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WO2006095270A1 - Therapie anticancer combinee ou om-174 et compositions pharmaceutiques afferentes - Google Patents

Therapie anticancer combinee ou om-174 et compositions pharmaceutiques afferentes Download PDF

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Publication number
WO2006095270A1
WO2006095270A1 PCT/IB2006/001180 IB2006001180W WO2006095270A1 WO 2006095270 A1 WO2006095270 A1 WO 2006095270A1 IB 2006001180 W IB2006001180 W IB 2006001180W WO 2006095270 A1 WO2006095270 A1 WO 2006095270A1
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cancer
cells
tumor
pharmaceutical composition
composition according
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Jacques Alain Bauer
Carlo Chiavaroli
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OM Pharma SA
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OM Pharma SA
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Priority claimed from PCT/IB2005/000944 external-priority patent/WO2006011007A1/fr
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Priority to EP06744661A priority Critical patent/EP2170318A1/fr
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    • 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
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • 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
    • A61K31/28—Compounds containing heavy metals
    • A61K31/282—Platinum compounds
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to the immunological control of cancer in humans or other warm-blooded animals.
  • This invention relates to pharmaceutical compositions increasing or improving the efficacy of known antineoplastic agents by stimulating the cancer patients immune system.
  • this invention relates to pharmaceutical compositions incorporating as the active ingredients a combination of an immunomodulating agent and a known or experimental antineoplastic agent in admixture or combination with a diluent, an excipient, a carrier or a vehicle intended for oral or injectable way.
  • the present invention has, as a subject matter, pharmaceutical compositions combining as the active ingredient an immuno stimulating agent :a triacylated diphosphorylated lipid A derivative (OM-174) of formula (I)
  • the invention also relates to the salts of OM- 174 with a mineral or organic base and namely a pharmaceutically acceptable base such as the sodium, potassium, calcium, magnesium, triethylamine or triethanolamine salt.
  • This invention also relates to a pharmaceutical composition wherein the immunologically-active compound is OM- 174 in combination with standard or experimental chemotherapies in admixture or combination with one or more non-toxic, inert, pharmaceutically-acceptable diluent(s) or carrier (s).
  • This invention also relates to methods for treating cancer in warm blooded animals comprising humans suffering from cancer, which consists in administering to them a combination of a therapeutically effective amount of a mixture of OM- 174 of formula (I) and a known antineoplastic agent selected from the group consisting of an alkylating agent, and an antimetabolite agent, in a pharmaceutically-acceptable carrier excipient or vehicle suitable for the oral, parenteral, such as intravenous, intratumoral, subcutaneous and rectal, topical or sub-mucosal ways of administration .
  • the active ingredients may be given either simultaneously mainly in a single unit dosage, or separately or sequentially in separate unit dosages, mainly as a kit containing in separate containers the active ingredients.
  • compositions and the method using the same are based on well established antineoplastic agents as well as newly developed methods for treating neoplastic diseases.
  • Healthy cells normally divide, grow, and finally die when necessary in a patterned and well controlled manner. Often during a life-time, it may happen incidentally that an individual cell starts to divide without control.
  • the generated uncontrolled cells concomitantly generally express on their surface modified antigens (tumor associated antigens) which normally are not present on non-tumor cells, allowing thus in the vast majority of the cases, the immune system to prevent the occurrence of many cancers.
  • tumor associated antigens tumor associated antigens
  • Cancer cells may escape immune recognition
  • cancer antigens are tissue-specific molecules shared by cancer cells and healthy cells. Thus, these weak antigens do not typically elicit immunity.
  • tumors have several features, that make their recognition and destruction by the immune system, difficult. Indeed cancer cells are known to release immunosuppressive substances (such as e.g. the cytokine TGF-beta or the prostaglandin PGE2) to escape immune recognition.
  • immunosuppressive substances such as e.g. the cytokine TGF-beta or the prostaglandin PGE2
  • immunostimulation e.g by filgrastim or NEUPOGEN®, a medication that stimulates blood cells proliferation to fight the potential complications of neutropenia
  • the common standard rational is to use immuno stimulating agents in order to restore "normal" blood cellular formulas to avoid as much as possible opportunistic infections in cancer patients undergoing an anticancer therapy.
  • Cancer presently refers to a family of related proliferative diseases, which kill millions of persons each year. Despite recent progresses such as the use of Gleevec®, effective therapeutic agents to fight cancer, continue to be lacking, and cancer rates could further increase by 50% to 15 million new cases in the year 2020, (World Cancer Report, 2003) if no counteraction is attempted.
  • Lung cancer is the most common cancer worldwide, accounting for 1.2 million new cases per year ; followed by cancer of the breast, just over 1 million cases; colorectal, 940,000; stomach, 870,000; liver, 560,000; cervical, 470,000; esophageal, 410,000; head and neck, 390,000; bladder, 330,000; malignant non-Hodgkin lymphomas, 290,000; leukemia, 250,000; prostate and testicular, 250,000; pancreatic, 216,000; ovarian, 190,000; kidney, 190,000; endometrial, 188,000; nervous system, 175,000; melanoma, 133,000; thyroid,, 123,000; pharynx, 65,000; and Hodgkin disease, 62,000 cases.
  • This method also called radiotherapy, refers to the use of high-energy radiation from X-rays, gamma rays, neutrons, and other sources to kill cancer cells and shrink tumors. It may be given before surgery (neoadjuvant therapy) to shrink a tumor so that it is easier to remove. In other cases, radiation therapy is given after surgery (adjuvant therapy) to destroy any cancer cells that may remain in the area.
  • Chemotherapy is usually given in cycles: a treatment period, one or more days, followed by a recovery period, several days or weeks, then another treatment period, and so on.
  • chemotherapeutic cycles designed to shrink the tumor and reveal tumor antigens
  • stimulation of the immune system by OM- 174 could be performed.
  • Any efficient and safe chemotherapy drug should kill the cancer cells and not harm the adjacent healthy cells. This can in theory be achieved by characterizing properties specific to cancer cells which are not found on normal tissues.
  • Chemo therapeutic agents are mainly active during the S and M phases of the cell cycle.
  • Chemotherapy has still largely insufficient clinical efficacy. This strategy has its own toxicological limitations, because some normal cells (such as e.g. proliferating T and B cells) need also to divide when necessary.
  • an adequate and timely controlled clinical combined therapy with well-recognized or experimental chemotherapeutic drugs used first to shrink and kill some cancer cells (and thus potentially reveal tumor- associated antigens), followed by an unspecific immuno stimulation with OM- 174 enhances the efficacy of oncostatic drugs, and allows the acquisition of an immunological (specific) memory to get rid of cells bearing the tumor associated antigen, and also to limit the level of the side effects observed, by allowing e.g. to reduce the number of administrations and/ or the doses of the chemo therapeutic drug.
  • the immunotherapeutic agent OM- 174 increases the production of cytokines in human beings (see figure 1 for an example with TNF- ⁇ ).
  • TNF- ⁇ is known to affect tumor vessel destruction and improves vascular permeability to drugs such as Melphalan, as shown in clinical trials (Lejeune et al., 1988, Lejeune 2002).
  • Chemotherapeutic agents can be divided into the following classes :
  • antifolic agents purine analogs, pyrimidine analogs
  • Examples thereof are Capecitabine, Cladribine, Cytarabine, Fludarabine, Fluorouracil (5-FU), Gemcitabine, Mercaptopurine, Methotrexate, Thioguanin and the like.
  • Agents acting on tubules e.q alcaloids and toxoids: Paclitaxel, Docetaxel, Taxol, Vinblastine, Vincristine, Vindesine,
  • Protein kinase inhibitors are used as anticancer therapeutic agents and biological tools in cell signaling. Two representative members of this family of compounds are Imatinib Mesylate (Gleevec®) and
  • Alkylating agents share a common mechanism of action to the poisonous nitrogen mustards compounds originally developed for military use. It is therefore not surprising that in addition such agents display a full array of adverse events. They act on the negatively charged sites on DNA. By linking to DNA, replication and transcription are altered, cellular activity is stopped, and cells start to die. This class of anticancer drugs is very powerful and is used in many types of cancer (both solid tumors and leukemia). Unfortunately, the noted side effects are considerable (mainly decreased sperm production, cessation of menstruation, and possibly cause permanent infertility). Alkylating agents can cause secondary cancers. The most common secondary cancer is a leukemia (Acute Myeloid Leukemia) ' that may occur years after the end of the therapy.
  • Acute Myeloid Leukemia Acute Myeloid Leukemia
  • Metal derivatives such as the platinum derivatives and salts, for example cisplatin, have demonstrated some activity against cancer, mainly against lung and testicular cancer. The most significant toxicity of cisplatin is kidney damage. Second-generation platinum derivatives, called carboplatin, have fewer kidney side effects, and may be an appropriate substitute for regimens containing cisplatin. Oxaliplatin is a third- generation platinum that is active in colon cancer and has no renal toxicity. However, its major side effects are neuropathies.
  • Intercalants/topoisomerase II inhibitors form a complex with the enzyme and the DNA, and therefore inhibit DNA re-ligation. They are used to treat mainly malignant hemopathies, breast cancer, digestive tract cancers, genital cancers, bronchial, or conjunctive sarcomas. Their main adverse events are myelo-suppression, vomiting, cardiotoxicity, and alopecia.
  • Topoisomerase I inhibitors inhibit specifically topoisomerase-I, and thus transcription and replication during the S-phase of the cell-cycle. They are mainly used to fight colorectal cancers. Their main adverse events are myelo-suppression, neutropenia, vomiting, alopecia, and cholinergic syndromes.
  • Antimetabo lites They are used mainly against trophoblastic carcinomas, breast cancer, ovarian cancer, acute leukemia, osteosarcomas, lymphomas...
  • 5-Fluorouracil Another widely used antimetabolite that disturbs DNA synthesis is the pyrimidin analogue 5-Fluorouracil, which is transformed in fluorodeoxiuridin monophosphate (5-FdUMP) which blocks the enzyme thymidilate synthase, needed for the endogenous synthesis of pyrimidin bases (C and T).
  • 5-FdUMP fluorodeoxiuridin monophosphate
  • C and T pyrimidin bases
  • OM- 174 with 5-Fluorouracil to treat colon cancer will be provided below.
  • the compound has a wide range of activities including colon cancer, breast cancer, head and neck cancer, pancreatic cancer, gastric cancer, anal cancer, esophageal cancer and hepatomas.
  • 5-Fluorouracil is metabolized by the enzyme dihydropyrimidine dehydrogenase (DPD), which is not expressed by a small population of patients.
  • DPD dihydropyrimidine dehydrogenase
  • these patients When these patients are challenged with this chemotherapeutic drug, they get acute and severe toxicity (bone marrow suppression, severe GI toxicities, and neurotoxicities which may include seizures and even coma).
  • Capecitabine is a derivative of 5-fluorouracil i.e. an oral pro-5-Fluorouracil compound that has similar side-effect potentials.
  • Premetrexed is an antifolate antineoplastic agent impeding cell replication intended for injection (Alimta®), produced by Eli Lilly and Company.
  • antimetabolites that inhibit DNA synthesis and DNA repair include: Cytarabine, Gemcitabine (Gemzar®), 6-mercaptopurine, 6-thioguanine, Fludarabine, and Cladribine.
  • agents acting on tubules e.g alcaloids and toxoids
  • Alcaloids such as Vinblastine , Vincristine, Vindesine, or Vinorelbine bind to tubulin, a cytoplasmic protein and therefore impede the formation of the mitotic spindle and block mitosis in the metaphase.
  • Vincristine, vinblastine, and vinorelbine were extracted from the leaves of a periwinkle plant, Vinca rosea. They are mainly used to treat malignant hemopathies (including Hodgkin), aero-digestive cancers, nephroblastomas, breast cancers...
  • Taxanes first isolated from the bark of the Pacific yew tree Taxus brevifolia in 1963, are specific for the M phase of the cell cycle. The familly includes paclitaxel and docetaxel. Taxanes bind with high affinity to the microtubules and inhibit their normal function. They are efficient against breast cancer, lung cancer, head and neck cancer, ovarian cancer, bladder cancer, esophageal cancer, gastric cancer and prostate cancer. These drugs however decrease the number of blood cells.
  • the Tyrosine kinase inhibitor Gefitinib (Iressa®, AstraZeneca) is used for the treatment of advanced non-small cell lung cancer (NSCLC), the most common form of lung cancer in the United States.
  • Gefitinib blocks the action of the EGF receptors on the cells of certain lung cancers and has shown some effects against these cancers.
  • Iressar® Some most common side effects with Iressar® include among others: diarrhea, rash, acne, dry skin, nausea, vomiting, itching, loss of appetite, weakness, and weight loss.
  • the tyrosine kinase inhibitor Imatinib Mesylate (Gleevec®, Novartis) has been approved for the treatment of patients with positive inoperable and/ or metastatic malignant gastrointestinal stromal tumors (GISTs) and for the treatment of chronic myeloid leukemia (CML) .
  • Imatinib Mesylate is a signal transduction inhibitor that acts by targeting the activity of tyrosine kinases.
  • the activity of one of these tyrosine kinases, known as c-kit, is thought to drive the growth and division of most GISTs.
  • Imatinib is an inhibitor of the receptor tyrosine kinases for platelet- derived growth factor (PDGF) and stem cell factor (SCF), c-kit, and inhibits PDGF- and SCF-mediated cellular events.
  • PDGF platelet- derived growth factor
  • SCF stem cell factor
  • imatinib inhibits proliferation and induces apoptosis in GIST cells, which express an activating c-kit mutation.
  • Bleomycin is a small peptide isolated form the fungus Streptomyces verticillus. Its mechanism of action is similar to that of anthracyclines.
  • Bleomycin is an active agent in the regimen for testicular cancer as well as Hodgkin's lymphoma. The most frequent side effect of this drug is lung toxicities due to oxygen free radical formation.
  • Asparaginase catalyses the hydrolysis of asparagin into aspartic acid and ammonia, and therefore can kill cancer cells sentitive to a lack of asparagine- synthetase (lymphocytes and cells of lymphoid origin). It is used to treat hemopathies (acute leukemias, non Hodgkin lymphomas..). Its main adverse events are hepatic toxicity, nausea, and some anaphylactic shocks.
  • Mouse, chimeric, humanized and human monoclonal antibodies are used for treatment of human cancer [Untch M et al, 2003).
  • the use of monoclonal antibodies involves the development of specific antibodies directed against antigens located on the surface of tumor cells. Samples of the patient's tumor cells are taken and processed to produce specific antibodies to the tumor-associated antigens. In order for this approach to operate, a sufficient amount of antigens specific to the tumor cells must be present. In addition, the tumor antigens must be sufficiently different from the antigens elaborated by normal cells to provoke an antibody response.
  • antibodies can be used either alone to kill cancer cells or as carriers for other substances used for either therapeutic or diagnostic purposes.
  • chemotherapeutic agents can be bound to monoclonal antibodies to deliver high concentrations of these toxic substances directly to the tumor cells. In theory, this approach is less toxic and more effective than conventional chemotherapy because it reduces the delivery of harmful agents to normal tissues.
  • Erbitux is a monoclonal antibody that targets epidermal growth factor receptor (EGFR), and thus regulates cell growth. Erbitux is believed to interfere with the growth of cancer cells by binding to EGFR so that endogeneous epidermal growth factors cannot bind and stimulate the cells to grow. Erbitux is used to treat metastatic colon or rectum cancers. The infusion of Erbitux can cause serious side-effects, which may include difficulty in breathing and low blood pressure, which are usually detected during the first treatment. Infrequent interstitial lung disease (ILD) has also been reported. Other more common side effects of Erbitux treatment are:, rash (acne, rash, dry skin), tiredness/ weakness, fever, constipation, and abdominal pain.
  • Rituximab (anti-CD20) was the first registered MAB for the therapy of follicular lymphoma. Impressive results have been seen in combination with CHOP chemotherapy (cyclophosphamide, doxorubicin, vincristine and prednisone) in follicular and high-grade lymphomas.
  • marketed monoclonal antibodies are: Alemtuzamab (Campath®, targets CDw52 expressed on lymphoid tumors); Gemtuzumab-ozogamicin (Mylotarg® targets CD33 expressed on myeloid leukemia blasts), and Tositumab (Bexxar®). Cytokines :
  • cytokines tested for the treatment of cancer are Tumor Necrosis Factor- ⁇ , Interleukin-2 and Interferons.
  • TNF vascular permeability
  • interstitial pressure restricted the penetration of chemotherapeutic agents from the circulation into the tumor tissue.
  • Lejeune and others have shown that TNF exerts two distinct effects that are selective for angiogenic vessels, namely an early increase of tumor vessels permeability, which can be induced with a low dose of TNF, and a later increase in vascular apoptosis, which appears to require high doses (Lejeune et al. 1998, 2002).
  • Figure 1 shows that even a single i.v. dose of OM- 174 increases the plasmatic levels of TNF- ⁇ in human beings. This induced and controlled production of TNF- ⁇ strongly suggests that OM- 174 would allow a better bio-availability, of chemotherapeutic drugs such as Melphalan, towards the target cancer cells.
  • chemotherapeutic drugs such as Melphalan
  • Interleukin-2 is a substance produced by lymphocytes. In addition to being an essential growth factor for T cells, IL-2 increases various NK and T-cell functions. IL-2 also activates lymphokine-activated killer (LAK). LAK cells destroy tumor cells and improve the recovery of immune function in certain immunodeficiency states. Patients with renal cell cancer, melanoma, and non-Hodgkin's lymphoma have demonstrated some responses to IL-2 therapy.
  • IL-2 The most severe -toxicities result from IL-2's ability to increase capillary permeability. This may cause hypotension, ascites, generalized body edema, and pulmonary edema. Chills and fever also frequently occur within a few hours after IL-2 administration. Headache, malaise, and other flu-like symptoms are also common. Gastrointestinal effects include nausea, vomiting, loss of appetite, diarrhea, and mucositis.
  • Interferons are small proteins that inhibit viral replication and promote the cellular (T-cell) immune response.
  • IFNs Interferons
  • alpha, beta, and gamma Each type has similar but distinctive abilities for altering biological responses.
  • Alpha-IFN main indication is for use in treatment of hepatitis C, but it is currently also prescribed for use in the treatment of hairy cell leukemia and AIDS- associated Kaposi's sarcoma. It also displays some therapeutic effectiveness against hematologic diseases such as low-grade Hodgkin's lymphoma, cutaneous T-cell lymphoma, chronic myelogenous leukemia, and multiple myeloma. It is also somewhat effective on some solid tumors, such as renal cell cancer.
  • Beta-interferon is currently in use for treatment of multiple sclerosis.
  • IFN therapy One of the most common side effects of IFN therapy is a flu-like syndrome. Symptoms include fever, chills, tachycardia, muscle aches, malaise, fatigue, and headaches.
  • IFN IFN-associated neurotrophic factor
  • a decrease of the white blood cell count IFN-associated neoplasm
  • anemia with prolonged therapy
  • decreased platelets Gastrointestinal symptoms such as a loss of appetite, nausea, vomiting, and diarrhea may also be present.
  • Central nervous system toxicities range from mild confusion and sleepiness to seizures. Acute kidney failure is rare, but can occur. Loss of hair may also be a problem.
  • LPS bacterial lipopolysaccharide
  • lipid A The biological and toxic activities of LPS are associated with its lipid moiety, called lipid A.
  • Different bacterial species synthesize different lipid A structures and these have varying degrees of toxicity. This fact suggests that by modifying the structure of the native bacterial lipid A, it would be possible to prepare derivatives that have attenuated toxicity but retain this beneficial biological activity. A number of different lipid A derivatives have been tested in animal models of cancer with some success.
  • chemotherapeutic treatment Once the first chemotherapeutic treatment has been performed, it would be necessary to initiate an inflammatory response to boost first the nonspecific host defense. Then, specific immune responses would be elicited by the presence of the revealed tumor associated antigen. These specific memory responses are generally divided into humoral (immunity conferred by the antibodies produced by B-lymphocytes) and cell-mediated immunity (immunity conferred by T-lymphocytes) . Other important cells are antigen presenting cells (APC) such as macrophages and natural killer (NK) cells. Macrophages bind to an antigen and "present" the antigen to naive T-cells. These, in turn, become activated and produce mature lymphocytes.
  • APC antigen presenting cells
  • NK natural killer
  • NK cells are cytotoxic to tumor cells and virus-infected cells.
  • Contemplated combined treatments with OM- 174 The goal of the present therapeutic strategy to fight cancer is to first attack cancer cells with standard or experimental chemotherapeutic drugs, and thus reveal "in situ" cancer antigens, and to subsequently boost the immune system to prepare an appropriate immunological response.
  • chemotherapeutic drugs and OM- 174 could be administered concomitantly, because it is postulated that OM- 174, by increasing plasmatic TNF- ⁇ levels, would allow a better distribution of the anticancer drug towards the tumoral site(s).
  • the invention resides in the fact that, when the nonspecific drug OM- 174 (activating innate immunity) is combined with the nonspecific standard antineoplastic drugs claimed in this application the resulting combination leads to an increased (synergistic) efficiency of the combined anticancer treatment .
  • OM- 174 could be used therapeutically to treat many forms of cancer in combination with the compounds and drugs listed below.
  • the analyzed cytokines (TNF- ⁇ , IL-Ib, IL-I ra, IL-6, IL-8, sTNF-RI, sTNF- RII, IL-IO, IL-2, IL-2sRa, IFN- ⁇ ) showed a secretion profile consistent with that of immuno stimulating agents. Secretion occurred in all steps, and appeared more "patient”- than "dose”-dependent. (see figure I for the TNF- ⁇ profile induced by OM- 174).
  • Table 1 Summary of pharmacokinetics data of OM- 174 in man
  • the compounds of the invention can be in the form either of the acid form or of any acceptable salt suitable for injection in warm blooded animals and human beings.
  • Compounds will be administered parenterally (i.v. preferentially) after (or concomitantly in any suitable formulation) a preliminary therapy involving standard classical or experimental chemo therapeutic drugs.
  • tumors would be treated conventionally with well defined or experimental chemotherapeutic agents to reveal the patients tumor antigens. Then (or concomitantly to allow a TNF- ⁇ -mediated increase in vascular permeability) immuno stimulation with the compounds of the invention (preferentially 1 to 7 injections /per week and at least 5 parenteral injections) will be performed. Cycle of conventional therapies could then optionally be performed with decreased doses. It has been known from previous work as disclosed in WO 95/ 14026 that when tested per se as an immuno therapeutic agent, OM- 174 displays a strong therapeutic activity even when treatment, in the BDIX/ ProB colon model of cancer, is started up to 14 days after tumor induction.
  • This initial non specific treatment could be followed by non-specific immunotherapy using the compounds of the invention, which would be more effective as a result of the initial chemotherapy.
  • Immunotherapy will lead to the specific rejection of remaining tumor cells by the immune system and to the prevention of any tumor regrowth and metastatic growth.
  • Example 1 Enhancement of the curative effect of cyclophosphamide by OM- 174 in the melanoma B 16 model.
  • NK natural killer
  • CTL cytotoxic T lymphocyte
  • OM- 174 therefore increases the anticancer effect of the well-known chemotherapeutic drug cyclophosphamide and is therefore a candidate for association with chemotherapy in the treatment of human cancers.
  • mice Four to six weeks-old male C57BL/6 mice have been purchased from Charles River (Calco, Corno, Italy). B 16 melanoma tumor cells, were serially passaged subcutaneously (s.c.) in syngenic mice. On day 0, mice were injected s.c. in the right flank with 2 x 10 5 B 16 melanoma cells. Tumor growth was measured daily in each mouse, using calipers, and mean tumor diameter per day was calculated. At day 7 after tumor injection, all mice with s.c. tumors of about 2-3 mm diameter were divided into different experimental groups, i.e. phosphate buffered saline (PBS)- injected control 3, CY, OM- 174 or CY with OM- 174.
  • PBS phosphate buffered saline
  • Cyclophosphamide (Sigma, St. Louis, MO) was dissolved at 20 mg/ml in PBS immediately before use, and 0.2 ml per mouse were injected intraperitoneally . Each treated animal received a single dose of 200 mg/Kg CY on day 7. This dose was chosen on the basis of previous experiments as the most active one, that did not lead to observable toxicity in this strain of mice.
  • Spleen cell preparation Mice were sacrificed by cervical dislocation on day 14 after tumor inoculation. Spleen cells were obtained by gently teasing the individual spleens in RPMI 1640 (Flow Laboratories, Irvine, Ayrshire, U.K.).
  • CM Complete Medium
  • FBS foetal bovine serum
  • HEPES penicillin 50 U /ml
  • streptomycin 50 ⁇ ml all from Flow Laboratories.
  • B 16 melanoma cells were obtained from tumor-bearing mice, seeded in cell-culture flasks
  • B 16 and YAC-I cell lines were obtained from the laboratory collection, and were originally obtained from the
  • the cytotoxic activity of the effector cells collected from individual mice was measured by a standard 4-hour 51 Cr-release assay. Briefly, target cells were harvested from the cultures, washed twice, resuspended at 5 x 10 6 cells in 0.9 ml of CM and labeled with 100 ⁇ Ci PCr) sodium chromate (New England Nuclear, Boston, MA) for 1 hour at 37°C in a 5% CO2 incubator. After labeling, the cells were washed three times in RPMI 1640 and seeded in U-shaped 96-well microtiter plates (Flow Laboratories) at 1 x 10 4 cells/ well. The effector cells suspension was added to quadruplicate wells to give three E/T ratios (i.e.
  • Spleenocytes from individual mice were analyzed by flow cytometry.
  • the following monoclonal antibodies were used for double fluorescence analysis of spleen cell subsets: fluorescein (FITC) -conjugated anti-mouse
  • NKl.1 PE (PharMingen, San Diego, CA), PE-conjugated anti-mouse CD4 (PharMingen), FITC-conjugated anti-mouse CD8 (PharMingen) .
  • Approximately 1 x 10 6 spleen cells were resuspended in 50 ml of CM and staining was performed at 4°C for 30 minutes. Cells were then washed twice in PBS containing 0.02% sodium azide and flow cytometric analysis was performed using a FACscan flow cytometer (Becton Dickinson).
  • Fluorescence data were collected using a 488 nm excitation wavelength from a 15 mW air-cooled argon-ion laser. Emission was collected through a 585/420 nm band pass filter. A minimum of 5,000 events were collected on each sample and acquired in list mode by a Hewlett Packard 9000 computer. To exclude dead cells, debris, non lymphoid cells, and cell aggregates, data collection was gated on live spleen lymphocytes by forward and side angle scatter. Data are represented as the percentage of positive cells over the total number of cells counted.
  • Tumor growth was analyzed by T-test for unpaired data.
  • Student's T-test was employed to analyze mean control values in the other experiments. Values of less than 0.05 were considered significant.
  • both cyclophosphamide (CY) and OM- 174 when used individually, inhibited slightly but significantly B 16 tumor growth as compared to the untreated controls. Importantly, the combination OM- 174 and CY leads to a better inhibition of tumor growth rate, which was significantly better than that obtained by means of the single treatments.
  • Tumor cell elimination is known to be mediated in part by the cytotoxic activity of NK cells. It has been therefore measured the cytotoxic activity of spleenocytes against NK-sensitive (YAC-I) tumor cells.
  • Spleen cells were obtained from normal mice or from tumor-bearing mice that had been treated with PBS, CY, OM- 174, or CY in combination with OM- 174. Results are represented graphically in Table 2.
  • mice per group On day 14 post- tumor injection, five mice per group were killed and cytotoxic NK and CTL activities were measured as described in Materials and Methods. Results are expressed as mean percentage cytotoxicity ⁇ S. E., derived from five individually tested mice per group.
  • Cytotoxic T lymphocytes also play an important role in the elimination of tumor cells. It has been tested from spleen cells from normal and tumor-bearing mice for specific cytotoxic activity against autologous tumor cells using in-vivo B 16 melanoma cells as target. The results of these experiments are shown in Table 2 above. As expected, it has been found that spleen cells from normal mice showed no detectable cytotoxic activity against B 16 cells. On the contrary, spleenocytes from tumor-bearing mice showed an appreciable cytotoxic activity against autologous tumor cells, which appeared not to be increased by CY treatment. The administration of OM- 174 was capable of inducing a marked stimulation of CTL activity in tumor-bearing mice (two-fold increase).
  • mice treated with the combination of OM- 174 and CY the highest levels of cytotoxic activity against autologous tumor cells has been shown to be increased 4-fold with respect to those of tumor controls and 2-fold with respect to those of tumor mice treated with OM- 174 alone.
  • mice On day 14 post- tumor injection mice were killed and cells obtained from individually processed spleens were stained with monoclonal antibodies for FACS analysis. Results are expressed as mean percentages of positive cells vs total spleen cells ⁇ S. E. M derived from five individually tested mice.
  • the present combined treatment is highly effective in the model of B- 16 melanoma, ascertaining the efficacy of immunochemotherapeutic protocols for the lipid-A derivative OM- 174.
  • the results obtained on the stimulation of cytotoxic activities (non specific NK and cancer specific CTL) of spleen cells and on the increase of NK, CD4 + and CD8 + phenotypes following treatment with OM- 174, alone or in combination with CY correlate with the delay in tumor growth and with the prolonged survival time .
  • OM- 174 may thus be considered as a candidate for association with chemotherapeutic regimens in the treatment of cancer at clinical level.
  • Example 2 Antitumor Activity of Intratumoral OM- 174 Combined with Intraperitoneal Cyclophosphamide on Advanced PROb Subcutaneous Colon Tumors in BDIX Rats.
  • OM- 174 was from OM PHARMA, cyclophosphamide (CY) from Sigma- Aldrich (L'Isle d' Abeau, France), intradermic BCG (BCG Vaccine) from Pasteur Vaccins (Lyon, France).
  • CpG synthetic polynucleotides
  • the DHD /Kl 2 cells originated from a dimethylhydrazine-induced colon tumor in BD IX rats.
  • the PROb clone was chosen for its regular tumorigenicity when injected into syngeneic rats.
  • PROb cells were maintained in culture in Ham's FlO medium supplemented with 10% fetal bovine serum. Cells were detached with trypsin and EDTA and centrifuged in the presence of complete culture medium with fetal bovine serum to inhibit trypsin. Cells (2 x 10 6 /rat) were suspended in 0.1 ml of serum-free Ham's FlO medium then s.c. inoculated in the anterior thoracic area of anesthetized rats. Treatments of animals
  • mice BDIX rats treatment started at day 36 after the s.c. inoculation of PROb cancer cells, when the tumor volume was about 1 cm 3 .
  • Control group received no treatment.
  • the other groups received either an unique injection of CY by the i.p. route (25 mg/kg in 5 ml of a sterile NaCl solution), or immuno stimulants by the intratumoral (i.t.) route starting at day 43, or i.p. CY at day 36 combined with i.t. immuno stimulant starting at day 43.
  • i.t. Injections were done at day 43 and 50 for BCG (100 ⁇ l of the reconstituted solution + 100 ⁇ l NaCl for every intratumoral injection).
  • CpG 100 ⁇ g/injection in 200 ⁇ l NaCl
  • OM-174 200 ⁇ g/injection in 200 ⁇ l NaCl
  • Intratumoral immuno stimulants alone have no antitumoral effect comparatively to untreated animals on these large, established PROb tumors (figure 4).
  • i.p. cyclophosphamide caused a transient regression of the subcutaneous tumors, followed by a growth resumption in all animals. This was in accordance with the known chemosensitivity of the PROb cells to alkylating agents (Warrt et al, 1992).
  • CY alone was unable to cure animals.
  • BCG had a deleterious effect, since its association to CY was less active than CY alone.
  • CpG did not modify the CY activity.
  • OM-174 strongly enhanced the antitumor affect of CY.
  • Example 3 Enhancement of the anticancer effect of the chemotherapeutic agent cisplatin in combination with OM-174 Introduction
  • the antitumoral effect of the immuno stimulating agent OM-174 has been demonstrated many times in the past in the BDIX/ ProB model of peritoneal carcinomatoses in the rat (e.g. Onier et al., 1999). It has been shown that the beneficial effect is maximal (90% of complete remissions) when the treatment starts 14 days (D 14) after the injection of the cancer cells (syngenic Prob cells). In contrast, the efficacy of the product is diminished when the treatment starts on D21, or D28, and completely disappears when treatment starts on D35 (when the tumor nodules are larger than 1 cm in diameter).
  • Colon cancer PROb cells were originally obtained from a tumor of a BDIX rat induced by 1,2-dimethylhydrazine.
  • the BDIX strain of rats was established in 1937 by H. Druckrey.
  • these rats come from Iffa-Credo (L'Asbresle, France).
  • BDIX rats 4 months ⁇ 1 month at the beginning of the experiment, 7 animals /group, received i.p. cultured syngenic PROb cells (i.p) on day 0.
  • Cisplatin (3 mg/kg ) was injected i.v. on day 21, and OM- 174 treatment (1 mg/kg, 3 injections i.v. per week in the penile vein) started either on days 28 or 35. Survival was followed until day 72 in the example presented here.
  • OM- 174 per se is fully able to display anticancer effects when treatment (1 mg/kg, up to 15 injections i.v. every 2nd day) starts until 2 weeks after tumor inoculation. However the anticancer effect is lost when treatment is started later (day 28 or day 35 as shown in figure 5). This less favorable condition is certainly closer to the real clinical situation encountered in many cancerous patients.
  • Example 4 Enhancement of the anticancer effect of the chemotherapeutic agent oxaliplatin in combination with OM- 174
  • Oxaliplatin is a clinically successful member of a recent generation of anticancer chemotherapeutic agents of the platinum complex series. Cisplatin and carboplatin, were until recently the only platinum compounds used clinically against solid tumors, such as testicular, ovarian, bladder and lung carcinomas. Unfortunately their use was limited by severe toxicity including nephrotoxicity, severe gastrointestinal intolerance (with nausea and vomiting), ototoxicity, and myelosuppression.
  • BDIX rats 4 months ⁇ 1 month at the beginning of the experiment, 10 animals /group, received i.p. cultured syngenic PROb cells (i.p) on day 0.
  • Oxaliplatin (3 mg/kg ) was injected i.v. on day 21, and OM-174 treatment (0.1; 0.3; or 1 mg/kg, from day 28 to 60, 3 injections per week for a total of 15 i.v. injections). Control injections were performed with physiological serum. Survival was followed for 112 days in the example presented below.
  • Example 5 Enhancement of the anticancer effect of the chemotherapeutic agent 5-Fluouracil (5-FU) in combination with OM- 174.
  • a clinically efficient antimetabolite drug that disturbs DNA synthesis is 5- FU, used since at least four decades (see e.g Rich et al., 2004). It has a wide range of activity including colon cancer, breast cancer, head and neck cancer, pancreatic cancer, gastric cancer, anal cancer, oesophageal cancer and hepatomas.
  • Carcinomatoses were evaluated blindly. As it is impossible to measure the volume of a carcinomatosis, they were classified according to the number and diameter of the nodules:
  • the Mann-Whitney test shows a significant difference between Control and OM- 174 groups as well as between Control and 5-FU + OM- 174 groups. No significant difference has been shown for 5-FU versus Control groups. There is a significant difference in the median scores between the Control group and both the OM-174-DP and the 5-FU + OM-174-DP groups (DP means diphosphorylated derivative).
  • the combination OM- 174 + 5-FU is better in term of carcinomatosis classes and survival time than both agents taken individually in this model of cancer.
  • the needed dosages of OM- 174 range from 0.05 to 100 mg/m 2 in humans and preferably from 0.1 to 20 mg/m 2 .
  • the needed dosages of the antineoplastic agent very broadly vary depending on the nature of the tumor, the delay in tumor growth and the mode of action of the antineoplastic agent. These dosages may extend from 0.1 to 200mg/kg.
  • Boyd LA Intravesical Bacillus Calmette-Guerin for treating bladder cancer. Urol Nurs. 2003 Jun;23(3): 189-91, 199; quiz 192.
  • Surgicalrt B Dimanche-Boitrel MT, Genne P, Petit JM, Onier N, Jeannin JF. Experimental chemotherapy of peritoneal carcinomatosis of colonic origin in rats. Gastroenterol Clin Biol. 1992; 16(3):215-9.
  • Jain R K Understanding barriers to drug delivery: high resolution in vivo imaging is key. Clin. Cancer Res., 5, 1605—1606 (1999). Jain RK. Barriers to drug delivery in solid tumors. Sci. Am., 271, 58 — 65 (1994).
  • mice were injected s.c. in the right flank with 2 x 10 5 B 16 melanoma cells. Tumor growth was measured daily in each mouse, using calipers, and mean tumor diameter was calculated.
  • all mice with s.c. tumors of about 2-3 mm diameter were divided into different experimental groups, i.e. phosphate buffered saline (PBS)-injected control, cyclophosphamide (CY), OM-174 or CY with OM-174.
  • PBS phosphate buffered saline
  • CY cyclophosphamide
  • OM-174 CY with OM-174.
  • Each treated animal received a single dose of CY, i.p. (200 mg/Kg) on day 7, or/and OM-174, i.p. (1 mg/kg) on days 8, 13, 18, 23 and 28 after tumor inoculation. Data are from one out of three separate experiments, which gave similar results.
  • mice (20 animals /group) injected with B 16 melanoma cells, and treated as described for Figure 2.
  • Data are from one out of three separate experiments, which gave similar results.
  • CY cyclophosphamide
  • BCG Bacillus Calmette-Guerin
  • CpG unmethylated cytidine-guanosine dinucleotides
  • mice BDIX rats treatment started at day 36 after the s.c. inoculation of PROb cancer cells, when the tumor volume was about 1 cm 3 .
  • Experiments consisted of 8 groups of rats (6 animals in each group) .
  • Control group received no treatment.
  • the other groups received either an unique injection of CY by the i.p. route (25 mg/kg), or immuno stimulants by the intratumoral (i.t.) route starting at day 43, or i.p. CY at day 36 combined with i.t. immuno stimulant starting at day 43. Injections were done at day 43 and 50 for BCG (100 ⁇ l of the reconstituted solution + 100 ⁇ l saline for every intratumoral injection).
  • CpG 100 ⁇ g/injection in 200 ⁇ l saline
  • OM-174 200 ⁇ g/injection in 200 ⁇ l saline
  • OM- 174 is an immunomodulating agent in humans and that when combined with alkylating agents or antimetabolite agents, the resulting anti-cancer activities of the combinations is surprisingly higher then the activities observed when the compounds are given alone.

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Abstract

L'invention se rapporte à une thérapie anti-cancer et plus précisément au contrôle immunologique du cancer. Cette invention concerne plus particulièrement des compositions pharmaceutiques intégrant comme ingrédient actif, un dissacharide de glucosamine OM-174 de formule (I) ainsi que des agents antinéoplasiques connus, sélectionnés principalement dans le groupe constitué d'agents d'alkylation et d'agents antimétaboliques, associés ou mélangés à un diluant ou un excipient inerte non toxique pharmaceutiquement acceptable. Cette invention concerne également des dérivés ioniques de OM-174 ainsi que leur utilisation pour traiter des états cancéreux, dans un conteneur unique ou dans des conteneurs distincts.
PCT/IB2006/001180 2004-07-23 2006-03-03 Therapie anticancer combinee ou om-174 et compositions pharmaceutiques afferentes Ceased WO2006095270A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008059035A3 (fr) * 2006-11-16 2009-09-24 Om Pharma Bêta 1,6-glucosamine-disaccharides fonctionnalisés et procédé de fabrication
US7985548B2 (en) 2006-03-03 2011-07-26 The United States Of America As Represented By The Department Of Health And Human Services Materials and methods directed to asparagine synthetase and asparaginase therapies

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0668289A1 (fr) * 1993-09-07 1995-08-23 Suntory Limited Nouveau derive de disaccharide
US6005099A (en) * 1993-11-17 1999-12-21 Laboratoires Om S.A. Glucosamine disaccharides, method for their preparation, pharmaceutical composition comprising same, and their use
WO2001046126A1 (fr) * 1999-12-22 2001-06-28 Om Pharma Pseudodipeptides acyles porteurs d'un bras auxiliaire fonctionnalise
US20020156033A1 (en) * 2000-03-03 2002-10-24 Bratzler Robert L. Immunostimulatory nucleic acids and cancer medicament combination therapy for the treatment of cancer

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0668289A1 (fr) * 1993-09-07 1995-08-23 Suntory Limited Nouveau derive de disaccharide
US6005099A (en) * 1993-11-17 1999-12-21 Laboratoires Om S.A. Glucosamine disaccharides, method for their preparation, pharmaceutical composition comprising same, and their use
WO2001046126A1 (fr) * 1999-12-22 2001-06-28 Om Pharma Pseudodipeptides acyles porteurs d'un bras auxiliaire fonctionnalise
US20020156033A1 (en) * 2000-03-03 2002-10-24 Bratzler Robert L. Immunostimulatory nucleic acids and cancer medicament combination therapy for the treatment of cancer

Non-Patent Citations (3)

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Title
D'AGOSTINI C ET AL: "Antitumour effect of OM-174 and Cyclophosphamide on murine B16 melanoma in different experimental conditions", INTERNATIONAL IMMUNOPHARMACOLOGY, ELSEVIER, AMSTERDAM, NL, vol. 5, no. 7-8, July 2005 (2005-07-01), pages 1205 - 1212, XP004898776, ISSN: 1567-5769 *
ONIER N ET AL: "Expression of inducible nitric oxide synthase in tumors in relation with their regression induced by lipid A in rats", INTERNATIONAL JOURNAL OF CANCER, vol. 81, no. 5, 31 May 1999 (1999-05-31), pages 755 - 760, XP002316983, ISSN: 0020-7136 *
See also references of EP2170318A1 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7985548B2 (en) 2006-03-03 2011-07-26 The United States Of America As Represented By The Department Of Health And Human Services Materials and methods directed to asparagine synthetase and asparaginase therapies
US9181552B2 (en) 2006-03-03 2015-11-10 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Materials and methods directed to asparagine synthetase and asparaginase therapies
WO2008059035A3 (fr) * 2006-11-16 2009-09-24 Om Pharma Bêta 1,6-glucosamine-disaccharides fonctionnalisés et procédé de fabrication

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