05-16 1998-11-19 Medical Defense Technologies, Llc Vaccin dirige contre les noyaux de lipopolysaccharides
WO2004043464A1 (fr) * 2002-11-06 2004-05-27 Celgene Corporation Methodes d'utilisation et compositions recourant a des composes immunomodulatoires pour le traitement et la gestion de syndromes myeloproliferatifs
WO2004078209A1 (fr) * 2003-03-04 2004-09-16 Anadis Ltd Composition et methode pour le traitement et la prevention d'infections bacteriennes enteriques
WO2005074978A1 (fr) * 2004-02-04 2005-08-18 Pharmaaware Sepsis B.V. Utilisation de phosphatase alcaline pour la desintoxication du lps
WO2005112928A1 (fr) * 2004-05-05 2005-12-01 Celgene Corporation Procédé d'utilisation et compositions comprenant des composés immunomodulateurs pour le traitement et la gestion des maladies myèloprolifératives
WO2007092427A2 (fr) * 2006-02-06 2007-08-16 Palingen, Inc. Traitement de l'endotoxemie a l'aide d'agents neutralisant l'endotoxine
WO2010125565A2 (fr) * 2009-04-27 2010-11-04 Hadasit Medical Research Services And Development Ltd. Préparation d'immunoglobuline enrichie en anti-lps destinée au traitement et/ou à la prophylaxie d'un trouble pathologique
WO2012023051A2 (fr) * 2010-08-17 2012-02-23 Immuron Ltd. Préparation d'immunoglobuline enrichie en anti-lps, destinée à être utilisée dans le traitement et/ou la prophylaxie d'un trouble pathologique

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004273A1 (fr) * 1996-07-30 1998-02-05 Dcv Biologics L.P. Procede servant a traiter les lesions gastro-intestinales
WO1998051217A1 (fr) * 1997-05-16 1998-11-19 Medical Defense Technologies, Llc Vaccin dirige contre les noyaux de lipopolysaccharides
WO2004043464A1 (fr) * 2002-11-06 2004-05-27 Celgene Corporation Methodes d'utilisation et compositions recourant a des composes immunomodulatoires pour le traitement et la gestion de syndromes myeloproliferatifs
WO2004078209A1 (fr) * 2003-03-04 2004-09-16 Anadis Ltd Composition et methode pour le traitement et la prevention d'infections bacteriennes enteriques
WO2005074978A1 (fr) * 2004-02-04 2005-08-18 Pharmaaware Sepsis B.V. Utilisation de phosphatase alcaline pour la desintoxication du lps
WO2005112928A1 (fr) * 2004-05-05 2005-12-01 Celgene Corporation Procédé d'utilisation et compositions comprenant des composés immunomodulateurs pour le traitement et la gestion des maladies myèloprolifératives
WO2007092427A2 (fr) * 2006-02-06 2007-08-16 Palingen, Inc. Traitement de l'endotoxemie a l'aide d'agents neutralisant l'endotoxine
WO2010125565A2 (fr) * 2009-04-27 2010-11-04 Hadasit Medical Research Services And Development Ltd. Préparation d'immunoglobuline enrichie en anti-lps destinée au traitement et/ou à la prophylaxie d'un trouble pathologique
WO2012023051A2 (fr) * 2010-08-17 2012-02-23 Immuron Ltd. Préparation d'immunoglobuline enrichie en anti-lps, destinée à être utilisée dans le traitement et/ou la prophylaxie d'un trouble pathologique

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020227263A1 (fr) * 2019-05-06 2020-11-12 Synthetic Biologics, Inc. Traitements oncologiques à base de phosphate alcalin
CN113993541A (zh) * 2019-05-06 2022-01-28 合成生物制品有限公司 基于碱性磷酸酶的肿瘤学治疗
CN114302729A (zh) * 2019-08-29 2022-04-08 生物医学研究集团有限公司 癌化学疗法支持剂、食品及药品

Also Published As

Publication number Publication date
AU2012269740A1 (en) 2013-01-31

Similar Documents

Publication Publication Date Title
Vivancos et al. Giardiasis: characteristics, pathogenesis and new insights about treatment
Lee et al. Immunoglobulin Y for potential diagnostic and therapeutic applications in infectious diseases
JP5340935B2 (ja) 抗ｃｓ１抗体に基づく組合せ療法を用いて多発性骨髄腫を処置する方法
Duran-Struuck et al. Principles of bone marrow transplantation (BMT): providing optimal veterinary and husbandry care to irradiated mice in BMT studies
Liang et al. Gut bacterial extracellular vesicles: important players in regulating intestinal microenvironment
CN112203669A (zh) 微生物组相关的免疫疗法
US20030143293A1 (en) Compositions and methods for treating diarrhea
WO2012154738A1 (fr) Composition et procédé pour améliorer la santé intestinale
Teng et al. An early fecal microbiota transfer improves the intestinal conditions on microflora and immunoglobulin and antimicrobial peptides in piglets
US20180028490A1 (en) Methods Of Treating Diarrhea And Promoting Intestinal Health In Non-Human Animals
Król et al. Selected factors determining the content of lactoferrin, lysozyme and immunoglobulins G in bovine milk
EP0484148A1 (fr) Procédé de préparation d'un médicament pour à la fois, le traitement et la prévention d'ulcères peptiques gastriques et de la gastrite, et des médicaments ainsi formulés
WO2012171077A1 (fr) Procédé et composition pour traiter ou inhiber une mucosite associée à une chimiothérapie ou à une lésion causée par un rayonnement
US20130012472A1 (en) Composition and methods of inhibiting gastrointestinal pathogen infection
US20180264061A1 (en) Methods of Treating Diarrhea in Companion Animals
US20170100429A1 (en) Methods of Treating Diarrhea in Neonatal and Young Non-Human Animals
US20170095442A1 (en) Methods of Treating Salmonella-Induced Diarrhea in Non-Human Animals
RU2678132C2 (ru) Продукт для здоровья собак, содержащий антитела против собачьего парвовируса типа 2
WO2016114677A1 (fr) Fabrication et utilisation de protéine pc2 d'œuf hyperimmun
JP4629964B2 (ja) ウシの消化器疾患治療剤
TW201808271A (zh) 治療高尿鈣症及腎結石之方法及組成物
JP3150162B2 (ja) 経口日和見感染症防止治療用組成物
US6806253B2 (en) Immunodulatory complex and use thereof in helicobacter diseases
CN102614180A (zh) 伊曲康唑在制备治疗多发性骨髓瘤药物中的应用
US20180021297A1 (en) Use Of Croton- Or Calophyllum-Derived Proanthocyanidin Polymers Or Botanical Extracts In Combination With Rifaximin For The Treatment Of Diarrhea In Non-Human Animals

Legal Events

Date Code Title Description
ENP Entry into the national phase

Ref document number: 2012269740

Country of ref document: AU

Date of ref document: 20120618

Kind code of ref document: A

121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12800457

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 28/03/2014)

122 Ep: pct application non-entry in european phase

Ref document number: 12800457

Country of ref document: EP

Kind code of ref document: A1