WO2005039614A2

WO2005039614A2 - Omega interferon for the treatment of hiv/aids, cancer and human and veterinary asthma

Info

Publication number: WO2005039614A2
Application number: PCT/OA2004/000003
Authority: WO
Inventors: née BELLET Anne Brigitte KOUNG; Zollo Paul Henri Amvam; Jean Yves Gauchet
Original assignee: Koung Nee Bellet Anne Brigitte; Zollo Paul Henri Amvam; Jean Yves Gauchet
Priority date: 2003-10-29
Filing date: 2004-10-10
Publication date: 2005-05-06
Also published as: WO2005039614A3; OA12835A

Abstract

The invention relates to a pharmaceutical composition with a whole immunotherapeutic activity, proven at 89 %, activating both cellular and humoral immunity in human and veterinary medicine, the protocol for use and therapeutic indications thereof. Said pharmaceutical composition, once subcutaneously and intramuscularly injected into well-specified sites of the lymphoid system and ganglionic areas of the sick organism, has a both cellular and humoral, progressive and perennial immunotherapeutic effect. The pharmaceutical formula of our composition is based on lymphocytic omega interferon, associated with vasodilator, antioxidant, anticoagulant and corticosteroid agents. The synergistic action of the cytokines and agents is provided for treatment of: chronic viral diseases, specifically HIV1, HIV2, AIDS and viral hepatitis; intracellular parasitic bacteria diseases: bacterial or trypanosomiasis leishmaniasis, tuberculosis, syphilis, chlamydia and mycoplasma; chronic allergic disorders: asthma; mesodermal and lymphoid cancer processes. Our invention and the mode of application thereof are suitable for treating said diseases both in human and veterinary medicine.

Description

The present invention relates to an immunotherapeutic compound based on interferon Omega combined with adjuvants: vasodilator, antioxidant and anticoagulant against VIII / AIDS, Asthma and cancer and its used in human and veterinary medicine. Our interferontherapy in HIV / AIDS, asthma and cancerous lymphoid processes is the new targeted and controlled therapeutic transduction pathway for the intranuclear signal which results in the modulation of the metabolism por ainiiiique the new continuous immuiiotic process 10 basis of our invention . cl ^" Inhibition of polyaminc metabolism biological signifîcancc and basis for nevv therapies edited by Peter Me Cann Λntony K Pegg Academy press 1987. The international application of this base nowadays results in the treatment of viral hepatitis with Interferon alpha and Virbac virus laboratory

15 animals. If it has been recognized since Pasteur in immunomicrobiology and Paul Ehrlich the Nobel Prize of 1908 that according to the modalities of introduction of an antigen, the organism can react according to the principle of selective toxicity "corpora non agunt nisiβxata" Immunity mediated highly selective and specific cell is

20 particularly suitable for combating intracellular microorganisms. Genetic engineering, which consists in manipulating the genome in vitro while ignoring the principles of in vivo regulation of proteonemic engineering, has so far come up against sustainable reproduction in vivo and its sustainability in the organism.

25 Already in 1983 Mitsui et al studied the synthesis of specific E coli proteins induced by auxotrophic amines. Likewise, D Watson and Crik in the molecular biology of genes in 1987 demonstrated in E-coli the coordination of this intelligent enzymatic metabolism which modulates and directs the translational response of the signal received by lactose spur a

30 through the promoter genes, repressor or structural inducers. But these therapeutic applications, disparate and limited, mentioned above, do not define the process of controlling the metabolic cascade of intranuclear transmission, transcription, transduction, translation and enzymatic translation through the promoter, regulator and or inhibitor genes.

35 eperonic of the transmitted molecular signal. The essence of our invention consists in the induction and interference of a specific and enzymatic protein production control mechanism controlling the targeted reaction cascade Mixed cellular and humoral immunotherapy in the antiviral, anti allergic and antitumor proteonemic fight.

40 Thus our invention based on these metabolic foundations targeted on the immunomodulation of the viral metabolic pathways of HIV / AIDS, immuno allergenic of asthma and lymphoproliferative lymphomas. In a continuous and perennial process which leads to total healing. Our invention is based on the induction and control of this cascade

45 translated and perennial immunobiochemical reaction through the targeted secretion of interferons and interleukins which provide solutions to the Millennium HIV / AIDS pandemic by mimicking and counteracting and neutralizing the metabolic pathways of viral reverse transcriptase. Similarly in Asthma and proliferative lymphomas nowadays incurable the triggering and control of this reaction cascade neutralizes and reverses the allergic and or proliferative process until complete recovery.

Our invention is supported by the work of the institute of immunostasis of Toulouse in France "

This theoretical and clinical work made it possible to lay the foundations for a new non-aggressive therapeutic approach: immunostasis. Starting from the observation that the immune system overlaps that of the nervous and endocrine systems, which share with it receptors and Hgands, iinniuiiostnsio is involved in the immunomodulatcur processes controlled by specific interleukincs, which neutralizes the local production of specific cytokines. For the past twenty years, we have witnessed the emergence of new diseases, which is based on the enzymatic demobilization of the immune system in the case of retro vi oscs of autoimmune diseases and chronic hypersensitivities in the case of asthma. Protein cancerous transformations, so many immune-based conditions on which the Pastorian principle "a disease, a germ, a vaccine" has demonstrated its limits.

However, basic research has made it possible to grasp on the one hand the enormous complexity of the functioning of the immune system, on the other hand to reduce the Pastorian dogma to only viruses and microorganisms with rapid development. Four major principles emerged from this fundamental research, known as Idiotypic Network Theory, advanced since 1974. a) The different but synergistic roles of two types of immune response. b) The humoral and cellular response, of the targeted specificity of the cellular response two types of T helper lymphocytes, the T Hclpcr type I and II. c) Reproducibility and vital sustainability of the response thus induced. The system of promotion and targeted gene control of enzymatic protein metabolism. d) Induction of this process by an endogenous enzymatic protein substance, for example interferons, exogenous such as reverse transcriptase, or mineral such as monoatomic ions. So therefore Any Immunotherapeutic action which ignores these immunological principles is doomed to the failure today observed in the treatments underway noted in cancerous lymphoid transformations, chronic viral infections of HIV / AIDS, parasitoses, bacteriosis with intracellular germs as well as chronic allergic processes of asthma. In 1974, the Danish Niel crne, future Nobel Prize winner, formulated a general concept explaining all the research results and clinical findings. To sum up, Jernc proposed a reciprocal action of immunoglobulins of all types, following the action of an antigen in the same organism. Thus, the action of an Agi antigen led to the production of an Acl antibody, which in turn caused the production of an Ac2 antibody, known as anti-idiotypic antibodies, whose rise in concentration came, on the one hand, to neutralize the Acl, on the other hand, dry up the production of Acl. There was therefore a self-regulatory system modulated by the appropriate eperonic genes of antibodies and immunoglobulins which made it possible to modulate and control in quantity and quality certain immunoglobulins, this is the case in hypersensitivities, including asthma. This mechanism also makes it possible to avoid the pathological action of the antibodies turned against the cells of the self: autoimmune diseases. The biochemical particularity of the configurations of the epitopes (active parts) of molecules Ac2 and of the antigen Agi all ύeux recognized by the Acl are equivalent one speaks molecular mimicry. Ac2 can be used in certain cases, at certain doses, to simulate the activity of Agi and deceive certain immune effectors. The first application of anti-idiotypic antibodies concerns us very early in our life: in fact, during the second half of pregnancy, the maternal immune system is stimulated by fetal antigens acting on paternal origins, somehow intruders for the maternal organism. We therefore have anti-fetal antibodies in circulation, then the establishment of a secondary production of anti-idiotipic antibodies Ac2 which exert neutralizing and immunosuppressive effects on Acl, and allow by controlling this anti-fetal reaction, maintain a normal pregnancy. In women who produce little Acl antibody, the anti-idiotipic production Ac 2 no longer takes place, and Acl cause abortions. In these patients, the injection of the lymphocytes of the husband brings the Agi necessary to push the production of Aacl, then of Ac2 which come all to rebalance the pregnancy goes to its term. Based on multiple observations like the example above, Jerne's theory has never been refuted. Whenever we looked for them, we found and measured these regulatory Ac2 antibodies. research teams have no clinical outlet for this network concept, in particular because of the difficulty in producing these Ac2. Jerne's theory, with applications that take into account the latest findings on the immune system, most of which have come from research on AIDS. In the case of AIDS, anti-idiotypic Ig G present epitopes equivalent to those of the patient. They can thus neutralize the CD4, CD20, and CD8 receptors of the patient's cells, and neutralize the infectious biochemical processes or the phenomena of syncytium of T4 lymphocytes. In our invention, the immunostasis protocol applied to patients with VHISIDA, lymphoid cancer processes and cases of asthma; intramuscular injections cause, by a phenomenon different from that of intradermal injections in the deep ganglia, this initiation of anti-idiotypic, protective, modulating and targeted antibodies. And level of the superficial ganglia humoral immunity action with in particular the production of anti-idiotypic Ig G, which reinforce the cellular immunity started by intradermal injections. This action, in AIDS patients with a high level of antibodies against their HIV viruses in their blood, provoke the production by B lymphocytes of the deep ganglia, of anti-idiotypic Ig G antibodies protecting the receptor sites of the HIV virus on the cells of the sick organism. Thus meeting an exogenous antigen, the immune system exerts its action on three forms: Antibodies (humoral immunity) which neutralize free viruses serve as a guide for the phagocytic cells to destroy the bacteria or the infected cells. Cytotoxic cells inducing cellular immunity which destroy in several ways the infected cells and the bacteria. Cytokines: interleukings and interferons which produce an amplifying action of the immune cells, and a regressive action of the development of the viruses. In the case of acute diseases, humoral immunity based on the Pastorian principles gives the best results. In the case of slow diseases and parasitoses where the pathogen is sheltered in the cells: cases of tuberculosis, leprosy, AIDS, Leishmaniasis, etc. * antibodies are not the adequate response, only cytokines and cytotoxic cells: CD8, killer cells, macrophages can overcome the disease. The T lymphocytes, leaders of the immune action, recognize the undesirable antigens, and trigger the production of specific antibodies by the B lymphocytes. The awakening of all cytotoxic cells by the cytokines. A storage of memory cells which will allow an even more effective reaction during a subsequent infection. This initial scheme has evolved considerably since 1987, when Mosmann and Coffman understood that in fact, the immune reactions could be different depending on whether the effector T lymphocytes belonged to one (TH 1) or another (1,112). has a TIN immune response to the Omega interferer. The type T helper T lymphocyte, after recognizing the antigen, will act on several immune effectors through the cytokines characteristic of its action, which will tend towards an action of cellular immunity: The production of interlukuk 2 ( IL2) will activate the macrophages (the cells which rid the organism of all undesirable substances) but also the cytotoxic cells NK and T8. The production of interferons will increase the body's sensitivity to undesirable antigens (CPA cells) but also increase the activity of NK cytotoxic cells and B lymphocytes producing IgC antibodies which will help macrophages find their target. We therefore have, with TH 1 lymphocytes, the initiation of a powerful and multiple antiviral defense activity. Three types of cells (macrophages, NK, and T8) are specifically sensitized, with a joint production of antibodies (IgG) directed specifically against the pathogenic microbe. "The type 1 immunological reaction at the level of the epidermis, a virus activates the CPA (langerhan cells) to produce the IL 12 inducing TIÏ1. These cells, through the IL-2 and the Omega IFNs activate cytotoxic T and NK cells vis-à-vis cells infected with the virus and the production of antiviral IgG, which, by binding to macrophages and reinforce the specific destruction of infected cells. the interferon Omega of type TH2. The TH2 lymphocytes recognize more specifically the antigens from bacteria, parasites or non-toxic substances (allergens of the pollen type or mite protein) their reaction is then very different: it passes all of first by the production of interleukin 10, which blocks the action of TIU, and the antiviral reaction is then suppressed. At the same time, the secretion of interleukin 4 mainly, will cause the production by B lymphocytes of a Particular antibodies, IgE, completely adapt to the fight against parasites, but unfortunately generating hypersensitivity pathology, such as asthma. It is remarkable to note that as much in tropical climate, where the parasitoses undermine the organisms, as in Western societies, where the various pollutions (atmospheric, food ...) pour quantity of allergens, in contact with the mucous membranes, the natural reaction of the body is a TH2 reaction at the expense of course of antiviral protection.

La-, type 2 immune reaction from bacteria, 265 known allergens- ₅ or parasites activate cells presenting CPA ° antigens to produce IL-10, which inhibits th.1 cells and IL -4. Activation of TH2 cells through the cytokines they produce IL-3, IL-4, IL-5, IL-6,1L-13), and activate the lymphocytes lî to produce IgE. These attach to mast cells and eosinocytes, inducing allergies and destroying microbes. The therapeutic action of our invention is divided into three phases

1- the intradermal injections trigger the intradermal inflammatory phase, according to the respective local reaction effects of the various substances contained in the pharmaceutical composition. These effects are different depending on the underlying cells concerned: the scusitive neurons release a mediator, substance P, which induces various local inflammatory phenomena, 1- including the degranulation of Basophils and Mast Cells.

2- the mobilization of young munocompέtentes cells in the ten ganglionic sites solicited by these substances and their rapid capacitations It is from the twelfth hour after the injection that interferonic proteins are produced. These interferons stimulate the secretion of interleukins of types 3, 6, 12, 13 18 which inhibits viral replication by selective toxicity on the 50 s viral ribosome the membrane peptidoglycancs the levogyrous amino acids, the Reverse Trancriptase and also activates apoptotic destruction of infested lymphocytes.

3-The triggering and perpetuation of the immunological memory due to the secretion of gamma and Omega interferon and of all the interleukins potentiating the neutralizing action of the virus in the circulating blood as well as in the infected cells at the level of the ganglionic sites. The immunotherapeutic principle of our invention based on interferon Omega antiviral anticancer or antiallergic is based on the control and coordination of protein metabolism by initiation, activation of genes promoting the production of cytokines and specific interleukins, l and perpetuation of the production of antagonistic and antiviral leukocyte cytokines initiate and maintain the process of protonemic fight against microbial protease by inhibiting the process of proliferation of the germ and activating the antagonist proteins which effectively fight against the transcription and genomic translation of virus proteins. The Immunotherapeutic application in VI H / AIDS i the current unlimited therapy for triple therapy of HIV infection and AIDS is based on Antiprotease and nucleo and non-nucleoside inhibitors of viral reverse transcriptase. This treatment leads to resistance due to mutation of the virus. And the ongoing phase III HIV vaccine trials give mediocre results of 34% because of the genetic variability of the strains of HIV. The Immunotherapeutic strategy of our invention against HIV / AIDS consists in imposing on the organism a powerful response of the TH1 type, that is to say cytotoxic but also generating anti-idiotipic antibodies, the molecular configuration is close to the virus, in order to protect the entry sites of CD4 cells which are still healthy. Omega interferon triggers control and perpetuates the targeted secretion of 1,3,6,9,12-type intleukings to neutralize free viruses and infected cells, but also the antibodies which will serve as a basis for anti-idiotipic protection.

Our pharmaceutical compound has an activity proven to 89% Immunotherapeutic both clinical and biological with normalization of CD 20 CD4 and CD8 and the progressive reduction of the viral load of the patients proof that it activates both cellular and humoral immunity in HIV patients /AIDS.

Clinical trial "our invention in patients with VII I / AIDS Our clinical trial Multicenter immunotherapeutic phase II I carried out on 280 AIDS patients at stage III and IV of the classification of WHO carrying strains HIV1 HIV2 of envelope immunotype type C genetics. This trial is based on the immunoprotective control and regulation of viral replication evaluated by CD4 CD8 CD20 counting. of patients before and after treatment. These patients were followed for three years. The clinical course with a clinical score of 90% improvement in the signs and symptoms of the patients and a gradual recovery in weight from the fortnight after the first injection. 86% efficacy made up of a progressive increase in CD4 which in 50 % of patients reached a normal rate after 28 months after the end of treatment. 99% safety no adverse effects were recorded during treatment. The stable composition, its easy and easy administration gave an immunotherapeutic effect effective, scalable and sustainable after three years. the development of the study is continuing on a larger cohort with viral quantification and protein and lipid assays.

The injection protocol of our invention and its therapeutic indications. This pharmaceutical composition is injected subcutaneously and intramuscularly, in 5 well specified and symmetrical sites of the lymphoid system and of the ganglionic areas of the body of the patients. the therapeutic indication of our invention targets: 1 patients with HIV / AIDS. 2 Asthmatics. 3 In lymphoid cancers. and mesodermic.

Our pharmaceutical compound is Formulated from: 1 Lymphocyte cytokines including interferon omega IFN-ω. Dose from there 2O IU / 2ml is, type l it is a glycosilated protein composed of 172 to 174 amino acids induced by viruses of molecular weight 22 to 24 Kda comprising 6 genes and 9 gene loci secreted by leukocytes and macrophages . 2 the local vasodilator adjuvants, associated with our compound is xylocaine dosed between 0.01 to 0.02g it allows to dilate the peripheral vessels in order to allow a better absorption of the active products from the injection sites. 3 the antioxidant composing our mixture is ascorbic acid dosed from 0.01 to 0.02g / l promotes intracytoplasmic and trahsnuclear signal transmission mcmhranairc. 4 The Anticoagulant of our mixture is based on heparin dosed between 0.05g to 0.2g allows the start and stop of the coagulation process. _Λ 5 The glucocorticoid of our compound is the Cortisone dosed from 0.003 to 0.008 mg it allows the intra nuclear transmission of the intra cytoplasmic signal as well as the product. The synergistic action of the omega interferon and the adjuvants of our compound is intended for antiviral immunotherapeutics specifically VIII I, Vllt 2. allows: 1 the progressive regeneration of the immune system with the increase of the immune cells CD4, CD8 and CD20. 2 Resistance to opportunistic infections. 3 Rapid rehabilitation of neurological psychoses and depressions. 4 Treatment of kaposi neoplasia. 5 A decrease in apoptosis. 6 A gradual and continuous decrease in viral load.

Claims

CLAIMS 1 Pharmaceutical Immunotherapeutic against HIV / AIDS asthma and cancer for human and veterinary use. Characterized in that it contains the mixture of omega interferon and antioxidant adjuvants, local vasodilator, anticoagulant and corticosteroid. 2 Pharmaceutical compound according to claim 1 characterized in that 2 ml of suitable mixture contains 20 IU of interferon Omega. 3 Pharmaceutical compound according to claim 1 and 2 characterized in that the antioxidant substance, component of the appropriate solution, is chosen 0 from tocopherols of alpha type or ascorbic acid dosed From 0.01 g to 0.02 g • 4 Compound Pharmaceutical according to claim 1 3 characterized in that the local vasodilatatcur is xylocaine or lydocaine dosed from 0.05 g to 0.2 g. 5 A pharmaceutical compound according to claims 1 to 4 characterized in that the anticoagulant is either the citric acid salts or the heparin derivatives. 5 dosed from 0.003 to 0.008mg. 6 Pharmaceutical compound according to claims there 5 characterized in that the corticosteroid, component of the appropriate solution, is chosen from the dexamethasonc salts dosed at 0.03 to 0.08g. 7 Pharmaceutical compound according to claims 1 to 6 characterized in that 0 its Mechanism of action is complete and mixed immunotherapeutic according to the principles of immunostasis. H Pharmaceutical compound according to claim 7 characterized in that it comprises a triple action Humoral, cellular and perennial immunotherapeutic 9 Pharmaceutical compound according to claim 8 characterized in that it is used 80% by intradermal injection and 20% by intramuscularly in five symmetrical lymph node areas of the diseased organism. 10 Pharmaceutical compound according to claims 1 to 9 characterized in that it is intended for the treatment of HIV / AIDS, lymphoid cancers and

30 Asthma. 11 Pharmaceutical compound according to claims 1 to 10 characterized in that it is indicated in human and veterinary medicine. 12 Pharmaceutical compound according to claim 10 and 11 characterized in that the complete therapy comprises three separate treatment doses thirty

35 days each. 13 Pharmaceutical compound according to claim there 12 characterized in that it has a proven activity of 89% in our study in patients with HIV / AIDS.