immunogenic composition for modulation of the imue system and its use, method of treatment and preve

专利摘要:
IMMUNOGENIC COMPOSITION FOR MODULATION OF THE IMMUNE SYSTEM AND ITS USE, METHOD OF TREATING AND PREVENTING DISEASES, METHOD FOR INDUCING CELLULAR REGENERATION AND METHOD FOR RECOVERING THE IMMUNE RESPONSE The present invention relates to immunogenic compositions for modulating the immune system that comprise a therapeutically effective amount of two or more immunoactive antigenic agents that have pathogen-associated molecular patterns (PAMPS) and / or hazard-associated molecular patterns (DAMPS) and a or more from a physiologically acceptable vehicle, excipient, diluent or solvent. The immunogenic compositions of the present invention are used in the manufacture of drugs for the prevention and / or treatment of and in the prevention and / or treatment of infectious diseases, autoimmune diseases, allergic diseases, inflammations, arthritis, inflammatory diseases, transplant rejection, diseases caused by vascular disorders, diseases caused by hemorrhagic or ischemic cardiovascular accidents, ischemia, infarction and hemorrhages that lead to tissue destruction, heart, renal, respiratory or liver failure, cancer, tumors and malignant and benign neoplasms. The present invention also relates to methods for inducing cell regeneration, tissue regeneration, organ regeneration and regeneration of organic systems, such as the circulatory system, the nervous system and the endocrine system. Finally, the present invention relates to methods for renewing the immune response in an animal, particularly humans.
公开号:BR112013023773A2
申请号:R112013023773-2
申请日:2012-03-19
公开日:2020-11-10
发明作者:Alexandre Eduardo Nowill
申请人:Alexandre Eduardo Nowill；
IPC主号:

专利说明:

t t 4 F Invention Patent Descriptive Report for: 4 "IMMUNOGENIC COMPOSITION FOR MODULATION OF THE IMMUNE SYSTEM AND ITS USE, METHOD OF TREATMENT AND PREVENTION OF DISEASES.
METHOD FOR INDUCING CELLULAR REGENERATION AND METHOD FOR 5 IMMUNE RESPONSE RECONDUCTION ".
FIELD OF THE INVENTION The present invention relates to immunogenic compositions for modulating the immune system that comprise a therapeutically effective amount of two or more immunoactive antigenic agents that have pathogen-associated molecular patterns (PAMPS) and / or hazard-associated molecular patterns ( DAMPS) and one or more of a physiologically acceptable vehicle, excipient, diluent or solvent.
Preferably the compositions of the present invention comprise immunoactive antigenic agents that have pathogen-associated molecular patterns (PAMPS) and / or hazard-associated molecular patterns (DAMPS) selected from the group consisting of: (A) antigenic agents with molecular patterns associated with bacteria ; (B) antigenic agents with molecular patterns associated with viruses; (C) antigenic agents with molecular patterns associated with fungi and yeasts; (D) antigenic agents with molecular patterns associated with protozoa; (AND)
antigenic agents with molecular patterns associated with multicellular parasites and / or (F) antigenic agents with molecular patterns associated with prions.
Another aspect of the present invention is the use of the 5 immunogenic compositions in the manufacture of medicines for the prevention and / or treatment of infectious diseases, autoimmune diseases, allergic diseases, inflammations, arthritis, inflammatory diseases, transplant rejection, diseases caused by vascular disorders, diseases caused by hemorrhagic or -ischemic cardiovascular accidents, ischemia, infarction and hemorrhages that lead to tissue destruction, heart, kidney, respiratory or liver failure, cancer, tumors and malignant and benign neoplasms.
The immunogenic compositions of the present invention are also used directly in the prevention and / or treatment of infectious diseases, autoimmune diseases, allergic diseases, inflammations, arthritis, inflammatory diseases, transplant rejection, diseases caused by vascular disorders, diseases caused by hemorrhagic cardiovascular accidents or ischemic, ischemia, infarction and hemorrhages that lead to tissue destruction, heart, renal, respiratory or liver failure, cancer, tumors and malignant and benign neoplasms.
The present invention also relates to methods for
P l induce cell regeneration, tissue regeneration,
I organ regeneration and organic system regeneration, such as the circulatory system, the nervous system and the endocrine system.
Finally, the present invention relates to methods for renewing the immune response in an animal, particularly humans.
BACKGROUND OF THE INVENTION The discovery of antibiotics and other drugs 10 From the pioneering discovery of antibiotics, in the second half of the 20th century, new antibiotics, semi-synthetic antibiotics and new chemotherapeutics with antimicrobial activity, began to be developed on a large scale, against most extracellular 15 and intracellular bacteria. These developments changed the history of medicine, allowing a broad spectrum of cure to be achieved for the vast majority of infectious bacterial diseases that plagued humanity.
Thus, the discovery of antibiotics was an important milestone, a watershed, since infections could be combated and cured, in a specific way and with a clear and measurable cause and effect relationship, when already established. This discovery greatly expanded the healing capacity of medicine, with an enormous positive impact on human health and life expectancy. The discovery of antibiotics, in the evolution and cure of diseases, deeply influenced the research and the researchers' thinking based on the success 5 achieved by this experimental model (Reeves G, Todd i.
Lecture notes on immunology. 2nd ed: Blackwell Scientific Publications, 1991; Neto va, Nicodemo AC, Lopes HV.
Antibiotics in medical practice. 6 eck Sarvier, 2007; Murray PR, Rosenthal KS, Pfaller MA. Medical Microbiology. 5th ed: Mosby, 2006; Trabulsi LR, Alterthum F. Microbiology. 5 Ed: Atheneu Editora, 2008).
Antibiotics were followed by the development and use of antifungal, antiparasitic and antiviral drugs.
Antineoplastic, cytotoxic and cytostatic drugs against malignant tumors, anti-inflammatory, antiallergic and immunosuppressive drugs (anti lymphocytes, anti leukocytes neutralizing the immune system) of hormonal and non-hormonal nature have also been developed, with a wide range of applications, as in infectious diseases, inflammatory diseases of any origin, autoimmune and genetic diseases, vascular diseases, allergic diseases, traumas, neoplastic diseases, hormonal diseases, degenerative diseases, among others.
Thus, the new drugs have brought an enormous capacity * for intervention in the medical field, with numerous benefits, with definitive, partial cures, with prolongation of life in incurable diseases, but with a huge morbidity, due to side effects due to their lack of specificity regarding the pathophysiology of the treated diseases.
Innate immunity In addition to preventing 10 microorganisms from entering and preventing their establishment, innate immunity has another vital function recently discovered: the discrimination between "self" and not "self" by standard recognition and the linked ability to raise the alarm and the command to initiate or inhibit an integrated immune response against an invading microorganism, or to stop, repair or inhibit a situation of destruction, or self-harm to the organism, such as in trauma, autoimmune diseases and diseases allergic reactions, among others. This double capacity was previously, erroneously, attributed exclusively to adaptive immunity. Innate immunity, through its own receptors, recognizes the invading pathogenic microorganism, or autologous or even allogeneic neoplastic cells, or allogeneic or heterologous transplants as not "self", that is, identifying it as not belonging to the organism. Thereafter, it gives the alarm signal * and jointly triggers the innate and adaptive immune response capable of eliminating them or suppresses a deleterious response to the Hurnan or animal organism (GoIdsby RA, Kindt tj, Osborne b. Kuby immunology 6th ed: ARTMED; 2008, 704 p; janeway C, Travers P, Walport M, Slhlomchik MJ. Immunobiology five. 5 ed: Garland Pub .; 2001. 732 p .; Voltarelli JC. Clinical immunology for medical practice: atheneu publisher ; 2009; janeway CA, jr., 10 Medzhitov R. Innate immune recognition. Annual review of immunology. 2002; 20: 197-216. Epub 2002/02/28; Matzinger P.
The danger model: a renewed sense of self. Science.
2002; 296 (5566): 301-5. Epub 2002/16/16; Steinman RM, Banchereau j. Taking dendritic cells into medicine. Nature.
15 2007; 449 (7161): 419-26. Epub 2007/09/28 .; Beutler BA.
TLRS and innate immunity. Blood. 2009; 113 (7): 1399-407.
Epub 2008/09/02; Moresco EM, Lavine D, Beutler B. Toll-like receptors. Current biology: CB. 2011; 21 (13): R488-93.
Epub 07/12/2011).
20 Standard recognition, not "Self", of an invading germ, of a neoplastic cell, or of an altered or transplanted cell is performed by sentinel cells, represented by epithelial cells, mucous cells and stromal cells, such as pericytes, dendritic cells, macrophages and fibroblasts, among others. These cells, strategically distributed throughout the body, have PRRs (Pattern Recognition Receptors) and DRRS (Danger 5 Recognition Receptors), which are respectively receptors capable of recognizing a) standard identification molecules, characteristics of a wide range of microorganisms, and b) certain patterns of chemical and physical substances called inert and changes in metabolic stress, such as the release of free radicals and tissue chemical changes, caused by ionizing radiation, or by chemical substances, among others.
PRRS do not discriminate against a specific individual microorganism, but the presence of microorganisms, different from the human organism. Each PRR receptor can bind to several different pathogens, recognizing carbohydrates, lipids, peptides and nucleic acids as PAMPs (Pathogen Associated Molecular Patterns) from bacteria, viruses, fungi or parasites, which are not found in the human body. or animal.
DRRS discriminate that there is tissue aggression, a situation of danger caused by agents said to be non-living or inert. DRRS identify DAMPS (Danger associated Molecular Patterns) associated with
#. tissue aggression by toxic substances, radiation, or trauma, which generate metabolic stress, release of free radicals and tissue chemical changes, recognized by these receptors. (janeway C, Travers P, 5 alport m, Slhlomchik MJ. Immunobiology five. 5 eCt Garland Pub .; 2001. 732 p .; Matzinger P. The danger model: a renewed sense of self. Science. 2002; 296 (5566) : 301-5.
Epub 2002/16/16; Beutler BA. TLRS and innate immunity.
Blood. 2009; 113 (7): 1399-407. Epub 2008/09/02; Moresco EM, 10 LaVine D, Beutler B. Toll-like receptors. Current biology: CB. 2011; 21 (13): R488-93. Epub 07/12/2011).
In this way, the cells. sentinels, through their PRRS and their DRRs, have a primary role in the discrimination of what belongs ("Self") and what does not belong (not "Self") and in the triggering of inflammation and immune response, through recognition of PAMPS of invading pathogens and DAMPS caused by neoplastic cells and toxic substances or alterations by trauma, which lead to a situation of real danger for the human and animal organism.
Instantly, these activated sentinel cells give the alarm signal, triggering the innate immune response, through the NF-kB (Nuclear Factor-kB) signal translation system, which leads to the secretion of pro-cytokines.
inflammatory cells and the IRF signal translation system, which produces Type I Alpha and Beta Interferons. These cytokines, acting on cells and vessels, cause a local inflammatory process to initially contain the invasive agent, autologous (tumor cells), heterologous (microorganisms, prions, grafts and transplants) or allogeneic (grafts and transplants), or repair dangerous situations. This containment occurs through pre-existing antibodies, opsonizing acute phase proteins and through leukocytes and macrophages, which start to phagocyte and destroy extracellular and intracellular microorganisms respectively, or eliminate other etiological agents of any nature.
In gout, in silicosis, in chemical aggressions, in foreign body granulomas, in trauma, the inflammatory process is formed to eliminate, if possible, the aggressor and then induce tissue healing and regeneration. When the offending agent is not eliminated, the inflammation becomes permanent and causes an incurable or uncontrollable, stable or progressive chronic inflammatory disease, which compromises the patients' life or health.
Interaction and integration of innate immunity with adaptive immunity Simultaneously, at the site of invasion, aggression and IO
K inflammation, sentinel cells of innate immunity with APC (Antigen Presenting Celis) function, such as dendritic cells and macrophages, pinocyte and phagocytose microorganisms, or tumor cells, or transplanted cells, among other aggressive agents and process the their antigens. These APC cells pulsed by the antigens migrate to the regional lymph nodes and activate them.
APC cells in reactive, activated and matured lymph nodes present antigens for lymphocytes, 10 secrete cytokines and thus induce, coordinate, polarize, amplify and maintain an adaptive immune response specific to the invading germ, or to the neoplastic cell, or to the transplanted cells, or to another aggressive agent, allowing their fight and their elimination, when feasible and the consequent cure of the infection, or of the inflammation and the repair and the regeneration or healing of the lesions.
Thus, these immunological mechanisms fight diseases through innate and adaptive responses in an integrated and synergistic manner, carried out by sentinel cells, APC function sentinels and innate, cellular and molecular effectors together with the cellular and molecular effectors of adaptive immunity that respectively lymphocytes, cytokines and antibodies.
In other words, the interaction of the two immunities, innate and adaptive, in the context of an infection or immune response against an aggressive agent of any nature 5 allows to fight the disease in an integrated and synergistic way. The integration of the two occurs initially by the action of innate immunity cells with APC function, such as dendritic cells and macrophages, but mainly by the action of dendritic cells, as they are the only ones that are able to initiate a primary adaptive immune response against an agent infectious or parasitic, effectively protecting the organism.
As noted, macrophages also function as APC cells, but are more specialized and involved as part of the effector loop, in phagocytosis and elimination of microorganisms. B lymphocytes, when mature, are also APC cells and their best known action is the presentation of antigens to T lymphocytes, within the context of the collaboration of the two lymphocytes, for the production of antibodies, against T-dependent antigens, of the antibody response. secondary. Macrophages, like other myeloid cells, are also involved in suppressing the immune response in cancer and in chronic incurable infections. In these cases, their performance is unfavorable to the defense of the organism, because they suppress the immune response and create tumor facilitation. Malignant tumor disease has the initial characteristic of causing silent, imperceptible inflammation and in the end it becomes extremely pro-inflammatory and symptomatic through the inflammatory tissue profile TH17, which usually leads the patient to prolonged suffering.
When the co-stimulation molecules are not expressed on the surface of the APC cells, due to the absence of the alarm signal characterized by the non-activation of the prrs by PAMPS and DAMPS, only the first signal, given by the TCR, occurs. After binding the TCR to the antigen, in the absence of the second signal, the T lymphocyte becomes specifically tolerant to the presented antigen and aborts the immune response.
On the other hand, the CD 40L molecule of T lymphocytes activated by binding to the CD40 molecule of APC cells significantly increases the expression of CD80 and CD86 molecules, potentiating the ongoing response, which in this way occurs only when the adaptive T response is already engaged in the defense of the organism. The third signal given by cytokines such as ILI, is only given by APC cells, after the binding of the co-stimulation and emission molecules of the second signal. The ILI secreted by the APC cells acts on the lymphocytes and leads to the complete expression of the receptor for IL2 and to the production of this cytokine by the virgin lymphocyte or memory engaged in the response initiating clonal expansion.
Therefore, the activation of innate immunity by pathogens 5 is the key to trigger the second and third signals and to occur a potentially effective immunity, through the complete activation of the T lymphocytes engaged in the response.
Without the occurrence of the second and third signals, the response is aborted and a specific tolerance to the presented antigen is generated.
At the same time that neutrophils, monocytes and macrophages start the fight, bacteria and other etiologic agents through the binding of PAMPS with PRRS in antigen presenting cells (APC), activate dendritic cells and macrophages, both locally and recently. - arrived. These cells phagocytize, pinocitate bacteria and bacterial antigens, processing them and starting their maturation process. The activated and maturing dendritic cells now migrate to regional lymph nodes to present the antigens and initiate the immune response against the invading agent.
Mature APC cells pulsed by antigens, especially dendritic cells, in the lymph node, collaborate with T and B lymphocytes and initiate the response
. adaptive. Dendritic cells are the most potent cells for presenting antigens and the only APC cells capable of activating a virgin CD4 T lymphocyte and initiating a new immune response.
5 after a period of approximately seven days, in the lymph node, through collaboration between virgin CD4 T lymphocytes, which become CD4 Th2 T lymphocytes, the B lymphocytes run and with the antigen presenting dendritic cells, differentiation of the sensitized specific B lymphocytes begins.
10 These B cells, now activated, recognize bacterial antigens by surface immunoglobulins, after contact with these antigens, they proliferate, mature and differentiate into plasma cells that now secrete specific antibodies against this bacterium. The 15 infections of all types, bacterial, viral, fungal and parasitic, can, in general, in the acute phase, evolve to complete healing, with regeneration and healing, or to healing with sequelae. They can also evolve to chronicity without cure, with or without disease control, to chronicity 20 with cure, with or without sequelae, or to death.
Polarization of the immune response The immunological profiles known and induced by dendritic cells by direct and indirect contact with different cytokines and generated by CD4 T cells are of four types: a) cellular Thl profile, which generates cellular immunity cell-mediated b) humoral Th2 profile, which generates humoral immunity 5 mediated by antibodies C) tissue or inflammatory Thl7 profile, which generates inflammatory tissue immunity, also mediated by cells and cytokines, which induce an important inflammation for the elimination of certain pathogens; and 10 d) Treg / Trl profile that suppresses the immune response and controls it, inhibiting the other three profiles described above, ensuring the organism's return to the equilibrium state.
e) Profiles not yet fully established, such as Tfh (follicular Helper), of the humoral response, Th9 profile 15 for certain parasites, or other profiles that may be discovered.
In this way, the various profiles ensure the defense of the organism and the elimination of heterologous etiologic agents (infectious) and colonizing autologues 20 (neoplasms). The latter profile ensures the end of the immune response, balance, regeneration, the safe return to normality and prevents self-harm and allergy and is therefore vital for the health and preservation of the human and animal species, as far as the other profiles.
['jl
The phenomenon of polarization of the immune response is defined as the predominance of a certain immune profile such as Thl or Th2 to the detriment of other profiles that become secondary or null. This phenomenon happens 5 according to the type of aggression suffered by the organism. That is, according to the type of infection, pathology, and stage of infection or stage of pathology, a type of immune response predominates, which may be cellular, humoral, tissue or immunoregulatory, while the other types of immune response are inhibited. , resulting in the phenomenon of polarization.
By definition, in the polarization one profile predominates, but the other non-dominant profiles are also necessary, expressed and help to complement the elimination of the disease. For example, in tuberculosis it is the appearance of Thl7 cells in the lung that allows Thl cells to establish themselves and can lead to the cure of this infection in the lung parenchyma (Stockinger, B. and Veldhoen, M. Differentiation and function of Thl7 t cells.
Current Opinion in Immunology, 19 (3), pp. 281-286. 2007).
In viral infections, CTL cells with a Thl profile destroy virus-infected cells to eliminate viruses.
However, antibodies are necessary to prevent viruses from infecting other healthy cells and thus preventing the spread of infection. The combination of the two coordinated profiles is essential for the cure of certain viral infections. Certain intestinal infections by extracellular Gram Negative bacilli require, for their cure, in the final 5 phase, in addition to the Th2 profile, the generation of an additional Thl7 profile, capable of generating a strong inflammation, which is necessary for the elimination of this type of bacteria .
In conclusion, as dendritic cells are the only professional APC cells capable of initiating a primary adaptive immune response and are the most potent to trigger a specific secondary immune response, of any profile, they are then the ones that command the interaction and integration of innate immunity with adaptive immunity, to produce an effective immune response capable of curing a disease. Dendritic cells in collaboration with other APC and sentinel cells and in contact with different aggressor agents, in different functional states, at sites of inflammation, lymph nodes, spleen and mucous membranes, are able to induce, coordinate, polarize and amplify the adaptive immune response, primary and secondary, specific to the peptides of the invading pathogens, for example, which, in this case, is the most suitable for the elimination of the ongoing infection.
F - therefore, the dendritic cells and the other * APC cells, are the key cells of the innate immune response, as they evaluate the nature of the heterologous and autologous etiologic agent, that is, the type of pathogen or colonizing cells and aided by the others. sentinel cells, dimension and evaluate the size of the heterologous or autologous aggression, its extent, its intensity and aggressiveness, in addition to commanding the adaptive response with the profile and intensity necessary for the elimination 10 of the pathogen.
After differentiation, redifferentiation may occur, induced by the microenvironment and / or by the type of antigen or its presentation; áo, in which a Thl or Th2 profile can be exchanged for an inflammatory profile or an immunosuppressive profile or vice versa. This extreme plasticity of the immune system to differentiate or rediffer in any direction points to a strategic window, for the manipulation of the immune system, during an infection, when the direction taken in the polarization, is not being the best to lead to the cure of the infectious process or neoplasm.
As an illustrative example, we have what happens in a severe infection or septicemia, when the massive inflammation caused by the large amount of
»6 microorganisms that touch sentinel cells throughout the body, further induce a Th17 profile, which in turn increases inflammation further, and therefore becomes harmful, leading to tissue destruction, instead of inducing healing. In these cases, the Thl7 profile, due to tissue destruction and the amplification of inflammation, is the main responsible for the generation of serious clinical complications such as ARDS (adult respiratory distress syndrome), shock lung, renal failure, or 10 shock, which compromise healing.
The redifferentiation of polarization to the Thl or Th2 profile, with inhibition of massive inflammation is the logical and strategic path of an immunotherapy designed or designed to try to reverse this type of dramatic and lethal situation, during a serious infection or during sepsis, which it has an important mortality and morbidity and for which antibiotic therapy and other antimicrobials, in the current mold, as a unique anti-infectious modality have disappointing results. The same example applies to the 20 serious intracellular, fungal, viral and parasitic infections, with extensive tissue destruction and massive inflammation, usually with a poor prognosis.
Using adjuvants to stimulate the immune response
The human and animal organisms generally do not produce antibodies against soluble proteins, requiring the use of adjuvants known as nonspecific or unrelated, 5 to obtain the desired immune response. These adjuvants used since the beginning of immunology, in immunizations and in vaccine applications, were and are made up of parts of microorganisms, mineral oils and other substances that activated innate immunity, which then gives the alarm signal and the necessary command for development the desired immune response to the protein or vaccine in question (GOLDSBY RA, KINDT TJ, OSBORNE BA.
KUBY IMMUNOLOGY. 6th ed: ARTMED; 2008. 704 p); (janeway C, Travers P, alport M, Slhlomchik MJ. Immunobiology five. 5th ed: Garland Pub .; 2001. 732 p.); (VOLTARELLI JC. CLINICAL IMMUNOLOGY IN MEDICAL PRACTICE: ATHENEU EDITORA; 2009); (janeway CA, jr., Medzhitov R. Innate immune recognition. Annual review of irmunology. 2002; 20: 197-216. Epub 2002/02/28.); (Matzinger P. The danger model: a renewed sense of self.
Science. 2002; 296 (5566): 301-5. Epub 2002/04/16.): (Steinman RM, Banchereau J. Taking dendritic cells into medicine. Nature. 2007; 449 (7161): 19-26. Epub 2007/09/28.); (Beutler BA. TLRS and innate immunity. Blood.
2009; 113 (7): 1399-407. Epub 2008/09/02.); (Moresco EM,
21 LaVine D, Beutler B. Toll-like receptors. Current biology: CB. 2011; 21 (13): R488-93. Epub 07/12/2011).
It should be noted that the use of adjuvants for immunizations, despite being a resource of the oldest and 5 still current, extremely used and essential for vaccinations and for immunology studies, was considered only as a useful non-specific effect. It has not been seen for more than a century, through it, the fundamental role of innate immunity in the discrimination of what is "Self" and not 10 "Self" and in the linked capacity, unique and fundamental, for the survival of the human and animal species: that of giving the alarm signal and the command to initiate or not to initiate, or to inhibit an integrated innate and adaptive protective or healing immune response (GOLDSBY RA, KINDT TJ, OSBORNE BA.
15 KUBY IMMUNOLOGY. 6th ed: ARTMED; 2008. 704 p); (janeway C, Travers P, Walport M, Slhlomchik MJ. Immunobiology five. 5th ed: Garland Pub .; 2001. 732 p.); (VOLTARELLI JC. CLINICAL IMMUNOLOGY IN MEDICAL PRACTICE: ATHENEU EDITORA; 2009); (janeway CA, jr., Medzhitov R. Innate immune recognition. Annual 20 review of immunology. 2002; 20: 197-216. Epub 2002/02/28.); (Matzinger P. The danger model: a renewed sense of self.
Science. 2002; 296 (5566): 301-5. Epub 2002/04/16.): (Steinman RM, Banchereau j. Taking dendritic cells into medicine. Nature. 2007; 449 (7161): 419-26. Epub
2007/09/28.); (Beutler BA. TLRs and innate immunity. Blood.
2009; 113 (7): 1399-407. Epub 2008/09/02.); (Moresco EM, Lavine D, Beutler B. Toll-like receptors. Current biology: CB. 2011; 21 (13): R488-93. Epub 2011/07/12).
5 Today's anti-infectious and anti-neoplastic treatments A large number of medical materials, hours of work, medicines and hospital beds could be better used with a therapy in which they evaluated, prioritized and optimized the variables that interfere with the displacement of the patient. biological balance in favor of the patient and modulate their immune system, reducing their inefficiencies and enabling a large number of medical discharges and in less time. The state of the art has not yet presented alternatives to intentionally perform a repolarization of the immune system in real time, that is, in terms of altering or reversing a response to a current disease or illness, if possible in time to improve the quality of life, or extend the life span, or even assist in the process of fighting the disease or illness underway in the patient.
Bacterial, fungal, viral, parasitic and neoplastic resistance to antibiotics, antifungals, antiparasitic and antineoplastic agents used in practice
^% clinica is identified as the main obstacle to the cure of bacterial, fungal, viral, parasitic and tumor diseases and is considered a serious health problem, on a global scale. This problem is overcome with the appropriate and rational use of antibiotics, antimicrobials and antineoplastics and the advent of new, more potent drugs. However, resistance sooner or later, inexorably is always established and, until now, no solution has been found for this problem. As the 10 antibiotics, antifungals, antivirals, antiparasitic and antineoplastic agents are considered as the only valid and effective anti-infectious, antiparasitic and antineoplastic treatment modality, the future perspective of the treatments is worrying and bleak, due to the phenomenon of microbial and tumor resistance.
Antibiotics, antifungals, antiviral drugs, antiparasitic and antineoplastic agents can be used at any stage of bacterial, fungal, viral, parasitic and tumor infectious disease. However, antibiotics, 20 antimicrobials and antineoplastics are unable to cure most bacterial, fungal, viral, parasitic and already advanced, severe and widespread neoplasms that, in general, have a very high rate of mortality and morbidity.
On the other hand, the discovery of new drugs is directed to drugs that are capable of eliminating the etiologic agent and curing infection, infestation and neoplasia, based on the concept of a single drug, capable of curing an infectious, parasitic and neoplastic disease.
Current neoplasm treatments Cytokines such as interleukin 2 and type I interferons alpha and beta are used to treat immunogenic tumors such as melanoma and hypernefroma. The 10 cytokines that function as bone marrow colony growth factors are used to combat anemia, leukopenia, cytopenia of the figurative elements of peripheral blood, caused by diseases or treatments, with good results. Type I interferons are widely used - 15 to fight viable hepatitis C and B, with good Ó "results and with less expressive results, for the treatment of multiple sclerosis. Autologous and allogeneic bone marrow transplants are used for Passive immunotherapies with CDL CD8 dendritic cells, leukocytes, autologous or allogeneic, with or without cytokine, are used for the treatment of certain tumors, with results that are still not very expressive, or expressive, but limited to certain exceptional pathologies. , such as virus-induced tumors, which grow in transplanted and immunosuppressed patients In these cases passive immunotherapy with EBV virus-specific CTL CD8 and CD4 T cells is usually successful and will cure these exceptional tumors that only grow in immunosuppressed patients. However, it is noteworthy that these techniques, as well as similar ones, but with less effectiveness, did not develop agents or sets of ag entities capable of effectively immunomodulating the immune system in order to start reacting against any pathogenic invader (infection), or 10 autologous colonizers (tumors) that are present in the body of the individual to be treated, or that can resolve states of disautonomy of the immune systems primary or secondary genetics, which lead to states of self-harm by the immune system, which should defend "15 the organism, precisely from aggressions.
d We can cite as a successful example of cancer treatment that uses an immunomodulatory agent that contains molecular patterns recognizable by the PPRS, the use of the BCG vaccine as one of the rare, established, accepted 20 techniques that are proven to somehow use immunomodulation as route of treatment. Brake and collaborators described the use of BCG in immunotherapy for patients with superficial bladder cancer, who were in Stage T1 (Brake M, Loertzer H, Horsch R,
Keller H (2000). "Long-term results of intravesical bacillus Calmette-Guérin therapy for stage Tl superficial bladder cancer". UROLOGY 55 (5): 673- 678). Immunotherapy was applied to patients after complete transurethral resection of the tumor in the bladder, with a second cycle of BCG being applied in case of recurrence of superficial tumors. The conclusion of the study was that BCG immunotherapy after transurethral resection of the bladder tumor represents a highly effective primary treatment for Stage 1 bladder cancer, with 89% being the tumor-free survival rate in all patients.
Following this line, Burguer and collaborators demonstrated a comparative randomized trial, in which patients with non-invasive bladder cancer of the muscle layer used BCG or autologous cell therapy with macrophages (BEXIDEM®) (Burguer M, Thiounn N, Denzinger S, Kondas j, Benoit G, et. Al (2010). "The application of adjuvant autologous antravesical macrophage cell therapy VS. BCG in non-muscle invasive bladder cancel a multicenter, randomized trial. Journal of Translation Medicine, 8:54. doi: 10.1186 / 1479-5876-8-54) Compared to BCG, the incidence of adverse effects was significantly lower in treatment with BEXIDEM (26% and 14%, respectively).
W, tumor recurrence in patients treated with BEXIDEM was significantly higher than in patients who used BCG as an auxiliary therapy.
Donald and colleagues described the use of BCG as a form of immunotherapy in patients with melanoma (Donald L. Morton, M.D., Frederick R.
Eilber, M.D., E. Carmack Holmes, M.D., john S. Hunt, M.D., et. al (1974). "BCG Imrnunotherapy of Malignant Melanoma: Summary of a Seven-year Experience". Ann. Surg. , p: 635-10641). The patients selected for the study had recurrent melanoma, known residual disease or a high risk of developing recurrence. First, direct injections were applied to malignant melanoma nodules using 0.1-0.5 cc BCG in each subcutaneous and "15 intracutaneous lesion. Patients in Stage II d received immunotherapy treatment only with BCG or BCG and allogeneic melanoma cells BCG was administered alone or as an adjuvant mixed with tumor cells in Stage III disease patients Patients with 20 intradermal metastases who were treated with intratumoral BCG injections responded best to treatment, with three factors appeared to be correlated with the response to BCG immunotherapy: the location of metastasis, the amount of tumor present and J 'I
^ -, the patient's immunocompetence. Low BCG antitumor activity was observed in patients with bulky disease or visceral metastasis. The result showed that 31 °: of the patients with intradermal metastasis were free 5 of the disease recurrence for a period of up to 6 years after the start of immunotherapy.
The immunotherapy described by Grant et al. Consists of the use of BEC2 (antiidiotypic antibody that mimics the GD3 ganglioside present on the surface of most small cell lung cancer tumors) in combination with BCG (Grant SC, Kris MG, Houghton AN, Chapman PB (1999). "Long Survival OE Patients with Small Celi Lung Cancer after Adjuvant Treatment with the Anti-Idiotypic Antibody BEC2 Plus Bacillus Calmette-" 15 Gue ". Clinical Cancer Research, Vol. 5, 1319-1323). applied to patients with lung cancer was 2.5 mg for a period of more than 10 weeks Patients treated with that immunotherapy had a considerable increase in survival and disease-free survival of the disease when compared to a similar group of patients. patients.
Popiela and colleagues evaluated the use of BCG immunotherapy and chemotherapy with FAM (5-fluoracil, adriamycin, mitomycin C) in patients with stage III or IV gastric cancer previously submitted to P
~
, curative gastrectomy (Popiela T, Kulig j, Czupryna A, Sczepanik AM, Zembala M (2004). "Efficiency of adjuvant immunochemotherapy following curative resection in patientes with locally advanced gastric cancer". Gastric
5 cancer, 7: 240-245). Patients were randomly divided into 3 groups: BCG + FAM, FAM and control
(surgery only). The dose of BCG administered in immunotherapy was 2-4 viable units per dose.
It was observed that in general a percentage of 47.1% of survival of
10 10 years in the immunotherapy group.
Powles and colleagues reported a study in which patients with acute myeloid leukemia received treatment with BCG and dead allogeneic tumor cells.
The estimated BCG dose was approximately 10 6 organisms (RL Powles, PJ Selby, DR
15 jones, JA Russel, HG Prentice, et. al (1977). "Maintenance of remission in acute myelogenous leukemia by a mixture of B.
C.G. and irradiated leukemia cells ". THE = CET, 1107-
1110). An improvement was observed in the patients, as they presented remission of the disease for a period, leading to
20 conclusion that immunotherapy combining leukemia and BCG tumor cells can be effective to prolong the remission of the disease.
Likewise, Vuvan and colleagues described the use of BCG immunotherapy in patients with acute non-lymphoid leukemia (H.
Vuvan, D.Fiere, M.
Doillon, P -
V Martin, B. Coiffier, et. al (1978). "BCG Therapy in Acute Non Lymphoid Leukaemias". Scand j Haematol 21, 40-46). A randomized study was carried out in which patients were divided into 2 groups: treated with chemotherapy only and 5 treated with chemotherapy and BCG, with BCG administered during the interval of chemotherapy cycles in doses of 6 x IOB viable units. The result showed that patients who received immunotherapy had a higher survival rate than the group that received only 10 chemotherapy. In addition, it was observed that BCG appeared to be more efficient in patients older than 40 years.
Finally, Hsueh and colleagues used a therapeutic vaccine composed of melanoma cells called "15 Canvaxin (Hsueh ED, Essner R, Foshag LJ, Ollila DW, Gammon EG, et al (2002)." Prolonged Survival After Complete, Resection of Disseminated Melanoma and Active Immunotherapy with a Therapeutic Cancer Vaccine ". Journal of Clinicai Oncology, Vol 20, n 23, pp 4549 - 4554). All 20 patients were tested with PPD (derived from purified protein) before receiving therapy with For the first two treatments, the vaccine was mixed with BCG In the first injection, bcg was applied in a dose of 2.7 to 10.8 x 106 colony-forming units in PPD rmv negative patients and half of that dose in PPD positive patients.
An extension of survival was observed in patients who received active immunotherapy with Canvaxin after the operation.
5 The aforementioned studies with the use of BCG, despite using an immunostimulating agent other than the causative agent of the disease or disease, to cause desirable effects in patients, combined or not with other therapies and medical procedures as proposed in the present invention, however, it is not using multiple antigenic components that have molecular patterns associated with different pathogens, especially a combination that has representatives of intracellular and extracellular bacteria, viruses, parasites, fungi and yeasts. The research groups and studies mentioned above only used BCG as a simple adjuvant function, without taking into account the bases of the present invention that aim to activate memory cells, or virgins, that can be inactivated 20 in the most diverse tissues of the body through a wide range of molecular patterns associated with pathogens that can activate as many d cells as possible and memory and effectors. As it does not present this combination of different nonspecific antigenic agents capable of stimulating r
W, / innate and specific immunity as described, many populations of immune memory cells will cease to be activated according to the foundations presented, which will not lead to a reprogramming recontextualization and 5 resumption of the immune response, which is as effective as the one presented. in the present invention.
Nor does the state of the art describe the importance of immunization protocols and the local and distal applications of immunostimulating agents, and how a large number of applications in different parts of the body are needed to programmatically and intentionally make patterns molecular PAMPS and damps reach the tissues that have APCS cells in adequate quantity and quality to provoke an optimal response and polarization "15.
. Tanaka et al. (Tanaka N., Gouchi A. Ohara T., Mannami T., Konaga E., Fuchimoto S., Okamura S., Sato K., Orita K (1994). "Intratumoral injection of a streptococcal preparation, OK -432, before sugery for gastric cancer. A 20 randomized Trial. Cooperative Study Group of Preoperative Intratumoral Immunotherapy for Cancer ". Cancer, 74 (12): 3097-3103) and Yasue et al. (Yasue M., Murakami M., Nakazato H., Suchi T., Ota K (1981). "A Controlled Study of Maintenance Chemoimmunotherapy VS Immunotherapy Alone r
; t Immediately Following Palliative Gastrectomy and Induction
Chemoimmunotherapy for Advanced Gastric Cancer ". Cancer
Chemother Prasmacol, 7: 5-10.) Report q use in patients with gastric cancer of an immunomodulatory agent prepared
5 from the attenuated Streptococcus pyogenes species,
called OK-432. Such an agent is able to activate the regional immune system and cause degeneration of the affected tissue in stomach carcinomas.
Tanaka describes the pre-
IOKE operative of ok-432 injected endoscopically, and
10 doses of ike at 5ke in intradermal injections in case of metastasis in the post-operation lymph nodes.
Tanaka concluded that intratumoral injections of Ok-432 may have a beneficial clinical effect in patients in the
Stage III gastric cancer, as it seems to improve the
"15 survival of this subset of patients.
Yoshida and
Y collaborators (Yoshida K., Sugiura T., Takifuji n., Kawahara M., Matsui K., et al (2007). "Randomized phase II trial of three intrapleural therapy regimens for the management of malignant pleural effusion in previously
20 untreated non-small cell lung cancer: JCOG 9515. Lunger
Cancer, 58: 362-368) evaluated the efficacy and toxicity of using OK-432 (0.2 KE / Kg, the maximum dose being IOKE / Kg) as an intrapleural therapy to control malignant pleural effusion in patients with cancer of non-small cell lung,
previously untreated.
In addition to OK-432, bleomycin and cisplatin together with etoposide, were also evaluated as intrapleural therapy.
It was concluded that the best intrapleural therapy used was the use of OK-432, because it was what b
"5 obtained the best disease-free survival rate. And a ·., Y m
. y.t, lower rate of pleural recurrence. r
Aftergut and collaborators (Kent Aftergut, MD, Mary
Curry, MD, Jack Cohen, DO (2005). "Cândida Antigen in the
Treatment of Basal Cell Carcinoma ". Dermatol Surg, 31: 16-
10 18) studied the intralesional use of Candida antigens in the treatment of basal cell carcinoma.
The study shows that 56% of treated patients had complete tumor cell regression.
The antigens were applied in doses of + 0.1 mg through intradermal injection.
Again, the
The present invention differs through the use of a
"a much more complex and elaborate combination of antigenic components, having the potential to achieve more advantageous results when used alone or in conjunction with other therapies.
The study described by Miles and
20 employees (Miles DW, Towlson KE, Graham R, Reddish m,
Longenecker BM, et al. (1996). "A randomized phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment of the active specific immunotherapy of breast cancer". British journal of Cancer,
74: 1292-1296) investigated the occurrence of improvement in the immune response provoked by the association of sially-Tn-KLH with DETOX-B (which contains in mycobacterial cell structure skeleton of Mycobacteríurn phlei) in patients with! 5 breast cancer, when subjected to a pretreatment with low doses of cyclophosphamide. 0.5 ml of the emulsion composed of STn-KLH in DETOX-B was used. As a result, it was observed that all patients developed IgG and IgM in relation to sialyl-Tn, and patients who received 10 pretreatment with cyclophosparnide, had a significantly greater increase in IgM. Korec and colleagues presented a study in which 11 patients with different types of tumor and 3 patients with purple thrombotic thrombocytopenia associated with mitomycin-C, were treated with 0 15 perfusion of extracorporeal plasma through filters - containing immobilized protein A of Staphylococcus aureus (Korec S, Smith FP, Schein PS, Phillips TM (1984).
"Clinical experiences with extracorporeal immunoperfusion of plasma from cancer patients". j Biol Response Mod. 3 (3): 20 330-5). As a result, there was a modest antitumor effect generated by the immunoperfusion. In 10 properly treated patients, there was a measurable reduction in the tumor (40% reduction in the mass of the original tumor).
Engelhardt and collaborators (Engelhardt R, Mackensen A,
Galanos C (1991). "Phase I Trial of Intravenously
Administered Endotoxin {Salmonella abortus equi) in Cancer
Patients ". CANCER.
RESEARCH 51, 2524 - 2530) described a trial related to the intravenous administration of
"5 endotoxin, prepared from the liposaccharide of [J
Salmonella abortus equi (basically free of proteins and nucleic acid). Twenty-four patients between the ages of 33 and 67 years were selected, with 10 patients diagnosed with colorectal cancer, 5 with lung cancer of non-
10 small, 2 with carcinoma, 2 with pancreatic cancer, 2 with sarcoma, 1 with gallbladder cancer, 1 with cancer in the anus and 1 with cancer in the trachea.
Pancreatic cancer patients have not received previous treatment, whereas the other patients had been treated with radiation,
15 chemotherapy and / or surgery, these treatments being completed four weeks before the beginning of the studied treatment. the dose of the initial endotoxin applied was 0.15 ng / kg, with the maximum tolerated dose being 4 ng / kg.
The results obtained showed two partial responses and four occurrences of disease stabilization in patients who had colorectal cancer, and such patients were in the group with the largest number of participants, indicating that this type of tumor is not necessarily more sensitive to liposaccharide than the other tumors studied in the research. The disease has also been stabilized for a period of time in patients with non-small cell lung cancer, kidney cell cancer and tracheal cancer. Otto and colleagues describe the "5 phase II study reported by Engelhardt. In this phase, 15 to patients with non-small cell lung cancer and 27
P with colorectal cancer received 4 injections of endotoxin (dose of 4ng / kg) and 1600 mg of ibuprofen orally at 2-week intervals. The results showed improvement in 10 3 patients with colorectal cancer, 2 of whom had partial remission of the tumor, which was stabilized for 7 and 8 months respectively, and 1 of them had complete remission of the tumor. There was also a minimal antitumor effect in patients with lung cancer. 0 15 As we have seen in the examples of the state of
R · technique described by Aftergut (Kent Aftergut, MD, Mary Curry, MD, jack Cohen, DO (2005). "Cândida Antigen in the Treatment of Basal Celi Carcinoma". Dermatol Surg, 31: 16-18), Miles (Miles D, Towlson KE, Graham R, Reddish M, 20 Longenecker BM, et al. (1996). "A randomized phase II study of sialyl-Tn and DETOX-B adjuvant with or without cyclophosphamide pretreatment of the active specific immunotherapy of breast cancer ". British journal of Cancer, 74: 1292-1296), Korec (Korec S, Smith FP, Schein PS,
Phillips TM (1984). "Clinical experiences with extracorporeal immunoperfusion of plasma from cancer patients". j Biol Response Mod. 3 (3): 330-5), Engelhardt (Engelhardt R, Mackensen A, Galanos C (1991). "Phase I" 5 Trial of Intravenously Administered Endotoxin (Salmonella 4
P abortus equi) in Cancer Patients ". CANCER RESEARCH 51, 2524 - 2530) and Otto (OttO F, Schmid P, Mackensen A, ehr U, Seiz A, et. Al (1996)." Phase II trial of intravenous endotoxin in patients with colorectal and non-small cell lung 10 cancer ". Eur j Cancer, 32A (10): 1712 - 8), only one antigenic component was used in each respective study.
Willian B. Coley was a pioneer in research relating the use of immunotherapy in cancer patients (Edward F. McCarthy, MD. "The Toxins of Willian B. Coley and 15 and the treatment of bone and soft-tissue sarcomas". The + "Iowa Orthopedic journal, v. 26, p: 154-157). In Coley's studies, he describes the success of using Streptococcus together with Serratia marcescens (Coley's Toxin) in the treatment of soft tissue sarcomas, note 20 also that such immunotherapy was not as effective in the treatment of other types of cancer, such as melanomas and carcinomas. As such studies were carried out more than a century ago and were relatively forgotten by modern medicine (very focused on obtaining a single drug for diseases) its primordial concepts and possibilities were not explored and clarified. Coley only used two bacterial components in its composition, and did not explore the process of utilization and all the possibilities "5 of modulation of the system immune as described in the present invention. Hayashi and colleagues were able to advance further in understanding the importance of the immune system and also combined two antigenic components, but these concepts have not yet been fully explored.
10 In this work Hayashi et al. Evaluated the effect of the importance of lymph nodes in the treatment of patients with ovarian cancer with Mycobacterium bovis cell wall skeleton associated with Bacillus Calrnette-Guérin (BCG-CWS) (Hayashi A, Nishida Y, Yoshii S , 15 Kim SY, Uda H, Hamasaki T (2009). "Immunotherapy of ovarian cancer with cell wall skeleton of Mycobacterium bovis Bacillus Calmette-Guérin: Effect of lymphadenectomy".
Cancer Sci, vol 100, No. 10, p: 1991-1995). After tumor removal surgery, patients received doses of 2 to 200 yg BCG-CWS intracutaneously. The vaccine was used in the study because of its potential to induce (IFN) -y and stimulate Langerhans cells (later differentiated to dendritic cells), as reported in previous trials. The prognosis of patients after surgery without having undergone lymphadenectomy was considerably better than those who had it, which confirms the importance of lymph nodes in obtaining immune reactions against ovarian cancer in "5 response to BCG-CWS immunotherapy. Although they already use two distinct antigenic components that are not specific to the disease being treated, they come from only two bacteria, not presenting in their composition other molecular patterns associated with 10 pathogens such as those found in viruses, parasites, fungi and yeasts.
According to the existing knowledge in the state of the art, the essential role of the immune system in the fight against diseases is observed, however few technologies were '15 capable of effectively stimulating and immunomodulating this system in order to better fight the disease, when it has already is established.
In addition, it is important to note that the cure of infections and neoplasms, contrary to what is preached and accepted 20 today, is always performed by the immune system. Antibiotics, antimicrobials and antineoplastic drugs act mainly as an important and often essential facilitator for the cure of infections. In other words, antibiotics do not cure the disease itself, but help and facilitate the healing process carried out by the immune system. Antibiotics act in this sense, as a biological balance shifter, in favor of the infected organism, by "5 inhibiting or killing, or destroying a portion of the bacteria r" in vivo, through its specific action, enabling and a more rapid and effective immune system.
However, there is no in vivo work demonstrating the elimination of microorganisms by the action of 10 antimicrobials.
Based on this new scientific assumption, it is necessary to develop immunomodulating agents, immunogenic compositions and treatment methods capable of selecting agents that enable the induction of an '15 innate immune response, in a real time that recontextualizes, ~ ¶ reprograms and brings the immune system back to a new effective specific adaptive response to the disease to be treated, through the correct presentation of pathogen antigens to APC cells, which via mnory 20 and virgin cells of the immune system, will effectively combat infectious diseases and other diseases present in a given patient . That is, without the need to generate and administer a specific antigen of the established disease, using the immune system's own mechanisms for this, after its recontextualization, reprogramming, renewal, ideally and induced by immunomodulatory agents, reaching immune responses with equivalent speed and effectiveness to the immune responses "5 triggered by repeated invasions of the same pathogen, previously memorized by the immune system. That is, the new immunomodelating agents, immunogenic compositions and treatment methods would shift the biological balance of antimicrobials and 10 chemotherapeutic agents in all neoplasms, infections and infestations. This new therapeutic perspective would combine the concomitant use of immunotherapy with traditional antimicrobials and in infectious processes of any kind and in parasitic infestations, increasing the chances of a cure and being able to drastically decrease morbidity.
B 'R "and mortality from these diseases, when compared to therapies that take into account only the function of antimicrobials and chemotherapies alone.
OBJECTIVES OF THE INVENTION It is an objective of the present invention to provide immunogenic compositions for modulating the immune system that comprise a therapeutically effective amount of two or more immunoactive antigenic agents that have molecular patterns associated with pathogens (PAMPS) and / or molecular patterns associated with danger (DAMPS) and one or more of a physiologically acceptable vehicle, excipient, diluent or solvent.
In particular, it is an objective of the present invention to provide immunogenic compositions for modulation of the immune system comprising immunoactive antigenic agents that have pathogen-associated molecular patterns (PAMPS) and / or hazard-associated molecular patterns (DAMPS) selected from the group consisting of erm (A) 10 antigenic agents with molecular patterns associated with bacteria; (B) antigenic agents with molecular patterns associated with viruses; (C) antigenic agents with molecular patterns associated with fungi and yeasts; (D) antigenic agents with molecular patterns associated with b , 15 protozoa; (E) antigenic agents with molecular patterns associated with multicellular parasites and / or (F) antigenic agents with molecular patterns associated with prions.
Another objective of the invention is to provide the use of said 20 immunological compositions for the manufacture of medications for the prevention and / or treatment of infectious diseases, autoimmune diseases, allergic diseases, inflammations, arthritis, inflammatory diseases, transplant rejection, diseases caused by vascular disorders ,
diseases caused by hemorrhagic or ischemic cardiovascular accidents, ischemia, infarction and hemorrhages that lead to tissue destruction, heart, kidney, respiratory or liver failure, cancer, tumors and "5 malignant and benign neoplasms.
The present invention also aims to provide methods to prevent or treat infectious diseases, autoimmune diseases, allergic diseases, inflammations, arthritis, inflammatory diseases, transplant rejection, diseases caused by vascular disorders, diseases caused by hemorrhagic or ischemic cardiovascular accidents, ischemia, infarction and hemorrhages that lead to tissue destruction, heart, kidney, respiratory or liver failure, cancer, malignant and benign tumors and neoplasms, 15 in animals, more particularly humans.
The present invention further aims to provide methods for inducing cell regeneration, tissue regeneration, organ regeneration and regeneration of organic systems, such as the circulatory system, the nervous system and the endocrine system.
Finally, the present invention aims to provide methods for renewing the immune response in an animal, particularly humans. DEFINITIONS
Within the scope of this patent application, abbreviations are used several times, the definitions of which as used in this application are summarized below: "BCG refers to attenuated Mycobacterium bovis," 5 Bacillus de Calmette-Guérin; · DA PS refers to molecular patterns associated with danger; · DECA refers to the composition 1 described in Example 1 of the present patent application; 10 "GM-CSF refers to" Granulocyte macrophage colony-stimulating factor ";" IL12 refers to Interleukin-12; "IL15 refers to Interleukin-15;" IL2 refers to Interleukin-2; 15 · IL21 refers to Interleukin-21; "IL4 refers to Interleukin-4;" IL5 refers to Interleukin-5; · IL7 refers to Interleukin-7; · PAMPS refers to molecular patterns associated with 20 pathogens.
· PFU: lysis plate forming units.
· PPD refers to a purified protein derivative of Koch's bacillus; · PPD refers to the purified protein fraction of the Koch bacillus culture extract ("Purified Protein Derivative"). PPD represents the main antigens of Mycobacterium tuberculosis; "TDCI50 is a unit for quantification of" · 5 viral particles and represents the infecting dose in 50% of the
V cells from a tissue culture; "Koch crude turberculine refers to inactivated lysate of Mycobacterium bovis;" Lf units or "Limes flocculations units" is the 10 international unit for quantifying antigens in toxoid vaccines accepted by the World Health Organization;
DESCRIPTION OF THE FIGURES The following figures are part of this report and are included here in order to illustrate certain 15 aspects of the invention. The object of the present invention can be better understood with reference to one or more of these figures, in combination with the detailed description of the preferred embodiment presented here.
"Figure 1 shows the effect of treatment with DECA, DECA + IL-2 on tumor growth in vivo. Murine melanoma cells (B16F1O) were inoculated on day zero (1 x 106; 100 µi, / animal) subcutaneously (SC), on the back of male C57B16 mice In (A) tumor volume (in mm3) measured every three days with the aid of a digital caliper.
In (B) percentage of growth calculated in relation to the volume of each tumor obtained on the 7th day. The results were expressed as Mean ± Standard Error of Mean (E.P.M.). * p <0.05 represents the statistically significant difference "5 in relation to the control group {one-way ANOVA, post-hoc: Dunnett test). n = 9-10 animals.« · Figure 2 shows the treatment done with DECA, DECA + IL-2 on survival of animals inoculated with murine melanoma cells B16F1O cells were inoculated on day 10 zero (1 x 106; 100 µ1. / 3A'í '[' í't3'f) via subcutaneous (Sc), on the back of male C57B16 mice. The graph represents the mortality curve and the percentages represent the animals that remained alive at the end of 30 days after tumor cell inoculation. n = 9-10 animals. * p, O, 05 15 (p = O, 0361), Statistical analysis: Logrank Test - Chi square.
"Figure 3 shows anatomopathological exams of the volunteer MBS. A. Pre-immunotherapy treatment exam, the black arrow indicates the tumor area and the white arrow indicates the absence of inflammatory infiltrate. The black delimited 20 region illustrates the inhibition of the immune system by the tumor. verified by the absence of inflammatory infiltrate b.
Examination after immunological treatment, where the tumor is completely eliminated; the white arrows indicate the dense inflammatory infiltrate and the area enclosed in black exemplifies areas of fibrosis and reparative changes permeated by inflammatory infiltrates. Ç.
Recontextualization of the immune system through the use of the present invention, attested by the positive reaction for S-IOO "5 in countless intra-epidermal dendritic cells (indicated by arrows) and in the midst of the dermal inflammatory infiltrate extending to the deep dermis, without melanocytic cells or residual melanorna.
· Figure 4 shows the pathological exams of the PPC volunteer. A. Pre-treatment immunotherapeutic exam showing an area of aggressive metastatic melanoma with some pigmented cells, and a small and discrete peripheral inflammatory infiltrate indicated by the arrow, attesting to the inhibition of the immune system by the tumor. B.
Examination after immunological treatment illustrating the disappearance of the tumor and replacement by intense and dense inflammatory infiltrate. C. Recontextualization of the immune system by treatment with the present invention, attested by the positive reaction for S-100 in countless intra-epidermal dendritic cells (indicated by the arrows) and in the middle of the dermal inflammatory infiltrate extending to the deep dermis, without melanoma residual.
"Figure 5 shows Nuclear Magnetic Resonance Examinations (Al, A2 and A3 of 07/30/2008 pre-immunological treatment) and CT scans (Bl, B2, B3 post-treatment of 05/13/2009; Cl and C3 post-treatment of 08/30/2011 and C2 post-treatment of 04/13/2010) from patient R - M. Al. Fat thickening showing carcinomatosis "5 (arrow). A2. Lymph node conglomerate of the celiac trunk (arrow; largest measuring 3.7 cm). A3. Lymph node conglomerate + hepatogastric ligament measuring 4 cm (arrow). Bl.
Disappearance of carcinomatosis, evidencing the disappearance of fat thickening (arrow). B2.
10 Reduction of the largest lymph node (from 3.7 cm to 1.4 crn) of the lymph node conglomerate of the celiac trunk (arrow). B3.
Disappearance of the lymph node conglomerate of the hepatogastric ligament (arrow). Cl. Disappearance of carcinomatosis (arrow). C2. Reduction of the largest lymph node (from 1.4 cm to 1.1 15 cm) in the lymph node conglomerate of the celiac trunk (arrow).
C3. Confirmation of the disappearance of the lymph node conglomerate of the hepatogastric ligament (arrow). These data show a complete oncological remission of peritoneal carcinomatosis and lymphatic spread of gastric adenocarcinoma 20 with the association of immunotherapy with the present invention associated with radio and palliative chemotherapies.
"Figure 6 shows computed tomography scans of the chest and abdomen of volunteer A -DA Pre-treatment immunotherapeutic examination carried out on 10/09/2006 identifying the tumors in the areas indicated with circles. B. Post-treatment immunological examination on 12/11/2006 evidencing the absence of these tumors in the analyzed areas.
"Figure 7 shows exams of serum levels of · 5 prostate specific antigen (PSA) from patient O - S. The first point refers to the residual value of the marker« showing the presence of a residual neoplastic cell from non-curative surgery, which when immunologically treated became undetectable (represented graphically as 10 zero) in 4 weeks. This data strongly suggests that the immunotherapy treatment, in the condition of pharmacological monotherapy adopted while waiting for the beginning of radiotherapy, was effective in the complete remission of the loco-regional tumor. and eradication of the tumor mass, since the current state of the art does not make it possible to differentiate complete eradication of the tumor mass from minimal residual disease DETAILED DESCRIPTION OF THE INVENTION Description of the immunogenic compositions The present invention relates to immunogenic compositions for modulating the immune system that comprise a therapeutically effective amount of two or more immunoactive antigen agents that present pathogen-associated molecular patterns (PAMPS) and / or hazard-associated molecular patterns (DAMPS) and one or more physiologically acceptable vehicles, excipients, diluents or solvents.
Preferably the compositions of the present invention comprise immunoactive antigenic agents that exhibit "5 pathogen-associated molecular patterns (PAMPS) and / or. Hazard-associated molecular patterns (DAMPS) selected from the group consisting of: (A) antigenic agents with molecular patterns associated with bacteria; (B) antigenic agents with molecular patterns associated with viruses; (C) antigenic agents with molecular patterns associated with fungi and yeasts; (D) antigenic agents with molecular patterns associated with protozoa; (E) antigenic agents with associated molecular patterns to multicellular parasites and / or (F) antigenic agents with 15 molecular patterns associated with prions.
Even more preferably, the compositions of the present invention comprise pathogen-associated molecular patterns (PAMPS) and / or hazard-associated molecular patterns (DAMPS) selected from at least 20 three of categories (A), (B), (C), ( D), (E) and (F) above described.
Even more preferably, the compositions of the present invention comprise molecular patterns associated with pathogens (PAMPS) and / or molecular patterns I '.
associated with danger (DAMPS) selected from at least four of the categories (A), (B), (C), (D), (E) and (F) described above.
The antigenic agents of the present invention can be "selected from epitopes, genetic materials, lipids,
And polysaccharides and / or immunoactive proteins of the present invention can be obtained by purifying isolated fragments of materials existing in nature or derived from fractions of plant, animal or microbiological extracts, or even produced by genetic recombination, being preferably derived from viral strains, fungal, parasitic, prionic or bacterial.
Therefore, the antigenic agents of the present invention with molecular patterns associated with bacteria of the present invention can be selected from, but are not limited to, antigenic agents with molecular patterns associated with bacteria of the genera Staphylococcus, Streptococcus, Enterococcus, Corynebacterium, Bacillus, hysteria , Clostridium, Mycobacterium, Actínomyces, 20 Nocardia, Escheríchia, Proteus, Klebsiella, Serratia, Enterobacter, Salmonella, Shigella, Pseudomonas, Burkholderia, Stenotrophomonas, Acinetobacter, Vibrio, Campylobacter, Helicobacter, Bacteroem, Hausset, Neisseria, Mora Francisella,
Pasteurella, Yersinia, Legionella, Gardnerella, Treponema, Leptospira, Borrelía, Mycoplasmas, Rickettsiae and Chlamydiae.
Antigenic agents with molecular patterns associated with viruses of the present invention can be selected from, but are not limited to, antigenic agents with molecular patterns associated with viruses of the Adenoviridae, Arenaviridae, Bunyaviridae, Coronaviridae, Filoviridae, Flaviviridae, Hepadnaviridae, Deltavirus families. Caliciviridae, Herpesviridae, Orthomyxoviridae, 10 Papovaviridae, Paramixoviridae, Parvoviridae, Picornaviridae, Poxyviridae, Reoviridae, Retroviridae, Rhabdoviridae and Togaviridae.
The antigenic agents with molecular patterns associated with fungi and yeasts of the present invention can be selected from, but are not limited to, antigenic agents with molecular patterns associated with fungi and yeasts of the genera Sporothrix, Aspergillus, Blastomyces, Candida, Coccidioides, Cryptococcus, Histoplasma and Pneumocystis.
The antigenic agents with molecular patterns associated with protozoa of the present invention can be selected from, but are not limited to, antigenic agents with molecular patterns associated with protozoa of the genera Criptosporidium, Ciclospora,
Entamoeba, Naegleria, Giardia, Leishmania, Plasmodium, Toxoplasma, Trichomonas, Trypanosoma, Microsporidia and Isospora.
Antigenic agents with molecular patterns "5 associated with pluricellular parasites of the present invention can be selected from, but are not limited to, antigenic agents with molecular patterns associated with trematode pluricellar parasites, baskets and nematodes.
The antigenic agents of the present invention comprise protein, polysaccharide, lipid and / or synthetic compounds that mimic protein, polysaccharide and / or lipid molecules.
More specifically, the antigenic agents of the present invention comprise protein immunoactive molecules that have enzymatic activity, such as, for example, kinases, phosphatases, streptokinases, streptodornases and, deoxyribonucleases (e.g., dornases).
The immunogenic compositions for modulating the immune system 20 of the present invention comprise from 0.001 to 500 micrograms per ml of each immunogenic agent.
Such immunogenic agents can be encapsulated in the form of capsules, microparticles, nanoparticles, dragons, liposomes.
Specifically, the immunogenic compositions for modulating the immune system of the present invention comprise 4 to 20 antigenic agents selected from the group consisting of antigenic agents from:
· 5 dornase, yeast, oidiomycin, PPD, prions,
streptokinase, Streptococcus toxoid, Diphtheria toxoid, Koch's crude tetanus toxoid,
inactivated lysate of Ascaris lumbricoides, Aspergillus spp.,
Aspergillus flavus, Aspergillus fumigatus, Aspergillus
10 terreus, Cândida spp., Cândida albicans, Cândida glabrata,
Candida parapsilosis, Chlamydia spp., Chlamydia pneumoniae,
Chlamydia psittaci, Chlamydia trachomatis, Cryptosporidium spp., Dermatophytes, Entamoeba hystolitica, Enterobius vermicularis, Enterococcus faecalis, Epiderrnophyton
15 floccosum, Escherichia coli, Giardia lamblia, Haemophilus influenzae, Microsporum cannis, Mycobacterium spp.,
Mycobacterium bovis, Mycobacterium leprae, Mycobacterium tuberculosis, Neisseria gonorrhoeae, papilloma virus, polio virus, Proteus spp., Proteus mirabilis, Proteus penerii,
20 Proteus vulgaris, Salmonella spp., Salmonella bongori,
Enteric Salmonella, Serratia spp., Serratia liquefaciens,
Serratia marcencens, Shigella spp., Shigella flexneri,
Shigella sonnei, Staphylococcus spp., Staphylococcus aureus, Staphylococcus epidermidis, Strongyloides stercoralis, Streptococcus spp., Streptococcus bovis, Streptococcus of the viridans group, Streptococcus equinus, Streptococis, trichococcus, pneumococcus, pneumococcus , Trichophyton rubrum, Trichophyton tonsurans, Tricophyton mentagrophytes, yellow fever virus, hepatitis B virus, rubella virus, Varicella zoster virus, smallpox virus, mumps virus, measles virus, herpes viruses and vaccine viruses or synthetic analogues that 10 present molecular patterns associated with pathogens (PAMPS) and / or molecular patterns associated with danger (DAMPS) associated with these antigenic agents.
A preferred immunogenic composition of the present invention comprises inactivated lysate of Mycobacterium 15 bovis, purified protein derivative of Koch's bacillus (PPD), inactivated lysate of Staphylococcus aureus, inactivated lysate of Staphylococcus epidermidis, inactivated lysate of Steptococcus pyogenes, inactivated pneumococcal isolate inactivated lysate of Enterococcus faecalis, 20 streptokinase / dornase, inactivated lysate of Candida albicans, inactivated lysate of Candida glabrata, inactivated lysate of Microsporum cannis, inactivated lysate of Trichophytonic acid, and inorganic lysate, and a variety of trichophytonic acid and lysate, and a variety of trichophytonic acid and a variety of different types of trichophyton. , inactivated lysate of Salmonella bongori, inactivated lysate of Salmonella enteric and inactivated lysate of underground Salmonella.
A preferred immunogenic composition of the present invention comprises 0.001 to 1 ng / ml of inactivated lysate of
W Mycobacterium bovis; 0.001 to 1 ng / ml of purified protein derivative of Koch's bacillus; 0.1 to 100 µg / mL inactivated Staphylococcus aureus lysate; 0.1 to 100 µg / mL of inactivated lysate of Staphylococcus epidermidis; 0.1 to 100 10 yg / ml of inactivated lysate of Steptococcus pyogenes; 0.1 to 100 µg / mL of inactivated Streptococcus pneumonie lysate; 0.1 to 100 g / ml of inactivated lysate of Enterococcus faecalis; 0.01 to 10 µg / mL streptokinase; 0.01 to 10 µg / ml of dornase; 0.1 to 100 µg / mL of inactivated lysate from 15 Candida albicans; 0.1 to 100 µg / mL of inactivated lysate of Candida glabrata; 0.1 to 100 µg / rriL of inactivated lysate of Epidermophyton floccosum; 0.1 to 100 µg / mL of inactivated lysate of Microsporum cannis; 0.1 to 100 µg / mL inactivated lysate of Tricophyton mentagrophytes variety 20 interdigitale; 0.1 to 100 µg / mL inactivated lysate of enteropathogenic Escherichia coli; 0.1 to 100 µg / mL inactivated Salmonella bongori lysate; 0.1 to 100 µg / mL inactivated inactivated Salmonella enteral and 0.1 to 100 µg / mL inactivated inactivated Salmonella underground.
In addition, in order to increase, decrease or polarize the immune response according to the purpose of immunotherapy, the antigenic compositions of the present invention may comprise cytokines and / or chemokines such as GM- "5 CSF, IL4, IL5, IL7, IL12, IL15, IL21 , gamma interferon, and more preferably IL2.
The compositions of the present invention can further comprise excipients, such as bactericides, bacteriostats, antioxidants, preservatives, buffers, stabilizers, pH adjusters, osmolarity adjusters, antifoam and surfactants; and residues of inactivating agents or fractionation of antigens, components of growth media and solvents commonly used in the production of vaccines and immunotherapeutic agents.
The compositions of the present invention can be a solid, liquid or gel. As used in the present invention, the use of the term "pharmaceutically acceptable" means a non-toxic, inert solid, semi-solid liquid excipient, diluent, auxiliary formulation of any kind, or simply a sterile aqueous medium, such as saline. . Some examples of materials that can serve as pharmaceutically acceptable carriers are sugars, such as lactose, glucose and sucrose, starches, such as corn starch and potato starch, cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate, cyclodextrin; oils, such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols, such as propylene glycol, polyols, such as glycerin glycol, sorbitol, mannitol and polyethylene; esters, such as ethyl laurate, ethyl oleate, agar; buffering agents, such as aluminum hydroxide and magnesium hydroxide; alginic acid; pyrogen-free water; isotonic saline, Ringer's solution; buffer solutions of ethyl alcohol and phosphate, as well as other compatible non-toxic substances used in pharmaceutical formulations.
A variety of animal or human administration routes of the immunotherapeutic compositions and vaccines described in the present invention are available. The particular mode selected will depend on that of the selected antigenic agents, the dosage required for therapeutic efficacy and the patient to whom the composition will be administered. The methods of the present invention can generally be practiced using any biologically acceptable mode of administration, that is, any mode that produces effective levels of immune response without causing clinically undesirable adverse effects. Such modes of administration include intradermal, oral, rectal, sublingual, topical, nasal, transdermal or parenteral routes. The term "parenteral" includes subcutaneous, intravenous, epidural, irrigation, intramuscular, delivery pumps, or infusion. Particularly, in this invention the oral,% intradermal, parenteral, subcutaneous, intravenous, intramuscular routes, as well as the nasal and / or oral mucosa are preferred for administration of the compositions claimed herein.
For parenteral administration, the active principles can also be dissolved in a pharmaceutical carrier and administered as a solution, emulsion, including micro and nanoemulsions, or suspension. Examples of suitable vehicles are water, saline, dextrose solutions, fructose solutions or oils of animal, vegetable or synthetic origin. Other vehicles may also contain other »ingredients, for example, preservatives, suspending agents, solubilizing agents, buffers and the like. . 20 Properties of the immunogenic compositions of the present invention.
The immunogenic compositions of the present invention have an unexpected effect on the immune response. As can be seen in the Examples below,
the immunogenic compositions of the present invention have the unexpected technical effect of eliciting an immune response that involves recontextualization, reprogramming and reconditioning of the immune response in real time.
· 5 More specifically, the immunotherapeutic compositions of the present invention are capable of provoking a recontextualization of the operational performance capacity of the immune system, changing the balance of forces against the aggressor agents in its favor, giving the immune system a competitive advantage, which it does not occur spontaneously in the evolution of diseases. This recontextualization determines a consequent reprogramming and renewal of the established or incipiently established, or wrongly established immune response 15, inautonomically attacking the human or animal organism, polarizing it to an adequate, primary and or secondary, active or inhibitory, immune response, more effective .
This effect occurs, via stimulation, activation and joint action of certain components of the immune system, such as + 20 sentinel cells, sentinel cells presenting. antigens and memory lymphocytes. Specifically, the compositions of the present correctly activate sentinel cells, dendritic cells and other APC cells generating the degree and intensity of activation of TCD4 cells and the degree and intensity of the immune profile to fight infection, infestation or neoplastic disease.
Thus, the immunomodulatory antigenic compositions of the present invention, when in greater or significant amounts, trigger an active specific adaptive immune response, desired in the fight against bacterial, viral or parasitic infections, in the fight against neoplasms, cancer and tumors.
In addition, treatment with the immunogenic compositions of the present invention is able to stimulate the regenerative power of the immune system, providing an effect after the elimination of infectious disease and other diseases: that of recovering cells and tissues, restoring the functions of the organs debilitated by trauma and 15 other damages that lead to the loss of part of the body.
Thus, the immunogenic compositions of the present invention are able to mobilize the immune system and lead to * an increase in the regenerative power of the body, through the mobilization of stem cells or the activation of clusters. 20 genic, which enable the regeneration of cells and tissues, and can even reconstitute organs and their functions and can reconstitute organic systems, such as the vascular system, such as the nervous system and the endocrine system, among others.
.
As can be seen in the Examples presented below, the immunogenic compositions of the present invention exhibit the unexpected technical effect of recontextualization, reprogramming and resumption of the immune response in real time and consequently significant cure rates when compared to drugs and methodologies existing in the state of technical.
In a first embodiment of the invention, a certain concentration of immunomodulatory agent (S) 10 is used to prepare an immunotherapeutic pharmaceutical composition capable of inducing an innate immune response, which triggers a cascade of immunological events, including activation of memory lymphocytes. from the agent (s) inoculated by human intervention and the concomitant activation by the antigens present in the patient's own organism, which result in the recontextualization, reprogramming and renewal of the immune response in progress to a certain established disease (or still in the process of establishment) ), generating a specific adaptive response 20 to this disease, making it possible to combat the pathogen. That is, the administration of the composition containing the agents of the present invention repolarizes, or improves the polarization of the immune system in the presence of a disease when the polarization is hitherto inadequately established, by the action of an etiological or colonizing agent. The performance of the agents of the present invention, alter the shape, time, precision and polarization of the immune response, preferably leading to · 5 a specific innate and / or adaptive response that is more effective in combating the disease, leading to a better reaction of the organism itself.
The present invention provides a way to combat these types of heterologous aggressions (infections and infestations) and 10 autologous ones (neoplasms) through the use of the described antigenic combinations. The present invention also provides for the possibility of adding traditional therapies to the agents of this invention, assisting the process of eliminating heterologous invasive etiologic agents and autologous colonizing cells, through the real therapeutic potential of antimicrobials and antineoplastics and other drugs selective for pathogens and other agents etiological factors. This is made possible by the principle of shifting the biological balance in favor of the patient in association with a correct polarization of the immune response as described in the present invention.
When the immune stimulus follows a situation of end of immune response, after the disease or aggression mechanism ceases, the continuation of the activation of the immune system by the antigens or immunomodulatory agents of the present invention, "leads, by the activation of stem cells, to the regeneration of tissues, organs and systems, by mechanisms not yet fully understood, however, 5 related to healing mechanisms or restitutio ad integrum observed in various medical situations.
The compositions of the present invention make it possible to recruit as many memory and virgin cells as possible from the individual, producing effects more significant than an increase in antibodies as described in the prior art. The use of multiple antigenic agents with PAMPS and DAMPS distinct enough to simulate the different types of attacks that the organism suffers and for which the organism already has an immunological memory, either through exposure in the environment or through vaccination programs, allows for recruitment much wider range of memory cells, and virgin cells, which allow real-time recontextualization of the immune response and thus potentially radically alter the type of immune response and 20 the progression of the disease or illness that affects the individual positively and, in several cases, surprisingly in relation to the state of the art. In addition, the present invention, contrary to the state of the art, applies a greater amount of bacterial components, which have representatives of intra and extracellular bacteria in the composition, in addition to components of viruses, parasites, fungi and yeasts. Hayashi and colleagues did not explore greater diversification in their composition to · 5 have a potentially greater effect. The application process of the antigenic agents was also different, since the present invention covers the exposure of most areas of the body and tissues that have APCS cells, and preferentially looking for an exposure near the infection or locality and other distal applications of the location of the disease (when it is the case in diseases or illnesses that manifest locally in the body). The compositions of the present invention, when applied according to the process of use of the present invention, in one or, generally, in several strategic places of the organism drained by territories or primary and / or secondary lymphoid organs or even intra-lesional, are perceived by all the RPPS (pattern receptors associated with pathogens) from all sentinel cells in the body.
20 In a first group of conditions of aggression or real danger, in which the immune system is being extemporaneously subdued, paralyzed or overcome by a bacterium, fungus, virus, prions, parasites or any other microorganism or macroorganisms, uni or multicellular,
(heterologous aggression) or by a malignant or benign neoplasm (autologous aggression), the alteration of its preparation occurs in the activation state and in the mobilization of its cellular and molecular apparatus of innate and adaptive immunity, which · 5 integrated are capable of reverse the situation of competitive disadvantage, in which the immune system and the organism meet.
In a second group of conditions of aggression, where the real danger comes from the immune system itself, that is, when it is attacking the human or animal organism itself, in an autoimmune or allergic disease, the recontextualization of the immune system occurs in the their preparation to be able to inhibit this harmful action. the present invention induces the immune system to suppress its activation state and to demobilize the memory effector loops, which maintain self-harm. This effect is achieved by mobilizing the cellular and molecular apparatus of innate and adaptive immunity responsible for suppressing and regulating the immune response and returning to the state of equilibrium known as homeostasis or normality.
In a third group of conditions, where the immune system deals with the consequences of tissue, organic or systemic aggressions derived from multiple causes, heterologous or autologous, or even traumatic, the action of the immune system occurs in repairing the damage caused in these aggressions. In this case, the preparation or mobilization of the immune system occurs through the mobilization of stem cells from the immune system itself. 5 from other cellular, autologous, allogeneic or heterologous systems. Or even by the activation of gene sets present in the patient's own cells.
Thus, the present invention uses immunomodulating agents in specific quantities, concentrations and locations 10 to recontextualize the immune system by activating and renewing the mechanisms of tissue regeneration and repair, as occurs in the healing and regeneration phase of a tissue, organ or system , leading to a "restitutio ad integrum" or reconstitution 15 with scarring. This repair is usually triggered at the end of the process of an immune response, after healing of a trauma, an infection, a tumor or an autoimmune or allergic disease.
Use of the immunogenic compositions of the present invention.
Considering the properties of the immunogenic compositions of the present invention, it is another aspect of the present invention to use immunogenic compositions in the manufacture of medications for the prevention and / or treatment of infectious diseases, autoimmune diseases, allergic diseases, inflammations, arthritis, inflammatory diseases, rejection transplants, diseases caused by vascular disorders, diseases caused by hemorrhagic or ischemic cardiovascular accidents, ischemia,. 5 infarction and hemorrhages that lead to tissue destruction, heart, kidney, respiratory or liver failure, cancer, tumors and malignant and benign neoplasms.
The immunogenic compositions of the present invention are also used directly in the prevention and / or treatment 10 of infectious diseases, autoimmune diseases, allergic diseases, inflammations, arthritis, inflammatory diseases, transplant rejection, diseases caused by vascular disorders, diseases caused by hemorrhagic cardiovascular accidents or ischemic, ischemia, 15 infarction and hemorrhages that lead to tissue destruction, heart, renal, respiratory or liver failure, cancer, tumors and malignant and benign neoplasms.
Said infectious diseases can be of viral, bacterial, fungal or parasitic origin.
Diseases of viral origin prevented and / or treated by the immunogenic compositions of the present invention can be caused ... by the following viruses but not limited to: HIV, hepatitis virus, herpes virus, rhabdovirus, rubella virus, smallpox virus, poxvirus , paramyxovirus and morbillivirus.
Diseases of bacterial origin prevented and / or treated by the immunogenic compositions of the present invention can be caused ... by the following bacteria but not limited to 5: Pneumococcus, Staphylococcus, Bacillus, Streptococcus,
P Meningococcus, Gonococcus, Eschericia, Klebsiella, Proteus, and Pseudomonas, Salmonella, Shigella, Hemophilus, Yersinia, Listeria, Corynebacterium, Vibrio, Clostridia, Chlamydia, Mycobacterium, Helicobacter and Treponema.
10 Diseases of fungal origin prevented and / or treated by the immunogenic compositions of the present invention can be caused ... by the following fungi but not limited to: Candida, Aspergillus, Cryptococcus neoformans, and / or fungi that cause superficial and deep mycoses. Diseases of parasitic origin are caused by the following parasites: Trypanosome, Schistosome, Leishmania, amoebae and tapeworm.
The immunogenic compositions of the present invention are also + used in the prevention and / or treatment of systemic and localized lupus erythematosus, rheumatoid arthritis, 20 polyarteritis nodosa, polyioriosis and dematomyositis. progressive, systemic progressive sclerosis, diffuse scleroderma, glomerulonephritis, myasthenia gravis, Sjogren's syndrome, Hashimoto's disease, Graves' disease, adrenalitis, hypoparathyroidism, pernicious anemia, diabetes, multiple sclerosis, demyelinating diseases, uveitis, pemphigus, pemphigus , myocarditis, regional enteritis, adult respiratory stress syndrome, and local manifestations of drug reaction,, 5 atopic dermatitis, childhood eczema, contact dermatitis, psoriasis, liquem plano, allergic enteropathies, bronchial asthma, transplant rejection, post-disease streptococcal as cardiac, renal and articular manifestations of rheumatic fever and other correlated manifestations 10, various and multiple forms of cancer, correct for example, carcinomas, adenocarcinomas, melanomas, sarcomas, malignant astrocytomas, hepatomas, hypernefromans, lymphomas and rhnelanomas, among others.
The immunotherapeutic compositions of the present invention are also useful in the treatment of neoplasms, autologous colonizations, by benign and / or malignant tumor cells, in all forms of cancer, known as: as carcinomas, adenomas, adenocarcinomas, hepatomas, * astrocytomas and other neoplasms of the central nervous system. 20 and peripheral, melanorns, sarcomas, lymphomas and leukemias and all benign tumors.
The immunotherapeutic compositions of the present invention can also be useful in the case of diseases arising from the impairment of the immune system (as already mentioned) such as: systemic lupus erythematosus; rheumatoid arthritis; nodular polyarteritis; polymyositis and dermatorniositis and progressive systemic sclerosis (diffuse scleroderma); glomerulonephritis; myasthenia gravis; Sjogren's syndrome; 0 5 Hashimoto's disease (hypothyroidism); Graves' disease (hyperthyroidism); adrenalites; hypoparathyroidism; pernicious anemia; diabetes; multiple sclerosis, and related or related demineralizing diseases; uveites; pemfigus and pemphigoid cirrhosis; ulcerative colitis; 10 myocarditis; regional enteritis; hepatitis and cirrhosis; adult respiratory distress syndrome (adult respiratory distress syndrome); local and systemic manifestations of reactions to drugs, such as pharmacodermias, dermatitis and others.
15 Still in the field of inauthenticity diseases, the treatment of arterial and venous strokes is also included as immunotherapy of the present invention, in diseases such as myocardial infarction, pulmonary embolic, cerebral and digestive thrombus phenomena or in any other territory of the world. organism where the stroke leads to ischemia or hemorrhage, which results in necrosis or atrophy of these segments, such as, but not limited to, the entire locomotor system, the entire central and peripheral nervous system, leading to occlusion blood supply and results in heart attacks and strokes. Thus, the immunotherapy of the present invention has an anti-inflammatory action and increased immunity that can lead to the blockage of ¢ 5 inflammatory processes important to the establishment of diseases such as: metabolic syndrome, obesity, type 2 diabetes, atherosclerosis, alcoholic fatty liver, steatosis non-alcoholic liver disease, hypertension, renal failure, post-thrombotic syndrome, post-thrombophlebitis and any other disease derived from an inflammatory action of the immune system.
In the case of allergic, autoimmune and inflammatory diseases, the immunotherapy of the present invention can be useful, but not limited to, the associated or inflammation caused by allergic skin reactions; in atopic dermatitis childhood eczema; contact dermatitis in asthma, bronchial asthma, bronchiolitis and allergic bronchitis, allergic rhinitis; allergic enteritis; allergic enteropathy; pseudo-tumor inflammatory processes of currently unknown origin; psoriasis (pseudoinflammatory tumor; lichen planus; post-streptococcal diseases; rejection of heart, liver, lung, kidney, pancreatic islet and other transplants; hypersensitivity or destructive immune responses against infectious agents; post-streptococcal disease, such as heart, kidney , myocarditis, pericarditis or rheumatic fever and equivalent by other etiologic agents, i "not limited by the forms of these manifestations. In the case of autoimmune and allergic diseases the concentrations and dosages will preferably be much lower, acting on the incomplete activation of immune cells , memories or not, being able to include, but not limited to the diseases already mentioned.
The immunogenic compositions of the present invention are also used to induce cell regeneration, tissue regeneration, organ regeneration and regeneration of organic systems, such as the circulatory system, the nervous system and the endocrine system.
Thus an embodiment of the invention constitutes a method 15 for inducing cell regeneration, tissue regeneration, organ regeneration and regeneration of organic systems, such as the circulatory system, the nervous system and the endocrine system in an animal characterized by comprising administering to the animal an effective amount of one or more immunogenic compositions of the present invention.
Another method of the present invention is a method for renewing the immune response in an animal comprising the following steps: a) administering systemically and / or locally in the animal a therapeutically effective amount of one or more immunogenic compositions, as defined in any [one claims 1 to 21; b) ensure contact of one or more immunogenic compositions, applied in step "a" with the animal's dendritic cells or other APC cells; C) optionally administer prosthetic agents, such as vitamins in the place or region where the disease to be treated occurs, in order to strengthen the metabolism and consequently the animal's immune system; and optionally administer other medications or specific treatments.
In one embodiment of the present invention, the compositions of the present invention are administered at once, in a single territory of the organism or in different territories in order to restore the immune system as efficiently as possible. The use of the immunogenic compositions of the present invention for modulation of the immune system, involving exposure of part or all of the immune system's antigen recognition system 20, such as dendritic cells, lymph nodes and macrophages from different parts of the body, will depend the objective imposed by the disease being fought, and it occurs preferably through injections or the use of pistols, or systems of controlled release or infusion or pulsed cells with antigens in vitro. The agent can be applied in only one place in the organism or in several dozen places, in subcutaneous, muscular, intravenous, oral form, through breathable, cutaneous aerosol 5 (patches) in specific organs, viscera or tissues, or in different cavities of the body. number, which can vary from one to 100 (one hundred) applications in one to 50 (fifty) sessions.
The antigenic compositions of the present invention can also be combined with other drugs capable of impairing reproduction, growth or any other form of strengthening the disease-causing agent, generating a shift in biological balance in favor of the host, human or animal immune defenses or still in concomitant treatment.
The antigenic compositions of the present invention can also be combined with other procedures such as, but not limited to, antibiotic therapy, chemotherapy, radiation therapy, therapy with antibodies and antisera, use of hormones or other physiological modulating agents (cytokines, chemokines , neurohormones, peptides), therapy with antiviral agents, use of herbal medicines, supplementation with vitamins, supplementation with other cofactors or postural agents, cell or tissue transplants, therapeutic or prophylactic vaccination techniques (with or without cells and without limiting the type vehicle), gene therapy, surgery or homeopathy, depending on the disease or illness related to an improper or inefficient immune activity being fought.
In particular, in order to increase, decrease or polarize the immune response as c) objective of immunotherapy, the antigenic compositions of the present invention can be used in conjunction with therapy with cytokines and / or chemokines such as GM-CSF, IL4, IL5, il7 , IL12, IL15, IL21, interferon gamma, and more preferably IL2.
Recon extualization, reprogramming and recon, duction of the immune response.
The recontextualization of the immune system, as already explained in the text of the present patent application, is done through the stimulation of the immune system by the antigens of different pathogens, unrelated to the pathology to be treated, for which the human or animal organism, of preferably already have an immunological memory.
These several and varied antigens in excess of five, with multiple PAMPS and DAMPS, should cause in the sentinel cells and APC cells, mainly in the 6 dendritic cells, an intense activation that allows the
L mobilization of these specific memory TCD4 lymphocytes
P antigens at the application site.
5 These stimuli must be capable of eliciting an intense, strong and effective specific immune response secondary to these antigens at the application site, at regional locus lymph nodes, at remote lymph nodes and a systemic mobilization of the immune system so that this 10 can, in parallel , provoke a specific effective response capable of eradicating the current pathology.
The innate and adaptive immune response intentionally provoked by the composition of the present invention should comprise the entire body extension of the area affected by the pathology to be treated and even exceed it if possible to be able to activate the sentinel cells and APC in number and intensity that I "would be necessary for them to correctly size © the aggression caused by the pathogen of the disease to be treated, activating and provoking the best response
Specifically adaptive, effective and correctly sequentially polarized in order to cure the pathology to be treated.
In this way the innate and adaptive response provoked by the present invention, will overlap geographically that of the pathology to be treated and by its intense and extensive activation it will correct the inefficient activation, purposely limited by the action of the pathogen, which is overcoming the 5 defenses of the organism, preventing through competition, its correct mobilization and the elaboration of an effective adaptive response according to its greatest genetic and biological potential. This ideal activation should also reverse the immunosuppression, tolerance and escape mechanisms established by the pathogens because it is known and proven that a strong and intense unrelated immune response, which fully covers the response to be corrected, through the activated cells and cytokines immune system, they correct these deficiency situations efficiently.
The effector cells and specific memories of the antigens of the present invention, activated and generated at the site of the application of the antigens, go through the blood into the already activated lymph nodes, which drain the region affected by the disease and will strongly and intensively activate all dendritic cells. existing there. In this way they will cause an activation of the whole lymph node, making it grow with increased irrigation, increasing its dimensions and making it a reactionary lymph node capable of provoking an immune response against weak antigens, which by themselves are not capable of provoking an immune response. This adjuvant effect, well known and demonstrated experimentally and clinically, of effector T lymphocytes / memory, will counteract the action of the target etiologic agent, which is blocking the necessary activation of the lymph node, for the elaboration of the immune response that is necessary to combat the disease in question.
- That, solely for the purpose and action of the present invention, through its potent antigenic composition, it may occur, that sentinel cells and dendritic and macrophage cells of the immune response will be the same, for unrelated antigens and for pathological antigens , however, from this action, they will be intensely and correctly activated. Dendritic cells intensively activated by multiple antigens will have a slow metabolism and will ideally present all dominant and subdominant epitopes of the ethyl agent, due to the known "helper" effect, mobilizing all possible and available T lymphocytes capable of specifically recognizing antigens of the autologous pathogen or heterologous, to be treated and to be able to react against it.
That the area of the inflammatory process and the lymphatic territories are exactly the same. The inflamed area, due to the known anti-inflammatory action of specific, unrelated memory cells, mobilized by the present invention through its antigenic composition, will block +
L inflammasomes and will exert an anti-inflammatory action that will correct the pathological inflammation responsible for the 5 disease morbidity and that was caused by its etiological agent. For the purpose of memory, it is important to note that this well-known action of the T cells is one of the main factors responsible for the fact that a second contact with any pathological agent, after established immunity 10, occurs completely asymptomatically without causing a disease.
- That the lymphatic territories are exactly the same, only now intensely activated and with the necessary alarm signal, given by the present invention, to provoke any immune response, even for a weak antigen, as is the case with dendritic cells common to this invention and to the autologous or heterologous etiological agent to be fought. The lymphokines and innate cells that command an effective secondary response 20 will be the same and the specific T lymphocytes against the etiologic agent to be fought, will take "a ride from this ideal microenvironment for the realization of an effective immune response.
- That in this way the dendritic cells activated by
V the present invention can capture the antigens of agent L.
etiological to be fought, at the pathology site and in the lymph territories concerned and may be in contact with the TCD4 lymphocytes specific to the pathological agent, in a correct and ideally activated lymphatic system. The action of activated and matured dendritic cells with TCD4 lymphocytes specific to the etiological agent, will occur in a microenvironment conducive to the realization of an immune response, with all the genetic and biological potential of the host organism's immune system.
These dendritic cells at the pathology site and in the lymph nodes will correctly measure the severity, extent, intensity and type of the aggression, activating, inducing, coordinating, polarizing, conducting and maintaining a new effective adaptive immune response, whose loop effector, with the collaboration of cells and effector molecules of intense innate immunity and 20 correctly activated may be able to eliminate the etiological agent to be fought. Thus the response will be reprogrammed and reappointed as indicated above, reversing the biological balance in favor of the host, who until then was under the yoke of the autologous or heterologous aggressor agent.
This action may occur with or without the help of a biological balance shifter such as antibiotics and antineoplastics, capable of blocking, weakening or neutralizing the action and potential of the etiological agent, allowing the immune system to have the chance to cure the target pathology of treatment. The immune system once activated by any etiologic agent, only for a response when it eliminates the etiologic agent or the organism dies, in this way the present invention will help to avoid the latter hypothesis, or will improve the patient's conditions if a chronic illness occurs. that cannot be cured.
In this way the action of the compositions of the present invention intentionally and strategically superposed and superimposed over the entire area under the action of the etiological agent to be combated. It will recontextualize the immune system by activating the PAMPS and DAMPS of common sentinel cells and APCS and by the unrelated specific secondary adaptive immune response. This intentionally induced immune response will efficiently activate all lymphatic territory and the organic territory reached by the etiologic agent. In the recontextualized area and in the bulge and within the context of a larger, stronger, more intense immune response,
more extensive, secondary, anti-inflammatory in nature, the target immune response will be, as described, reprogrammed and reapplied efficiently within the greatest possibilities of the host, now with a chance of reversing 5 the biological balance in its favor.
Adequacy of the protocol to the pathophysiological characteristics of the pathology to be treated: a) the bases of immunotherapy against neoplasms.
Malignant neoplasms have as their main characteristic the domain of the microenvironment, as defined in the study of the present invention and which differs from that traditionally based on the current state of the art, which is that of the environment caused by the action of tumor cells with the cells of the organism that by this action start to work in your favor. The micro environment defined here is the space around a single neoplastic cell or a set of these, which through the surface molecules and / or by other molecules secreted by it come to dominate this environment totally in your favor.
In this dominated space, the connective tissue starts to support and nourish these cells through its structural elements and new vessels destined to supply the neoplastic cells and their supporting tissue. Through surface molecules and substances and enzymes secreted in this environment by tumor cells, they destroy the tissue from which they originated and the healthy tissues invaded by them, which are then colonized and replaced. Surface and secreted molecules 5 completely block the immune system by immobilizing and inactivating sentinel, APC and lymphocytic cells, inducing nonspecific and specific immunosuppression and disabling loco-regional and distant lymph nodes.
Through the domain of the microenvironment, neoplastic cells by enzymes and surface molecules enter the blood and lymph vessels gain circulation and colonize sites at a distance from the original tumor and cause distant metastases, both lymphatic and hematogenous.
In this way, the total domain of the micro-environment around a single cell leads a tumor cell, through its indiscriminate proliferation, to initially pathologically subdue the space around itself, its original tissue, the adjacent areas, the organ and finally through metastasis the organism as a whole. So too, immunoignorance, immunosuppression and induced specific and nonspecific tolerances are first in situ, then local, loco-regional, organic, and finally systemic, completely dominating the host body's immune system.
The domain of the microenvironment is, therefore, the strategic, crucial and determining effect produced by the genomic potential of a neoplastic cell, which leads a single tumor cell to dominate the space in situ, local, 5 regional, organic and systemic colonizing the host and the led to death.
In short, an immunotherapy must, mandatorily, break the domain of the established microenvironment and tumor macroenvironment and cover all immunological territories dominated by the neoplasm. The immunotherapeutic treatment should also cover the lymphatic territories at a distance from the tumor area, inducing a recontextualization, reprogramming and renewal of the immune system from outside to inside the affected area with a strong inertia capable of reversing, together with the locoregional treatment (intratumoral and perilesional, completely the tumor domain.
Immunotherapy should be performed every 4 or 5 days, as it is the physiological period of generation of suppressor cells that control the immune response. Successive waves of antigenic stimulation repeated in this period of time perpetuate the immune response indefinitely perpetuating the antigenic stimulus just as it occurs in an infection before its phase of chronification and generation of an immune dysfunction. The non-generation of suppressor cells and recontextualization prevent the suppressor cells from dominating the tumor and protecting it from the environment.
5 The action of a neoplastic cell in the micro and set of them in the macroenvironment takes place for 24 hours a day and throughout the period in which the disease exists.
Therefore, immunotherapy with the aforementioned scope, scope and frequency should be applied continuously as long as there are tumor cells. It is interesting to mention that traditional immunotherapy that causes discontinuous stimuli, similar to protocols for immunization with inert antigens (soluble or not) or attenuated agents, does not find application in the pathophysiological context induced by tumors.
Any specific immune response can be amplified and potentiated efficiently by the addition of cytokines and / or chemokines, preferably exogenous IL2 at the level of receptor saturation, which will produce the proliferation of immune cells that have recognized the antigen and, for this reason, present on its surface the complex expression of the interleukin 2 receptor. Therefore, only the response of the antigens induced by the invention and those induced by the etiological agent (autologous or heterologous) will be amplified. In an anti-tumor immunotherapy in which only weak antigens exist, this must be complemented with IL2 in order to obtain an effective and robust immune response.
5 The basis of immunotherapy counts septicemia, sepsis and "septic shock" Septicemia is defined as an extremely serious infection, in which one or more bacteria, or microorganisms, from their point of entry, enter the bloodstream and start to generally circulate in large numbers, settling in distant points colonizing tissues, organs successively being able in the most serious cases to reach the majority of the corporal surface. Generally when the load of microorganisms is very large, a large number of bacteria, with their toxic and metabolic products, with countless PAMPS and DAMPS, touching all also countless RPPS and RDPS of most of the body surface, at the same time generate an extensive, generalized intense and violent inflammatory process, due to the massive release of cytokines from the translation of all these signs.
The unfavorable evolution of septicemia leads to sepsis, due to the massive release of pro-inflammatory cytokines such as TNFS, ILI, IL18, IL6 and others, which cause an inflammatory collapse with characteristic hemodynamic changes,
such as hypotension, an accelerated pulse, which can culminate in septic shock, which is usually irreversible. Septicemia, sepsis are serious infections with high morbidity and mortality. In these serious infections, the immune system, in turn, with its impaired operability, due to the deficiencies and blockages induced by the bacteria, starts to act in order to eliminate the bacteria at any cost, due to the inflammatory Thl7 tissue profile increasing inflammation in a way disproportionate harming the organism.
In this tissue inflammatory profile, the effector loops of innate immunity commanded by TCD4 lymphocytes cause injuries and tissue destruction, sometimes massive, which compromise organs and tissues and worsen infections, leading, for example, to respiratory failure, in the shock lung and in the S.A.R.A. (Adult Respiratory Distress Syndrome) and also lead to kidney failure and multiple organ failure.
Therefore, in septicemia, sepsis and septic shock, there are two variables that should be strategically considered and should be the target of immunotherapy for this to be successful. These two variables are the massive inflammation caused by the spread of countless bacteria throughout the body and its connection with
RPPS and DPPS and the polarization for the Thl7 profile caused by the functional infeasibility of the Thl and Th2 profiles. These variables are the cornerstone of the severity, severity, morbidity and mortality of these pathologies.
5 Taking these two variables into account, an immunotherapy to be effective in these infections should be applied in order to cover the entire body surface, including the largest number of lymphatic territories, to geographically overlap the action of pathogens or pathogens. If possible, it should also be applied to the injured areas and the perilesional region so that together they can cause a generalized recontextualization that recovers through its action the integrity of the loop produces a wide and intense anti-inflammatory effect through the effector T cells / memories generated application sites. It should be paralleled by the reconstextualization and reprogramming described above to polarize the TCD4 response of the inflammatory tissue Thl7 profile to the humoral TH2 and cellular THI immunity profiles, further decreasing the generalized inflammation.
Loop amplification by IL2 should be very weak, just enough to specifically amplify the repolarization of the immune response from the inflammatory profile to the immunity profile.
Thus, the recontextualization and reprogramming achieved by immunotherapy using the compositions of the present invention, through the rescue of immune cells, 5 through the anti-inflammatory action of specific unrelated T-lymphocytes, through the repolarization of the inflammatory tissue profile TH17 for the profiles of elective and effective immunity th2 and THI, would lead to an immune response. This immune response, reapplied in real time, during the infectious process, may, together with a biological balance shifter, in the case with the use of several antimicrobials, have the chance to reverse this biological balance at the end of the curve in which it is widely favorable to the microorganism, to be now favorable to the host and it has a chance of solution.
Adequacy of the protocol to the "status" of the immune system in pathology and in the patient to be treated.
In the case of neoplasms and septicemias, due to the pathophysiological mechanisms themselves, there is a break in the integrity and functionality of the T loop with an inadequate polarization for a suppressive TREG profile in neoplasms and inflammatory tissue Thl7 in septicemias with an almost complete inoperability of the immune system overcome by disease. In these cases, as in the examples cited here, the recontextualization must reach the entire organism in order to reverse all immunosuppression, tolerance and immunoignorance induced by the pathology, as well as to restore all the functional and operational capacity of the immune system to have a reprogramming. and renewing an effective immune response.
Rationale of the therapeutic protocol.
The therapeutic protocol of the present invention designed to be applied in cases of cancer and septicemia should: - be applied mostly in the strategic lymphatic regions of the body or infection. In the cases described in this document, more than 10 lymphatic territories were reached. It should be applied within the tumor areas and infected in the perioperal areas - the immunotherapeutic formulation must contain at least 5 antigens in order to contain PAMPS and DAMPS in order to be able to recontextualize the immune system.
- the application area should overlap, encompass and supplant the entire extension of the regions dominated by the tumor and the infection.
- antigenic stimuli should be repeated every 4 or 5 days in order to avoid the generation of suppressor cells capable of aborting the new desired immune response or suppressing an achieved repolarization.
- the treatment must be maintained in this way until the last neoplastic cell is eliminated, or the infection ends, or the lesions, organs or systems are healed.
5 - in practice, 1 to 3 mL of this immunotherapy should be applied to 10 or more lymphatic territories.
Together the present inversion should be applied intra and extra tumor or lesion in the areas injured by the neoplasia, or by the infection.
In summary, immunotherapy is "systemically" distributed in several (at least ten) lymphatic, peri and intratumoral or lesioanal territories with a volume capable of disrupting and destabilizing the tumor and the domain of its micro and macroenvironments, or of significantly covering the area affected by infection and inflammation, as well as to restore the microenvironment, which is favorable to the body's immune response. It will be applied every 4 to 5 days with the use of exogenous interleukin 2 in low doses, in an uninterrupted way, during the duration of the disease. In the case of sepsis septicemia and septic shock, as already mentioned, this dose should be the lowest possible.
EXAMPLES To allow a better understanding of the present invention and to clearly demonstrate the technical advances obtained, the following are presented, as examples, the results of the different tests carried out in relation to this invention.
In Example 1, several preferred immunogenic compositions of the present invention are described. Examples 2 to 8 illustrate the properties, use and therapeutic methodologies employing the immunogenic compositions of the present invention. In Examples 2 to 8, the immunogenic composition described in Example 1, composition 1, and here called DECA, was used.
These Examples are presented for illustrative purposes only and should in no way be considered as limiting the scope and scope of the present invention.
Example 1: Immunogenic compositions.
In order to achieve the recontextualization, reprogramming and reconditioning of the immune response in real time in accordance with the innovative concepts described in the present invention, a specialist experienced in the technique will be able to design different and distinct compositions, combinations or formulations of products that fall within the scope of this invention.
As described, in order for such compositions to meet the technical requirements necessary for the advantageous or unprecedented results in combating a number of ailments and diseases to be achieved, they must have a high diversity of pathogen antigens, in order to obtain the maximum effects synergistic in the binding of PAMPS and DAMPS to their receptors, making it possible to achieve a high degree of activation of innate immunity in sentinel cells (with or without ATC function) thus allowing recontextualization, reprogramming and reconditioning of the immune response in real time.
Such compositions should preferably use the antigenic agents for which most people, due to previous contact, would have memory clones in their immune system capable of inducing a wide anti-inflammatory action in parallel to the recontextualization. For that, antigenic agents should preferably be selected that: · correspond to the most common infections contracted by the individual from childhood to maturity (when the animal or the human being acquires his "immunity repertoire").
"are used in immunization programs such as childhood vaccination programs, against endemic diseases and / or epidemic diseases.
"come from potentially pathogenic microbiota organisms, mainly from the gastrointestinal tract, where memory lymphocytes exert an active + dynamic barrier ensuring the survival of the
V individual.
5 "Ideally each of the antigenic agents should be present at a concentration of 0.001 to 500 micrograms per mL.
According to these concepts, several formulations were developed using antigenic agents in the 10 forms already available, safe and approved for use in humans in vaccination programs or allergic response tests and immunity assessment tests.
Thus, we present below several examples of compositions that fall within the scope of the present invention, without however aiming to limit it, since the present invention and its concepts allow the design of immunogenic compositions comprising a very high number of combinations of antigenic agents.
Composition 1 20 Component Concentration Koch crude turberculine (inactivated lysate of Mycobacterium bovis).
0.004 ng / mL
PPD 0.004 g / mL 0 Staphylococcus inactivated lysate (Staphylococcus aureus and Staphylococcus epidermidis in equal parts 6.94 µg / ml).
5 Inactivated lysate of Steptococcus (Streptococcus pyogenes, Streptococcus pneumonie and Enterococcus 6.94 ug / mL faecalis in equal parts).
Streptokinase from purification from 0.444 µg / mL inactivated lysate of Streptococcus beta-10 hemolytic.
Dornase from purification from 0.111 µg / mL inactivated beta-hemolytic Streptococcus.
Candida inactivated lysate (Candida albicans and 6.94 15 g / mL Candida glabrata in equal parts).
Inactivated lysate of dermatophytes (Epidermophyton floccosum, Microsporum cannis, Tricophyton 6.94 µg / mL mentagrophytes variety interdigitale in equal parts).
Escherichia coli 20 lysate and inactivated 6.94 µg / mL enteropathogenic (EPEC) Salrnonella lysate and inactivated (Salmonella bongori, Salmonella enterica and Salmonella 6.94 µg / mL underground in equal parts).
Sodium chloride 7,
5 mg / mL Dibasic sodium phosphate heptahydrate 0.48 mg / mL Potassium phosphate monobasic 0.06 mg / mL Phenol 2, 5 5 mg / mL Water q. s . P . .
Composition 2 Water q. s . P .
Composition 3: Concentration component PPD concentration component.
0.004 ug / mL Inactivated lysate of Streptococcus pyogenes, lysate 6, 94 µg / mL inactivated Streptococcus pneumonie and inactivated lysate of Enterococcus faecalis in equal parts.
Inactivated lysate of Staphylococcus aureus and lysate 6, 94 µg / ml inactivated Staphylococcus epidermidis in equal parts.
Inactivated lysate of Candida albicans, 6.94 ug / mL inactivated Candida parapsilosis and inactivated Candida glabrata lysate in equal parts.
Sodium chloride 7.5 mg / mL Sodium phosphate dibasic heptahydrate 0.48 mg / mL a Monobasic potassium phosphate 0.06 mg / mL Phenol 2.5 mg / mL 5 Water q. s . P .
Composition 4: Component Concentration BCG inactivated lysate. 50 mg / mL Staphylococcus aureus inactivated lysate and 10 6.94 µg / mL inactivated Staphylococcus epidermidis in equal parts.
Equal parts of inactivated Streptococcus lysate 6.94 µg / mL agalactiae and mixture of Streptococcus lysadcis consisting of inactivated lysate of 15 Streptococcus pyogenes, inactivated Streptococcus pneumonie lysate and inactivated Enterococcus faecalis lysate in equal parts.
Inactivated lysate of Candida albicans, 6.94 µg / mL inactivated Candida parapsilosis and 20 inactivated lysate of Candida glabrata in equal parts.
Sodium chloride 7.5 mg / mL Dibasic sodium phosphate heptahydrate 0.48 mg / mL
Monobasic potassium phosphate 0.06 mg / mL Phenol 2.5 mg / mL Water q. s . P .
5 Composition 5: Water q. s . P .
Composition 6: Component Concentration Koch crude turberculine (inactivated lysate of 0.004 ng / mL Mycobacterium bovis).
Inactivated lysate of Streptococcus pyogenes, 6.94 µg / mL inactivated Streptococcus pneumonie and inactivated lysate of Enterococcus faecalis in equal parts.
Inactivated lysate of Neisseria meningitidis.
6.94 pg / mL Inactivated lysate of Aspergillus fumigatus, 6.94 µg / mL Aspergillus flavus and Aspergillus terreus in equal parts.
Sodium chloride 7.5 mg / ml sodium dibasic phosphate heptahydrate 0.48 mg / ml Potassium phosphate monobasic 0.06 mg / ml Phenol 2.5 mg / ml
Water q. s . P .
Composition 7: + Concentration Component
W Koch crude turberculine (0.004 5 ng / mL inactivated Mycobacterium bovis).
BCG inactivated lysate.
50 mg / mL Staphylococcus aureus inactivated lysate and 6.94 g / mL inactivated Staphylococcus epidermidis in equal parts.
Inactivated lysate of Streptococcus pyogenes, 6.94 µg / mL inactivated Streptococcus pneumonie and inactivated lysate of Enterococcus faecalis in equal parts.
Inactivated lysate from Candida albicans, lysate 6.94 15 µg / mL inactivated from Candida parapsilosis and inactivated lysate from Candida glabrata in equal parts.
Inactivated lysate of Streptococcus equinus, 6.94 µg / rnL Streptococcus bovís and Streptococcus of the viridans group in equal parts.
20 Escherichia coli inactivated lysate 6, 94 g / mL enteropathogenic (EPEC), producing shiga-like toxin (STEC), enteroaggregative (EAEC), entrerotoxygenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) in parts equals.
Inactivated lysate of Salmonella typhi, Salmonella 6.94 µg / mL paratyphi and enteric Salmonella in equal parts. 0 Inactivated lysate of Aspergillus fumigatus, 6.94 µg / mL 4 Aspergillus flavus and Aspergillus terreus in equal parts.
5 Antigens of the measles virus ("Schwarz strain") 10,000 lysed and inactivated.
TDCI50 / mL Glycerin 500 mg / mL Phenol 2, 10 5 mg / mL Water q. s . P .
Composition 8: Component PPD concentration 0.004 g / ml 15 Inactivated lysate of Myccubacteriujn tuberculosis.
0.004 ng / mL Staphylococcus aureus inactivated lysate and 6.94 µg / mL inactivated Staphylococcus epidermidis in equal parts.
20 Escherichia coli inactivated lysate 6.94 µg / mL enteropathogenic (EPEC), producing shiga-like toxin (STEC), enteroaggregative (EAEC), entrerotoxygenic (ETEC), enteroinvasive (EIEC) and
Water q. s . P .
0 Composition 9: Concentration Component - BCG inactivated lysate.
5 50 mg / mL Inactivated lysate of Mycobacterium tuberculosis 0.004 ng / mL Inactivated lysate of Staphylococcus aureus and 6.94 µg / mL inactivated Staphylococcus epidermidis in 10 equal parts.
Escherichia coli lysate and inactivated 6.94 µg / mL enteropathogenic (EPEC), producing shiga-like toxin (STEC), enteroaggregative (EAEC), Water q. s . P .
15 Composition 10: Component Concentration Inactivated lysate of Mycobacterium africanum. 0.004 ng / mL Koch crude turberculine (inactivated lysate of 0.004 20 ng / ml Mycobacterium bovis).
Escherichia coli inactivated lysate 6.94 µg / mL enteropathogenic (EPEC), producer of "shiga-like" (STEC) r enteroaggregative (EAEC), Water q. s . P .
Composition 11: 0 Component Concentration Component Concentration Inactivated lysate of Mycobacterium leprae. 0.004 ng / mL% Koch crude turberculine (inactivated lysate of 0.004 5 ng / ml Mycobacterium bovis).
Inactivated lysate of Staphylococcus aureus and 6.94 µg / mL inactivated Staphylococcus epidermidis in equal parts.
Inactivated lysate of Candida albicans, lysate 6.94 10 µg / mL inactivated from Candida parapsilosis and inactivated lysate of Candida glabrata in equal parts.
Equal parts of inactivated Streptococcus lysate 6.94 ug / mL agalactiae and mixture of Streptococcus lysates consisting of inactivated lysate of 15 Streptococcus pyogenes, inactivated lysate of Streptococcus pneumonie and inactivated lysate of Enterococcus faecalis in equal parts.
Inactivated lysate of Streptococcus equinus, 6.94 µg / mL Streptococcus bovis and Streptococcus of the viridans group in 20 equal parts.
Inactivated lysate of Haemophilus influenzae.
6.94 µg / mL Inactivated lysate of Proteus rnirabilis, Proteus 6.94 µg / mL vulgaris and Proteus penerii in equal parts.
l '105 |, i Rubella virus antigens ("Wistar RA 10,000 strain!' 27 / 3M") lysed and inactivated. © TDCI50 / mL
G Varicella zoster virus antigens lysed 5 149,231 and inactivated. PFU / mL Glycerin 500 mg / mL Phenol 2.5 mg / mL Water q. s .p.
Composition 12: 10 Water q. s .p.
Composition 13: Component Concentration Inactivated lysate of Mycobacterium tuberculosis. 0.004 ng / mL 15 Mycobacterium avium inactivated lysate. 0.004 ng / mL Neisseria meningitidis inactivated lysate. 6.94 µl µg / mL 67 units Lf diphtheria toxoid / mL 20 Equal parts of inactivated Streptococcus lysate 6.94 µg / mL agalactiae and mixture of Streptococcus lysates consisting of inactivated lysate of Streptococcus pyogenes, inactivated lysate of Streptococcus pneumonie and inactivated lysate of Enterococcus faecalis in equal parts.
Inactivated lysate of Candida albicans, lysate 6.94 6 µg / mL inactivated from Candida parapsilosis and inactivated lysate and Candida glabrata in equal parts.
5 Helicobacter pylori inactivated lysate.
6.94 µg / mL Lysado de Serra tia marcencens and Serratia 6.94 µg / mL liquefaciens in equal parts.
149,231 10 HSV-I and HSV-II antigens lysed and inactivated.
pFU / mL Antigens of the measles virus ("Schwarz strain") 10,000 lysed and inactivated.
TDCI50 / mL 15 Glycerin 500 mg / mL Phenol 2.5 mg / mL Water q. s . P .
Composition 14: 20 Component Concentration Inactivated lysate of Mycobacteriurn africanurn.
0.004 ng / mL Inactivated lysate of Mycobacterium tuberculosis.
0.004 ng / mL
Inactivated lysate of Neisseria gonorrhoeae.
6.94 µg / mL 0 Water q. s . P .
B Composition 15: 5 Component PPD concentration 0.004 pg / ml BCG inactivated lysate.
50 mg / mL Inactivated lysate of Streptococcus equinus, 6.94 µg / m1j 10 Streptococcus bovis and Streptococcus of the viridans group in equal parts.
Inactivated lysate of Staphylococcus aureus and 6.94 µg / mL inactivated Staphylococcus epidermidis in equal parts.
15 Tetanus toxoid 50 units Component Lf / mL concentration 67 units Diphtheria toxoid Lf / mL Inactivated lysate of Acinetobacter baumannii. 6.94 20 µg / mL Escherichia coli inactivated lysate 6.94 µg / mL enteropathogenic (EPEC), producer of shiga-like toxin (STEC), enteroaggregative (EAEC), entrerotoxygenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) in equal parts.
Inactivated lysate of Aspergillus fumigatus, 6.94 µg / mL © Aspergillus flavus and Aspergillus terreus in equal parts. b Mumps virus antigens ("Urabe AM9 strain") 5 50,000 lysed and inactivated.
TDCI50 / mL Glycerin 500 mg / mL Phenol 2.5 mg / mL 10 Water q. s .p.
Composition 16: Component Concentration Koch crude turberculine (inactivated lysate of 0.004 ng / mL Mycobacterium bovis).
15 Inactivated lysate of Mycobacterium tuberculosis. 0.004 ng / mL Inactivated Salmonella typhi lysate, Salmonella 6.94 µg / mL paratyphi and Salmonella enteral in equal parts.
Inactivated lysate of Streptococcus pyogenes, 20 6.94 µg / mL inactivated Streptococcus pneumonie and inactivated lysate of Enterococcus faecalis in equal parts.
Inactivated lysate of Epidermophyton floccosum, 6.94 µg / mL Water q. s . P .
Composition 17: Component Concentration Koch crude turberculine (inactivated lysate of 0.004 ng / mL Mycobacterium bovis).
5 BCG inactivated lysate.
50 mg / mL PPD 0.004 ug / ml Inactivated Staphylococcus aureus lysate and 6.94 g / ml inactivated Staphylococcus epidermidis in equal parts.
Inactivated lysate of Streptococcus pyogenes, 6.94 µg / mL inactivated Streptococcus pneumonie and lysate Component Inactivated concentration of Enterococcus faecalis in equal parts.
Inactivated lysate of Klebsiella oxytoca and 6.94 µg / mL inactivated Klebsiella pneumoniae in equal parts Inactivated lysate of Epidermophyton floccosum, 6.94 µg / mL Microsporum cannis and Tricophyton mentagrophytes interdigitale variety in equal parts.
Inactivated lysate of Streptococcus equinus, 6.94 g / mL Streptococcus bovis and Streptococcus of the viridans group in equal parts.
67 units
Diphtheria toxoid of Lf / mL Inactivated escherichia coli lysate 6.94 µg / mL of enteropathogenic (EPEC), producer of "shiga-like" toxin 8 (STEC), enteroaggregative (EAEC), entrerotoxygenic (ET.EC), 5 enteroinvasive (EIEC) and extraintestinal (ExpEC) in equal parts.
Inactivated lysate of Salmonella typhi, Salmonella 6.94 µg / mL paratyphi and enteric Salmonella in equal parts.
Bordetella pertussis toxoid.
10 75 µg / mL Inactivated lysate of Aspergillus fumigatus, 6.94 µg / mL Aspergillus flavus and Aspergillus terreus in equal parts.
Antigens of the measles virus ("Schwarz strain") 10,000 lysed and inactivated.
'15 TDCI50 / mL Candida inactivated lysate, Candida parapsilosis inactivated lysate and 6.94 µg / mL inactivated Candida glabrata lysate in equal parts.
Glycerin 500 mg / mL 20 Phenol 2.5 mg / mL Water q. s . P .
Composition 18: Concentration Component
PPD 0.004 g / ml Inactivated lysate of Mycobacterium tuberculosis. ~ 0.004 ng / mL 4 Koch crude turberculine (inactivated lysate of 0.004 5 ng / mL Mycobacteriurn bovis).
Inactivated lysate of Staphylococcus aureus and 6.94 g / mL inactivated Staphylococcus epidermidis in equal parts.
Inactivated lysate of Salmonella typhi, Salmonella 6.94 10 µg / mL paratyphi and enteric Salmonella in equal parts.
Inactivated lysate of Streptococcus pyogenes, 6.94 g / mL inactivated Streptococcus pneumonie and inactivated lysate of Enterococcus faecalis in equal parts.
Streptokinase from purification from 15 0.444 µg / mL inactivated lysate of beta-hemolytic Streptococcus.
Dornase from purification from 0.111 g / mL inactivated beta-hemolytic Streptococcus lysate.
Inactivated lysate of Klebsiella oxytoca and lysate 6.94 20 µg / mL inactivated Klebsiella pneumoniae in equal parts Equal parts of inactivated lysate of Streptococcus 6.94 g / mL agalactiae and mixture of Streptococcus lysates consisting of inactivated lysate of pyogenes Streptococcus, inactivated lysate of Streptococcus pneumonie and inactivated lysate of Enterococcus faecalis in equal parts.
Helicobacter pylori inactivated lysate.
6.94 pg / mL Water q. s .p.
Composition 19: BCG inactivated lysate component.
50 mg / mL Inactivated lysate of Mycobacterium tuberculosis.
0.004 ng / mL Koch crude turberculine (0.004 ng / mL inactivated Mycobacterium bovis).
Inactivated lysate of Staphylococcus aureus and 6.94 µg / mL inactivated Staphylococcus epidermidis in equal parts.
Inactivated lysate of Streptococcus pyogenes, 6.94 µg / mL inactivated Streptococcus pneumonie and lysate Component Inactivated concentration of Enterococcus faecalis in equal parts.
Serratia marcencens lysate and Serratia 6.94 µg / mL liquefied in equal parts.
Inactivated lysate of Haemophilus influenzae.
6.94 g / mL,
6.94 µg / rriL Equal parts of inactivated lysate of Streptococcus + agalactiae and Mixture of lysates of Streptococcus 0 consisting of inactivated lysate of Streptococcus pyogenes, 5 inactivated lysate of Streptococcus pneumonie and inactivated lysate of Enterococcus faecalis in equal parts.
Inactivated lysate of Klebsiella oxytoca and 6.94 µg / mL inactivated Klebsiella pneumoniae in equal parts Inactivated lysate of Epidermophyton floccosum, 6.94 10 µg / mL Microsporum cannis and Tricophyton mentagrophytes variety interdigitale in equal parts.
Inactivated lysate of Proteus mirabilis, Proteus 6.94 µg / mL vulgaris and Proteus penerii in equal parts.
Inactivated lysate of Salmonella typhi, Salmonella 6.94 15 µg / mL paratyphi and Salmonella enteral in equal parts.
Antigens of the measles virus ("Schwarz strain") 10,000 lysed and inactivated.
TDCI50 / mL Inactivated lysate of Candida albicans, lysate 6.94 20 µg / mL inactivated from Candida parapsilosis and inactivated lysate of Candida glabrata in equal parts.
Antigens of the vaccinated virus ("smallpox") lysed and 1 to 10 x 10 inactivated PFU / mL Glycerin 500 mg / mL
Phenol 2.5 mg / mL Water q. s . P .
Composition 20: 5 Component Concentration Inactivated lysate of Mycobacterium africanum.
0.004 ng / mL Koch crude turberculine (0.004 ng / mL inactivated Mycobacterium bovis).
BCG inactivated lysate.
50 mg / mL Inactivated lysate of Aspergillus fumigatus, 6.94 g / mL Aspergillus flavus and Aspergillus terreus in equal parts.
Inactivated lysate of Staphylococcus aureus and 6.94 µg / mL inactivated Staphylococcus epidermidis in equal parts.
Inactivated lysate of Neisseria meningitidis.
6.94 µg / mL Inactivated lysate of Streptococcus pyogenes, 6.94 ug / mL inactivated Streptococcus pneumonie and inactivated lysate of Enterococcus faecalis in equal parts.
Escherichia coli inactivated lysate 6.94 µg / mL enteropathogenic (EPEC), producing shiga-like toxin (STEC), enteroaggregative (EAEC), entrerotoxygenic (ETEC),
enteroinvasive (EIEC) and extraintestinal (ExPEC).
Salmonella typhi inactivated lysate antigens, 6.94 0 µg / mL Salmonella paratyphi and Salmonella enterica in equal b parts.
5 Inactivated lysate of Acinetobacter baumannii.
6.94 µg / ml, 6.94 µg / ml Inactivated Helicobacter pylori lysate.
Component Concentration 10 Inactivated lysate of Haemophilus influenzae. 6, 94 µg / mL Mumps virus antigens ("Urabe AM9 strain")
50,000 lysed and inactivated.
TDCI50 / mL 15 40UD type 1 antigens; 1.8UD Polio virus inactivated lysate antigens type 2 and 32UD type 3 antigens Candida albicans inactivated lysate, 6.94 µg / mL inactivated Candida parapsilosis and 20 inactivated lysate of Candida glabrata in equal parts.
Glycerin 500 mg / ml Phenol 2.5 mg / ml Water q. s . P .
Composition 21: Concentration Component <, Mycobacterium leprae inactivated lysate. © 0.004 ng / mL 5 · Koch crude turberculine (inactivated lysate of 0.004 ng / mL Mycobacterium bovis).
Inactivated lysate of Mycobacterium tuberculosis.
0.004 ng / mL Staphylococcus aureus inactivated lysate and 10 6.94 g / mL inactivated Staphylococcus epidermidis in equal parts.
Inactivated lysate of Epidermophyton floccosum, 6.94 µg / mL Microsporum cannis and Tricophyton mentagrophytes variety interdigitale in equal parts.
V '15 Diphtheria toxoid 67 units Component Concentration "of Lf / mL Equal parts of inactivated lysate of Streptococcus 6.94 g / mL agalactiae and Mixture of Streptococcus lysates consisting of inactivated lysate of 20 Streptococcus pyogenes, inactivated lysate of Streptococcus pneumonie inactivated lysate of Enterococcus faecalis in equal parts.
50 units Lf tetanus toxoid / mL
Inactivated lysate of Neisseria meningitidis.
6.94 yg / mL © Inactivated lysate of Haemophilus influenzae 6.94 g / mL
P Inactivated lysate of Proteus mirabilis, Proteus 6.94 5 yg / mL vulgaris and proteus penerii in equal parts.
Serratia marcencens lysate and Serratia 6.94 yg / mL liquefied in equal parts.
Rubella virus antigens {"Wistar RA 10,000 strain 27 / 3M") TDCI50 / mL 10 Antigens of the varicella zoster virus lysate virus
149,231 and inactivated. PFU / mL Inactivated lysate of Aspergillus fumigatus, 6.94 yg / mL Aspergillus flavus and Aspergillus terreus in equal parts. * 15 Glycerin 500 mg / mL Phenol 2.5 mg / mL Water q. s .p.
Composition 22: Component Concentration 20 Inactivated lysate of Mycobacterium avium.
0.004 ng / mL Inactivated lysate of Mycobacterium kansasii.
0.004 ng / mL Concentration Component
Koch crude turberculine (inactivated lysate of 0.004 ng / mL Mycobacterium bovis). a, - Inactivated lysate of Aspergillus fumigatus, 6.94 µg / mL »Aspergillus flavus and Aspergillus terreus in equal parts.
5 Neisseria gonorrhoeae inactivated lysate.
6, 94 µg / mL 50 units Lf tetanus toxoid / mL Inactivated lysate of Streptococcus equinus, 6.94 µg / mL 10 Streptococcus bovis and Streptococcus of the viridans group in equal parts.
Inactivated lysate of Candida albicans, 6.94 µg / ml inactivated Candida parapsilosis and inactivated Candida glabrata lysate in equal parts. % 15 Salmonella typhi inactivated lysate, 6.94 'µg / mL Salmonella paratyphi and Salmonella enteral in equal parts.
Equal parts of inactivated Chlamydia lysate 6.94 µg / mL trachomatis, Chlamydia psittaci and Chlamydia 20 pneumoniae.
Escherichia coli inactivated lysate 6, 94 µg / mL enteropathogenic (EPEC), producing shiga-like toxin (STEC), enteroaggregative (EAEC), entrerotoxygenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) in equal parts .
Klebsiella oxytoca inactivated lysate and 6.94 0 'µg / mL inactivated Klebsiella pneumoniae in equal parts »Rubella virus antigens (" RA 10.000 5 27 / 3M strain ") TDCI50 / mL Vaccine virus antigens (" srnallpox ") lysate and 10 10a Component Inactivated PFU / mL 3000000 YF-17D inactivated lysate. PFU / rnL 10 Glycerin 500 mg / mL Phenol 2.5 mg / mL Water q. s . P .
Composition 23:. 15 Component Concentration Inactivated lysate of Mycobacterium tuberculosis. 0.004 k ng / mL Mycobacterium avium inactivated lysate. 0.004 ng / mL Koch crude turberculine (inactivated lysate of 0.004 ng / ml 20 Mycobacterium bovis).
Inactivated lysate of Neisseria meningitidis. 6.94 g / mL 67 units Lf diphtheria toxoid / mL 50 units
Tetanus toxoid of Lf / mL Equal parts of inactivated lysate of Streptococcus 0 J 6.94 µg / mL agalactiae and Mixture of lysates of »Streptococcus consisting of inactivated lysate of 5 Streptococcus pyogenes, inactivated lysate of inactivated pneumoniae Streptococcus and inactivated lysate of inactivated pneumococcal enterocylococcus and inactivated lysate. in equal parts.
Inactivated lysate of Candida albicans, 6.94 g / mL inactivated Candida parapsilosis and inactivated lysate of 10 Candida glabrata in equal parts.
Inactivated lysate of Epidermophyton floccosum, 6.94 µg / mL Microsporum cannis and Tricophyton internagrophytes, interdigital variety in equal parts.
Water q. s .p. * 15 Composition 24: Component Concentration Inactivated lysate of Mycobacterium africanum. 0.004 ng / mL Inactivated lysate of Mycobacterium tuberculosis. 0,004 20 ng / mL PPD 0,004 g / ml Inactivated lysate of Neisseria gonorrhoeae.
6.94 g / mL
Inactivated lysate of Candida albicans, 6.94 g / mL inactivated Candida parapsilosis and inactivated lysate of Candida glabrata in equal parts. The inactivated lysate of Salmonella typhi, Salmonella 6.94 5 µg / ml paratyphi and Salmonella enteral in equal parts.
Inactivated lysate of Neisseria meningitidis. 6.94 µg / mL 67 units Lf diphtheria toxoid / mL Water q. s . P .
10 Composition 25: Component PPD concentration 0.004 g / ml BCG inactivated lysate. 50 mg / mL Koch crude turberculine (0.004 15 ng / mL inactivated Mycobacterium bovis).
Inactivated lysate of Streptococcus pyogenes, 6.94 µg / mL inactivated Streptococcus pneumonie and inactivated lysate of Enterococcus faecalis in equal parts.
Inactivated lysate of Staphylococcus aureus and lysate 20 6.94 ug / mL Component Inactivated concentration of Staphylococcus epidermidis in equal parts.
67 units Lf diphtheria toxoid / mL 50 units
Lf tetanus toxoid / mL Inactivated Salmonella typhi lysate, Salmonella 6,94
Ô d g / mL paratyphi and Salmonella enterica in equal parts. »Inactivated lysate of Epidermophyton floccosum, 6.94 5 µg / mL Microsporum cannis and Tricophyton mentagrophytes interdigitale variety in equal parts.
Inactivated lysate of Acinetobacter baumannii. 6.94 µg / mL Escherichia coli inactivated lysate 6.94 yg / mL 10 enteropathogenic (EPEC), producer of shiga-like toxin (STEC), enteroaggregative (EAEC), entrerotoxygenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) in equal parts.
Inactivated lysate of Candida albicans, lysate 6.94
P 15 µg / mL inactivated by Candida parapsilosis and inactivated lysate "by Candida glabrata in equal parts.
Inactivated lysate of Aspergillus fumigatus, 6.94 µg / mL Aspergillus flavus and Aspergillus terreus in equal parts.
Mumps virus antigens ("Urabe AM9 strain") 20 50,000 lysed and inactivated. TDCl50 / mL Vaccine virus antigens ("smallpox") lysed and 10 x 10a inactivated PFU / rnL Glycerin 500 mg / ml Phenol 2,
5 mg / ml Water q. s . P . ú, Composition 0 Component Concentration 5 Koch crude turberculine (inactivated lysate of 0.004 ng / mL Mycobacterium bovis).
Inactivated lysate of Mycobacterium tuberculosis. 0.004 ng / mL BCG inactivated lysate.
10 50 mg / mL Inactivated lysate of Aspergillus fumigatus, Aspergillus 6.94 µg / mL flavus and Aspergillus terreus in equal parts.
Inactivated lysate of Streptococcus pyogenes, 6.94 µg / mL inactivated Streptococcus pneumonie and lysate
Inactivated F 15 of Enterococcus faecalis in equal parts.
0 Equal parts of inactivated Chlamydia lysate 6.94 µg / mL trachomatis, Chlamydia psittaci and Chlamydia pneumoniae.
Bordetella pertussis toxoid.
20 75 µg / mL Inactivated lysate of Haemophilus influenzae 6.94 µg / mL Inactivated lysate of Neisseria gonorrhoeae.
6.94 µg / mL 50 units
Tetanus toxoid of Lf / mL Inactivated lysate of Candida albicans, inactivated lysate W 6.94 µg / mL of Candida parapsilosis and inactivated lysate of 0 Candida glabrata in equal parts.
5 Enteropathogenic Escherichia coli inactivated lysate 6, 94 µg / mL (EPEC), producing shiga-like toxin (STEC), enteroaggregative (EAEC), entrerotoxygenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) in parts equals.
10 40D Polio virus inactivated lysate antigens type 1; 1.8D antigens Component Concentration type 2 and 32D type 3 antigens Vaccine virus ("smallpox") lysate antigens and 10 x 10 9 inactivated PFU / mL 15 3000000 YF-17D inactivated lysate. PFU / mL Composition 27: Water q. s . P .
Composition 28: 20 Component Concentration Rubella virus antigens ("Wistar RA 27 / 3M strain")
10,000 TDCI50 / mL 0.4 µq / ml Inactivated lysate of Mycobacterium tuberculosis. 0.004
- 125 ng / mL Koch crude turberculine. Inactivated lysate of 0.004
Ò, ng / mL Mycobacterium bovis f Inactivated lysate of Mycobacterium avium. 0.004 ng / mL 5 Staphylococcus aureus inactivated lysate and 6.94 µg / mL inactivated Staphylococcus epidermidis in equal parts.
Inactivated lysate of Streptococcus pyogenes, 6.94 µg / mL inactivated Streptococcus pneumonie and 10 inactivated lysate of Enterococcus faecalis in equal parts.
Inactivated lysate of Epidermophyton floccosum, 6.94 µg / mL Microsporum cannis and Tricophyton mentagrophytes variety interdigitale in equal parts.
Inactivated lysate of Neisseria meningitidis. and 15 6.94 µg / mL "Streptokinase from purification from 0.444 µg / mL inactivated beta-hemolytic Streptococcus lysate from purification from inactivated beta-hemolytic Streptococcus lysate.
20 Dornase from purification from 0.111 µg / mL inactivated beta-hemolytic Streptococcus lysate.
from purification from inactivated lysate of beta-hemolytic Streptococcus.
Inactivated lysate of Salmonella typhi, Salmonella 6.94
Qt , -i i µg / mL paratyphi and Salmonella enterica in equal parts.
Equal parts of inactivated Streptococcus 6.94 µg / mL agalactiae and Mixture of Streptococcus lysates consisting of inactivated lysate of 5 Streptococcus pyogenes, inactivated lysate of Streptococcus pneumonie and inactivated lysate of Enterococcus faecalis in equal parts.
Equal parts of inactivated lysate of Enterobacter 6.94 yg / mL aerogens, Enterobacter cloacae and Enterobacter 10 agglomerans group.
Helicobacter pylori inactivated lysate. 6, 94 yg / mL 50 units Lf tetanus toxoid / mL Enteropathogenic Escherichia coli inactivated lysate
W 15 6.94 yg / rnL (EPEC), producer of "shiga-like" toxin (STEC), r enteroaggregative (EAEC), entrerotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (EXPEC) in equal parts.
Antigens of vaccine virus ("smallpox") lysed and 10 x 20 inactivated PFU / mL Inactivated lysate of Candida albicans, inactivated lysate 6.94 yg / mL of Candida parapsilosis and inactivated Candida glabrata lysate in equal parts.
Inactivated lysate of Aspergillus fumigatus, Aspergillus k 6.94 yg / mL flavus and Aspergillus terreus in equal parts.
3000000 YF-17D inactivated lysate. PFU / mL Glycerin 500 mg / ml 5 Phenol 2.5 mg / ml Water q. s.p.
Composition 29: Component Concentration 10 Mumps virus antigens ("Urabe AM9 strain")
50,000 lysed and inactivated. TDCI50 / mL BCG inactivated lysate.
50 mg / mL Inactivated lysate of Mycobacterium tuberculosis. 0.004 ~ 15 ng / mL Component Concentration to Koch crude Turberculina. Inactivated lysate of 0.004 ng / mL Mycobacterium bovis Inactivated lysate of Mycobacterium leprae. 0.004 ng / mL Inactivated Staphylococcus aureus lysate and 20 6.94 µg / mL inactivated Staphylococcus epidermidis in equal parts.
Inactivated lysate of Streptococcus equinus, 6.94 g / ml Streptococcus bovis and Streptococcus of the viridans group in equal parts.
^ k Lysate of Serratia marcencens and Serratia liquefaciens 6.94 µg / mL in equal parts.
Inactivated lysate of Epidermophyton floccosum, 6.94 µg / mL Microsporum cannis and Tricophyton mentagrophytes 5 interdigitale variety in equal parts.
Inactivated lysate of Haemophilus influenzae 6.94 µg / mL 6.94 µg / mL Equal parts of inactivated lysate of Streptococcus agalactiae and Mixture of Streptococcus lysates 10 consisting of inactivated lysate of Streptococcus pyogenes, inactivated lysate of inactivated Streptococcus pneumonie Enterococcus faecalis in equal parts.
Inactivated lysate of enteropathogenic Escherichia coli 6.94 µg / mL (EPEC), producing shiga-like toxin (STEC),
P 15 enteroaggregative (EAEC), entrerotoxigenic (ETEC),. enteroinvasive (EIEC) and extraintestinal (ExPEC).
Serratia marcencens lysate and Serratia liquefaciens 6.94 µg / mL in equal parts.
50 units): 20 Tetanus toxoid of Lf / mL Water q. s .p.
Composition 30: Component Concentration Inactivated lysate of Aspergillus fumigatus, Aspergillus
+ r. 6.94 µg / mL flavus and Aspergillus terreus in equal parts.
Inactivated lysate of Mycobacterium africanum 0.004 ng / mL Koch crude turberculina. Inactivated lysate of 0.004 5 ng / mL Mycobacterium bovis BCG inactivated lysate. 50 mg / mL Inactivated lysate of Mycobacterium tuberculosis. 0.004 ng / mL Inactivated lysate of Streptococcus equinus, 6.94 µg / mL 10 Streptococcus bovis and Streptococcus of the viridans group in equal parts.
Inactivated lysate of Staphylococcus aureus and lysate 6.94 µg / mL Component Inactivated concentration of Staphylococcus epidermidis in equal parts.
Y 15 Neisseria meningitidis inactivated lysate. 6.94 g / mL% 67 units Lf diphtheria toxoid / mL Inactivated lysate of enteropathogenic Escherichia coli 6.94 g / mL (EPEC), producer of shiga-like toxin (STEC), 20 enteroaggregative (EAEC), entrerotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (EXPEC).
Inactivated lysate of Epidermophyton floccosum, 6.94 µg / mL Microsporum cannis and Tricophyton mentagrophytes variety interdigitale in equal parts.
) '
a Inactivated lysate of Streptococcus equinus, 6.94 µg / mL Streptococcus bovis and Streptococcus of the viridans group in equal parts.
Inactivated lysate of Salmonella typhi, Salmonella 6.94 5 µg / mL paratyphi and enteric Salmonella in equal parts.
Inactivated lysate of Acinetobacter baumannii. 6.94 µg / mL Helicobacter pylori inactivated lysate. 6.94 µg / mL Inactivated lysate of Haemophilus influenzae 6.94 µg / mL 10 3000000 YF-17D inactivated lysate. PFU / mL Mumps virus antigens ("Urabe AM9 strain")
50,000 lysed and inactivated. TDCI50 / mL 40UD type 1 antigens; and 15 Polio virus inactivated lysate 1, 8UD type 2 antigens and Component Concentration 32UD type 3 antigens Candida albicans inactivated lysate, inactivated lysate 6.94 µg / mL of Candida parapsilosis and inactivated lysate of 20 Candida glabrata in equal parts.
Glycerin 500 mg / ml Phenol 2.5 mg / ml Water q. s . P .
Composition 31: Component Concentration Inactivated Salmonella typhi, Salmonella 6.94 µg / mL paratyphi and Salmonella enteral in equal parts.
5 Inactivated lysate of Mycobacterium leprae. 0.004 ng / rnL Koch crude turberculine. Inactivated lysate of 0.004 ng / mL Mycobacterium bovis Inactivated lysate of Mycobacterium tuberculosis. 0.004 ng / mL PPD 0.004 pg / mL Staphylococcus aureus inactivated lysate and 6.94 µg / mL inactivated Staphylococcus epidermidis in equal parts.
Inactivated lysate of Streptococcus pyogenes, 6.94 µg / mL inactivated Streptococcus pneumonie and inactivated lysate of Enterococcus faecalis in equal parts.
67 units Lf diphtheria toxoid / mL Inactivated lysate of Neisseria gonorrhoeae. 6.94 µg / mL 6, 94 µg / mL Component Concentration Equal parts of inactivated lysate of Streptococcus agalactiae and Mixture of Streptococcus lysates consisting of inactivated lysate of Streptococcus pyogenes,
s inactivated lysate of Streptococcus pneumonie and inactivated lysate of Enterococcus faecalis in equal parts.
Inactivated lysate of Epidermophyton floccosum, 6.94 µg / mL Microsporum cannis and Tricophyton mentagrophytes 5 interdigitale variety in equal parts.
Inactivated lysate of Neisseria meningitidis. 6.94 µg / mL Enteropathogenic Escherichia coli inactivated lysate 6, 94 ug / mL (EPEC), shiga-like toxin (STEC), enteroaggregative (EAEC), entrerotoxygenic (ETEC), 10 enteroinvasive (EIEC) and extraintestinal (ExPEC) in equal parts.
Inactivated lysate of Haemophilus influenzae 6.94 pg / ml Inactivated lysate of Proteus mirabilis, Proteus 6.94 µg / mL vulgaris and Proteus penerii in equal parts. * 15 Serratia marcencens lysate and Serratia liquefaciens + 6.94 µg / mL in equal parts.
Inactivated lysate of Candida albicans, inactivated lysate 6.94 g / mL of Candida parapsilosis and inactivated lysate of Candida glabrata in equal parts.
20 10,000 Rubella virus antigens ("RA 27 / 3M strain") TDCI50 / mL Varicella zoster virus antigens lysed virus and
149,231 inactivated. PFU / mL
Inactivated lysate of Aspergillus fumigatus, Aspergillus 6.94 µg / mL flavus and Aspergillus terreus in equal parts.
Composition Component Concentration 5 Candida inactivated lysate, Candida parapsilosis inactivated lysate and Candida inactivated 6.94 µg / mL glabrata in equal parts.
Inactivated lysate of Mycobacterium avium. 0.004 ng / mL Inactivated lysate of Mycobacterium kansasií. 0.004 ng / mL Koch crude turberculine. Inactivated lysate of 0.004 ng / mL Mycobacterium bovis BCG inactivated lysate. 50 mg / mL Inactivated lysate of Aspergillus fumigatus, Aspergillus 6.94 µg / mL flavus and Aspergillus terreus in equal parts.
Inactivated lysate of Neisseria gonorrhoeae. 6.94 yg / mL 50 units Tetanus toxoid of Lf / mL Inactivated lysate of Streptococcus pyogenes, lysate 6.94 g, / Inactivated Streptococcus pneumonie and inactivated lysate of Enterococcus faecalis in equal parts.
Inactivated lysate of Streptococcus equinus, 6.94 yg / mL Streptococcus bovis and Streptococcus of the viridans group in equal parts.
Inactivated lysate of Epidermophyton floccosum, 6,94
"g / mL Microsporum cannis and Tricophyton mentagrophytes variety interdigitale in equal parts.
Salmonella typhi inactivated lysate antigens, 6.94 yg / mL Salmonella paratyphi and Salmonella enterica in equal parts.
Helicobacter pylori inactivated lysate. 6.94] iq / mL Equal parts of inactivated Chlamydia lysate 6.94 yg / mL trachomatis, Chlamydia psittaci and Chlamydia pneumoniae.
10 Component Concentration inactivated lysate of enteropathogenic Escherichia coli 6.94 µg / mL (EPEC), shiga-like toxin (STEC), enteroaggregative (EAEC), entrerotoxygenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) in parts and 15 equal.
E Klebsiella oxytoca inactivated lysate and 6.94 µg inactivated Klebsiella pneumoniae lysate in equal parts Inactivated lysate of Aspergillus fumigatus, Aspergillus 6.94 µg / ml flavus and Aspergillus terreus in equal parts.
20 10,000 Rubella virus antigens ("strain strain RA 27 / 3M"). TDCI50 / mL Lysed vaccine virus antigens ("smallpox") and 10 x 10 inactivated PFU / mL
Inactivated lysate of YF-17D. PFU / mL Glycerin 500 mg / ml Phenol 2.5 mg / ml 5 Water q. s .p.
Composition 33: Component Concentration Inactivated Lysate of Enteropathogenic Escherichia coli 6.94 yg / mL (EPEC), shiga-like toxin producer (STEC), 10 enteroaggregative (EAEC), entrerotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) in equal parts.
Inactivated lysate of Mycobacterium leprae. 0.004 ng / mL Mycobacterium avium inactivated lysate. 0.004 ng / mL to 15 Koch crude turberculine. Inactivated lysate of 0.004 ng / mL
T Mycobacterium bovis Component Concentration Inactivated lysate of Mycobacteriurn tuberculosis. 0.004 ng / mL 20 Neisseria meningitidis inactivated lysate. 6.94 µg / mL 67 units Lf diphtheria toxoid / mL 50 units
© Lf tetanus toxoid / mL Streptococcus pyogenes inactivated lysate, 6.94 µg / mL inactivated Streptococcus pneumonie lysate and inactivated Enterococcus faecalis lysate in equal parts.
5 Inactivated lysate of Aspergillus furnigatus, AsÊ) ergillus 6.94 µg / mL flavus and Aspergillus terreus in equal parts.
Inactivated lysate of Candida albicans, inactivated lysate f 6.94 µg / mL of Candida parapsilosis and inactivated lysate of Candida glabrata in equal parts.
10 Neisseria mehingitidis inactivated lysate. 6.94 µg / mL Inactivated lysate of Shigella flexneri and Shigella 6.94 µg / mL sonnei in equal parts.
6.94 µg / mL Inactivated lysate of Helícobacter pylori.
15 Serratia marcencens lysate and Serratia liquefaciens 6.94 µg / mL in equal parts.
Inactivated lysate of Salmonella typhi, Salmonella · 6.94 µg / mL paratyphi and Salmonella enteral in equal parts.
Antigens of the vaccinated virus ("smallpox") lysed and 10 x 20 1Oa inactivated PFU / mL
149,231 HSV-I and HSV-II antigens lysed and inactivated. PFU / mL Lysed measles virus ("Schwarz strain") antigens
10,000 and inactivated. TDCI50 / mL
% Inactivated lysate of Aspergillus fumigatus, Aspergillus 6, 94 µg / mL Component Concentration flavus and Aspergillus terreus in equal parts.
Glycerin 500 mg / ml 5 Phenol 2.5 mg / ml Water q. s . P .
Composition 34: Component Concentration Inactivated lysate of Candida albicans, inactivated lysate 10 6.94 µg / mL of Candida parapsilosis and inactivated lysate of Candida glabrata in equal parts.
Inactivated lysate of Mycobacterium africanum. 0.004 ng / mL Inactivated lysate of Mycobacterium tuberculosis. 0.004 15 ng / mL PPD 0.004 g / ml BCG inactivated lysate. 50 mg / mL 50 units Lf tetanus toxoid / mL 20 Streptococcus pyogenes inactivated lysate, 6.94 µg / ml inactivated Streptococcus pneumonie lysate and inactivated Enterococcus faecalis lysate in equal parts.
Inactivated lysate of Salmonella typhi, Salmonella 6.94 µg / mL paratyphi and enteric Salmonella in equal parts.
± + Inactivated lysate of enteropathogenic Escherichia coli 6.94 g / mL (EPEC), producing shiga-like toxin (STEC), enteroaggregative (EAEC), entrerotoxygenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC).
5 Neisseria meningitidis inactivated lysate. 6.94 ug / mL 67 units Lf diphtheria toxoid / mL Inactivated lysate of Streptococcus equinus, 6.94 µg / mL Streptococcus bovis and Streptococcus of the viridans group 10 Component Concentration in equal parts.
Inactivated lysate of Salmonella typhi, Salmonella 6.94 g / mL paratyphi and enteric Salmonella in equal parts.
Inactivated lysate of Aspergillus fumigatus, Aspergillus 6.94 µg / mL flavus and Aspergillus terreus in equal parts.
15 Inactivated lysate of Shigella flexneri and Shigella 6.94 g / mL sonnei in equal parts.
Inactivated lysate of Proteus mirabilis, Proteus 6, 94 g / mL vulgaris and Proteus penerii in equal parts.
Inactivated lysate of Aspergillus fumigatus, Aspergillus 20 6.94 g / ml flavus and Aspergillus terreus in equal parts.
Hepatitis B virus surface antigens (HBS 200 pg / ml Ag) lysed and inactivated.
Lysed measles virus ("Schwarz strain") antigens
110,000 and inactivated. TDCI50 / mL
"3000000 YF-17D inactivated lysate. PFU / ml Glycerin 500 mg / ml Phenol 2, 5 mg / ml 5 Water q.s. p.
Composition Component Concentration Inactivated lysate of Candida albicans, inactivated lysate 6.94 g / mL of Candida parapsilosis and inactivated lysate of 10 Candida glabrata in equal parts.
PPD 0.004 g / ml BCG inactivated lysate. 50 mg / rnL Koch crude turberculine. Inactivated lysate of 0.004 ng / mL Mycobacterium bovis 15 Component Concentration Inactivated lysate of Mycobacterium tuberculosis. 0.004 ng / mL Inactivated lysate of Streptococcus pyogenes, 6.94 µg / ml inactivated Streptococcus pneumonie and 20 inactivated lysate of Enterococcus faecalis in equal parts.
Inactivated lysate of Staphylococcus aureus and 6.94 µg / mL inactivated Staphylococcus epidermidis in equal parts.
Inactivated lysate of Epidermophyton floccosum, 6.94 g / mL Microsporum cannis and Tricophyton mentagrophytes variety interdigitale in equal parts.
Inactivated lysate of Neisseria meningitidis. 6.94 µg / mL 5 50 units Tetanus toxoid of Lf / mL 67 units Diphtheria toxoid of Lf / mL Inactivated lysate of Streptococcus equinus, 6.94 µg / mL Streptococcus bovis and Streptococcus of the viridans group in equal parts.
Serratia marcencens lysate and Serratia liquefaciens 6.94 µg / mL in equal parts.
Inactivated lysate of Acinetobacter baumannii. 6.94 µg / mL Enteropathogenic Escherichia coli inactivated lysate 6.94 µg / mL (EPEC), shiga-like toxin (STEC), enteroaggregative (EAEC), entrerotoxygenic (ETEC), enteroinvasive (EIEC) and extraintestinal toxin (ExPEC) in equal parts.
Salmonella typhi inactivated lysate antigens, 6.94 µg mL Salmonella paratyphi and Salmonella enteral in equal parts.
Inactivated lysate of YF-17D.
· 3000000 Component Concentration PFU / mL Inactivated lysate of Aspergillus fumigatus, Aspergillus 5 6.94 µg / mL flavus and Aspergillus terreus in equal parts.
Mumps virus antigens ("Urabe AM9 strain") lysed 50,000 and inactivated. TDCI50 / mL Vaccine virus antigens ("smallpox") lysed and 10 10a inactivated PFU / mL 10 Glycerin 500 mg / ml Phenol 2, 5 mg / ml Water q. s . P .
Composition Component Concentration 15 Inactivated lysate of Aspergillus fumigatus, Aspergillus 6.94 g / mL flavus and Aspergillus terreus in equal parts.
Koch crude turberculina. Inactivated lysate of 0.004 ng / mL Mycobacterium bovis Inactivated lysate of Mycobacterium tuberculosis. 0.004 20 ng / mL Inactivated bcg lysate. 50 mg / mL PPD (purified protein derivative derived from English 0.004 g / ml "Purified Protein Derivative")
· Inactivated lysate of Aspergillus fumigatus, Aspergillus 6.94 µg / mL flavus and Aspergillus terreus in equal parts.
Inactivated lysate of Streptococcus pyogenes, 6.94 µg / mL inactivated Streptococcus pneumonie and 5 inactivated lysate of Enterococcus faecalis in equal parts.
Equal parts of inactivated Chlamydia lysate 6.94 µg / mL trachomatis, Chlamydia psittaci and Chlarnydia pneumoniae.
Inactivated lysate of Epidermophyton floccosum, 6.94 10 µg / mL Component Concentration Microsporum cannis and Tricophyton mentagrophytes of the interdigitale variety in equal parts.
Bordetella pertussis toxoid. 75 µg / mL Inactivated lysate of Haemophilus influenzae 6.94 g / mL 15 Streptokinase from purification from 0.444 g / mL inactivated lysate of beta-hemolytic Streptococcus.
Dornase from purification from 0.111 µg / mL inactivated beta-hemolytic Streptococcus lysate.
20 Inactivated lysate of Salmonella typhi, Salmonella 6.94 g / ml paratyphi and enteric Salmonella in equal parts.
50 units Lf tetanus toxoid / mL Hepatitis B virus surface antigens (HBS
"200 µg / ml Ag) lysed and inactivated.
Inactivated lysate of enteropathogenic Escherichia coli 6.94 µg / mL (EPEC), producing shiga-like toxin (STEC), enteroaggregative '(EAEC), entrerotoxygenic (ETEC), 5 enteroinvasive (EIEC) and extraintestinal (ExPEC) in ExPEC equal parts.
Inactivated lysate of Candida albicans, inactivated lysate of Candida parapsilosis and inactivated lysate of Candida 6.94 µg / mL glabrata in equal parts.
10 40UD type 1 antigens; 1, 8UD Polio inactivated lysate antigens type 2 and 32UD antigens Component Concentration type 3 15 Vaccine virus antigens ("smallpox") lysed and 10 x 109 inactivated PFU / mL 3000000 Inactivated YF-17D lysate. PFU / mL Glycerin 500 mg / ml 20 Phenol 2.5 mg / ml Water q. s . P .
When there are associated or to be combated parasitic diseases, the formulations preferably contain antigenic agents of parasitic origin.
In this case, according to the concepts described in the present invention, the formulations must comprise antigenic agents from the most prevalent parasites 5 for which individuals have more memory cells according to the geographic distribution and local and regional human development (countries developed or undeveloped). Such parameters are determinant for the occurrence of these parasites and the existence of memory cells in the immune system of people in a given region.
Composition 37: Association of Composition 2 with: Component Concentration Inactivated Toxoplasma gondii. 400 ug / mL Composition 38: Association of Composition 3 with: Component Concentration Inactivated Lysate of Giardia lamblia. 400 g / mL Composition 39: Association of Composition 4 with: Composition 40: Association of Composition 5 with: Composition 41: Association of Composition 6 with: Composition 42: Association of Composition 7 with: Composition 43: Association of Composition Composition 45: Association of Composition 10 with: Component Concentration inactivated Lysate of Giardia lamblia. 400 ug / mL Lysate P
- inactivated from Ascaris lumbricoides. 400 µç / mL
Composition 46: Association of Composition 11 with:
Concentration Component
Inactivated lysate of Toxoplasma gondii. 400 µç / mL
5 Inactivated lysate of Entamoeba hystolitica. 400 g / mL
Composition 47: Association of Composition 12 with:
Concentration Component
Inactivated lysate of Strongyloides stercoralis. 400 µg / mL
10 Inactivated lysate of Cryptosporidium spp. 400 µg / mL
Composition 48: Association of Composition 13 with:
Concentration Component
Inactivated lysate of Ascaris lumbricoides. 400 µg / mL
Inactivated lysate of Toxoplasma gondii. 400 µg / mL
15 Composition 49: Association of Composition 14 with:
Concentration Component
Inactivated lysate of Entamoeba hystolitica. 400 µg / mL
Inactivated lysate of Giardia lamblia. 400 µg / mL
Composition 50: Association of Composition 15 with
20 Concentration Component
Inactivated lysate of Strongyloides stercoralis. 400 µg / mL
Inactive lysate of Enterobius vermicularis. 400 µg / mL
Composition 51: Association of Composition 16 with:
Concentration Component
Inactivated lysate of Trichomonas vaginalis. 400 µg / mL
Inactivated lysate of Ascaris lumbricoides. 400 ug / mL
Composition 52: Association of Composition 17 with:
5 Concentration Component
Inactivated lysate of Entamoeba hystolitica. 400 g / mL
Inactivated lysate of Ascaris lumbricoides. 400 g / mL
Inactive lysate of Enterobius vermicularis. 400 pg / rriL
Composition 53: Association of Composition 18 with:
10 Concentration Component
Inactivated lysate of Giardia lamblia. 400 µg / mL
Inactive lysate of Enterobius vermicularis. 400 ug / mL
Inactivated lysate of Toxoplasrna gondii. 400 g / mL
Composition 54: Association of Composition 19 with:
15 Concentration Component
Inactivated lysate of Strongyloides stercoralis. 400 ug / mL
Inactivated lysate of Entarnoeba hystolitica. 400 g / mL
Inactivated lysate of Giardia lamblia. 400 µg / mL
Composition 55: Association of Composition 20 with:
Concentration Component
Inactivated lysate of Giardia lamblia. 400 g / rnL
Inactivated lysate of Ascaris lumbricoides. 400 ug / mL
Inactivated lysate of Strongyloides stercoralis. 400 ug rnL
Composition 56: Association of Composition 21 with:
Concentration Component
Inactivated lysate of Toxoplasma gondii. 400 ug / mL
5 Inactivated lysate of Entamoeba hystolitica. 400 ug / rnL
Inactivated lysate of Giardia lamblia. 400 yg / mL
Composition 57: Association of Composition 22
Concentration Component
Inactivated lysate of Strongyloides stercoralis. 400 µg / mL
Inactivated lysate of Cryptosporidium spp. 400 yg / mL
Inactivated lysate of Entamoeba hystolitica. 400 yg / mL
Composition 58: Association of Composition 23 with:
Concentration Component
Inactivated lysate of Ascaris lumbricoides. 400 g / mL
Inactivated lysate of Toxoplasma gondii. 400 yg / mL
Inactivated lysate of Enterobius vermicularis. 400 yg / mL
Composition 59: Association of Composition 24 with:
Concentration Component
Inactivated lysate of Entamoeba hystolitica. 400 g / mL
Inactivated lysate of Giardia lamblia. 400 g / mL
Inactivated lysate of Ascaris lumbricoides. 400 yg / mL
Composition 60: Association of Composition 25 with:
Concentration Component
Inactivated lysate of Strongyloides stercoralis. 400 yg / mL
Inactive lysate of Enterobius vermicularis. 400 yg / mL
Inactivated lysate of Entamoeba hystolitica. 400 yg / rnL
5 Composition 61: Association of Composition 26 with:
Concentration Component
Inactivated lysate of Trichomonas vaginalis. 400 yg / mL
Inactivated lysate of Ascaris lumbricoides. 400 yg / mL
Inactivated lysate of Giardia lamblia. 400 g / mL
Composition 62: Association of Composition 27 with:
Concentration Component
Inactivated lysate of Entamoeba hystolitica. 400 ug / mL
Inactivated lysate of Ascaris lumbricoides. 400 µg / mL
Inactive lysate of Enterobius vermicularis. 400 yg / mL
Inactivated lysate of Cryptosporidium spp. 400 µg / mL
Composition 63: Association of Composition 28 with:
Concentration Component
Inactivated lysate of Giardia lamblia. 400 ug / mL
Inactive lysate of Enterobius vermicularis. 400 µg / mL
Inactivated lysate of Toxoplasrna gondii. 400 ug / mL
Inactivated lysate of Ascaris lumbricoides. 400 ug / mL
Composition 64: Association of Composition 29 with:
Concentration Component
Inactivated lysate of Strongyloides stercoralis. 400 µg / mL
Inactivated lysate of Entamoeba hystolitica. 400 µg / mL
Inactivated lysate of Giardia lamblia. 400 µg / mL
Inactive lysate of Enterobius vermicularis. 400 µg / mL
5 Composition 65: Association of Composition 30 with:
Composition 66: Association of Composition 31 with:
Concentration Component
Inactivated lysate of Toxoplasma gondii. 400 ug / mL
Inactivated lysate of Entamoeba hystolitica. 400 µg / mL
Inactivated lysate of Giardia lamblia. 400 yg / mL
Inactive lysate of Enterobius vermicularis. 400 µg / mL
Composition 67: Association of Composition 32 with:
Concentration Component
Inactivated lysate of Strongyloides stercoralis. 400 ug / mL
Inactivated lysate of Cryptosporidium spp. 400 ug / mL
Inactivated lysate of Entamoeba hystolitica. 400 g / mL
Inactivated lysate of Ascaris lumbricoides. 400 µg / mL
Composition 68: Association of Composition 33 with:
Concentration Component
Inactivated lysate of Ascaris lumbricoides. 400 µg / mL
Inactivated lysate of Toxoplasma gondii. 400 ug / rnL
Inactive lysate of Enterobius vermicularis. 400 g / mL
Inactivated lysate of Cryptosporidium spp .. 400 g / mL b Composition 69: Association of Composition 34 with: Component Concentration Inactivated lysate of Entamoeba hystolitica. 400 g / mL Giardia lamblia inactivated lysate. 400 µg / mL 5 Inactivated lysate of Ascaris lumbricoides. 400 µg / mL Inactivated lysate of Trichomonas vaginalis. 400 µg / mL Composition 70: Association of Composition 35 with: Component Concentration inactivated Strongyloides stercoralis lysate. 400 µg / mL 10 Inactivated lysate of Enterobius vermicularis. 400 µg / mL Inactivated lysate of Entamoeba hystolitica. 400 µg / mL Inactivated lysate of Cryptosporidium spp. 400 µg / mL Composition 71: Association of Composition 36 with: Component Concentration 15 Inactivated lysate of Trichomonas vaginalis. 400 µg / mL Inactivated lysate of Ascaris lumbricoides. 400 µg / mL Giardia lamblia inactivated lysate. 400 µg / mL Inactivated lysate of Strongyloides stercoralis. 400 µg / mL 20 Example 2: Treatment of an experimental model of melanoma in mice using the PECA antigenic composition.
Animals C57BL6 Specific Pathogen mice were used
W Free (SPF) females (25 -35 g, 8-12 weeks). The animals were kept in an environment with controlled temperature and humidity (22 ± 2 ° C and 60 - 80%, respectively), in a light / dark cycle of 12 h and with free access to water and 5 rations until c) time of the experiments.
Murine melanoma induction Melanoma cells of the B16-F1O strain were inoculated on day zero (1 x 10 6 cells in 100 µl of culture medium per animal), subcutaneously (SC) on the back of 10 male C57BL / 6 mice (Lee , YS, et al.
Suppression of tumor growth by a new glycosaminoglycan isolated from the African giant snail Achatina fulica.
European journal of Pharmacology, 465: 191- 198, 2003). The animals (n = 8 per group, table 3) were treated 15 from the 70's. Day (and every 4 days thereafter) with vehicle (control), DECA or DECA + IL2, according to the scheme shown in table 1. The group DECA + IL-2, also received daily injections of IL-2 (20,000 IU, twice a day, subcutaneously). Tumor volumes were assessed with the aid of a digital caliper and determined (mm3) according to the formula: tumor volume (mm3) = width2 x length x 0.5 (Lee, YS, et al. Suppression of tumor growth by a new glycosaminoglycan isolated from the African giant snail Achatina fulica.
& · Pharmacology, 465: 191-198, 2003). The volume of the solid tumor mass was assessed every 3 days during the 28-day period after the injection of the tumor cells. Animal survival was assessed for a period of 30 days after the injection of tumor cells.
Table 1. Treatment schedule Beginning at 7 °. day and thereafter every 4 days Control GROUP (Vehicle) 1st systemic saline - 24 intradermal injections of 10 saline solution (NaCL 0, 9% sterile) at predetermined points in the dorsal and ventral region 2nd intratumoral saline - two injections ( 1 in the center 0.02 mL and base of the lesion 0.02 mL); 3rd Perilesional saline (6 points of application - with the objective of circling the tumor) DECA GROUP '-' 1st systemic DECA - 24 intradermal injections of DECA solution (sterile) at predetermined points in the dorsal and ventral region 2 ° Intratumoral DECA (center 0.02 mL and 20 lesion base 0.02 mL) 3rd perilesional DECA (6 points of application) DECA GROUP + IL-2 W, 1st systemic DECA - 24 intradermal saline injections (NaCL 0 , 9% sterile) at predetermined points in the dorsal and ventral region W
¥ 2 ° intratumoral DECA - two injections (center 0.02 mL and lesion base 0.02 mL)
3rd perilesional DECA (6 points of application - in order to surround the tumor)
5 4 ° IL-2 20,000 IU intratumor (0.02 mL at the tumor center) 50 IL-2 20,000 IU perilesional (1 application close to the region surrounded by DECA)
6th IL-2 20,000 IU intraperitoneal
OBS .: Daily from the 7th. day: IL-2 -20,000 IU
10 intraperitoneal (2x / day)
Results
The results showed that 28 days after the inoculation of the tumor cells, the tumor volume reached its maximum peak of 6,728.65 ± 2,027.01 mm3 (mean ± E.P.M),
15 with survival of 33.3% of the animals (3 of the 9 animals that started the study remained alive 30 days after inoculation of the B16FIO cells) (Figure 1). Despite not showing a statistically significant difference, the group of animals that received treatment with DECA, on the 28th day after
20 model induction showed a lower volume tumor mass when compared to the vehicle group (3,524.87 ±
871.01 mm3) and 50% survival (5 out of 10 animals that started the study). It is important to mention that, although not significant, there was, on the 28th day, a 47.6% inhibition in the
D · tumor volume (when compared to the control group) and that the lack of significance may be due to the standard error of the mean presented by the control group. For the DECA + IL-2 group, the results showed that the 5 association was able to significantly reduce the tumor volume from 13th day (57% inhibition) to 28th day, when it presented approximately 67% inhibition (2,198, 36 ± 450, 39 mm3) with 80% survival (8 out of 10 animals that started the study). In addition, animals 10 showed good tolerance to repeated treatment with IL-
2. In the clinic, IL-2 is administered in high doses (600,000 - 720,000 IU / kg) and the toxic symptoms presented are compared to the induction of the controlled state of septic shock (low blood pressure, low systemic vascular resistance, liver toxicity and renal and pulmonary edema) (Rosenberg SA, Yang YC, Topalian SL, et al.
Treatment of 283 consecutive patients with metastatic melanoma or renal cell cancer using high-dose bolus interleukin-2. JAMA, 271: 907-913, 1994.). The analysis 20 presented in figure 1B corroborates the data in figure IA, demonstrating that the reduction in volume is related to the reduction in the rate of tumor growth (for the DECA + IL-2 group).
In general, the results demonstrated that the
* treatment with the association DECA + IL-2, in addition to reducing the growth rate / tumor volume (Figure 1) increased the survival of the animals when compared to the control group (vehicle) (figure 2), suggesting it is beneficial for the 5 treatment of melanoma.
Example 3: Treatment of metastatic malignant melanoma in the fourth recurrence.
Patient data MBS patient, 46 years old, female.
10 Diagnosis Metastatic malignant melanoma in Clark and Breslow's fourth level III relapse of 1.32 mm2 diagnosed on 05/16/2006.
Previous conventional treatments 15 a. First surgical treatment for cancer On 06/01/2006, surgery was performed to enlarge the margin at the tumor lesion site with a sentinel lymph node survey that was negative for malignancy. The complementary anatomopathological examination with immunohistochemistry of the 20 lymph nodes showed the presence of micrometastases, greater than 0.17 mm, confirming a posteriori the diagnosis of metastatic and immunogenic malignant melanoma, due to the presence of the Melan A antigen.
B. Second surgical cancer treatment
. · On February 20, 2008, extraction of two superficial nodules suspected of recurrence in the left thigh was performed, whose pathology revealed the diagnosis of metastatic malignant melanoma. Then, an enlargement of the surgical margin 5 was performed, with biopsy, of all lesions operated on 04/09/2008.
ç. Third surgical treatment for cancer Eight months after (10/15/2008) there was a second recurrence in the skin of the left thigh that showed metastasis of malignant melanoma, 10 with lesion coinciding with the surgical margin. An enlargement of the surgical margin was again performed, whose pathological examination of 11/27/2008 did not reveal the remains of the tumor in the surgical bed.
d. Fourth surgical treatment for cancer 15 On 05/13/2010 a new lesion in the gluteal region was surgically removed on 05/19/2010 without a freezing test. Pathology showed a new metastasis of melanoma with compromised surgical margins indicating the third recurrence of the disease.
20 e. Results of the fourth pre-administration surgical cancer treatment for DECA.
On 06/23/2010, a PET / CT scan was performed, which showed that it was a tumor lesion, proving the fourth recurrence. The short time in which the fourth recurrence was formed, starting from b
W · a residual lesion, showed an aggressive character of metastatic cells.
Pre-administration immunological evaluation of DECA The immunological evaluation consisted of an in vitro part of blood tests (complete blood count, lymphocyte phenotyping, immunoglobulin dosage, RAST test (allergy) electrophoresis of acute phase proteins and autoimmunity tests ) and in vivo (primary and secondary delayed hypersensitivity test).
10 Secondary delayed hypersensitivity tests were performed with a battery of nine antigens (administered 0.1 CC) namely: 1) tuberculin Eruta Koch 1: 100000; 2) PPU 20Ul / ml; 3) staphylococcal toxin 1: 100; 4) 1: 100 streptococcal toxin; 5) streptokinase / Dornase 15 40/10 UDS / mL; 6) Oidimycin 1: 100; 7) Trichophytin 1: 100; 8) Escherichia coli 1: 100; 9) Salmonella spp 1: 100.
The primary delayed hypersensitivity tests were performed with skin patches of 0.5% and 2% DNCB.
20 The result of the immunological evaluation expressed a change in proteins in the acute phase, with an increase in ESR, CRP and alpha 1 acid glycoprotein, showing a systemic inflammatory repercussion to tumor growth after surgery, according to blood tests performed on g + · 06/12/2010.
The assessment of primary hypersensitivity proved to be abolished. Secondary systemic delayed hypersensitivity was shown to be decreased from + / ++ to +++++ for the 5 intracellular and normal antigens from ++ / ++++ for the other antigens, at a distance from the tumor. In the areas of relapse, all antigens showed a very reduced reaction of 0 / + for intracellular antigens and + / +++ in +++++ for the other antigens. In the peritumoral region 10, the reaction was practically abolished, with 0/0 for intracellular antigens and 0 / + for the other antigens.
These results, of secondary delayed hypersensitivity, also showed an important immunosuppression.
Treatment with DECA It started on 06/26/2010 and ended on 08/04/2010 in the waiting period for the release of the health insurance for surgery. Immunotherapeutic treatment was performed 20 with the patient's free and informed consent. Immunotherapy with DECA was performed as follows: "Application of 1.8 cc of the antigenic composition divided into 2 applications of 0.9 ml along the 10 main lymph territories.
and gµ m J "3 to 4 cm margin of distance to facilitate reading the evolution of treatment with an interval of 4 + 1 days.
0 Administration of 9 perilesional extra sets of 5 l, 8cc in two applications of 0.9 per game used, bypassing the scars of the surgery of the primary tumor, the second and third recurrence, as well as the region of the fourth and fifth recurrence, also with interval of 4 ± 1 days.
"From the evaluation of the second application, an intratumoral application was carried out jointly with a volume equivalent to ten 1.8 ml compositions.
"Application of recombinant human interleukin 2 at low doses, at the level of receptor saturation at a concentration of 1 to 2 million units per meter of body surface located within 5 cm of the lesion. For the patient, 1 million subcutaneous daily units On the days of the antigen application, after the application of these, two extra doses of 1 million units were administered, one in the intraperilesional region 20 and another 1 million units in the intratumoral area. These applications totaled 3 million units in these occasions, even within the limits of low doses recommended by body surface.
Thus, up to the date of the surgery, 11
^ '"j Y systemic and perilesional immunotherapy sessions between 06/24/2010 to 02/08/2010, as well as 5 intratumoral intervals in the interval of 4 + 1 days concomitantly or one day after the systemic and perilesional ones.
5 It is interesting to mention that the Doppler ultrasound exams (on 07/19/2010 and 08/04/2010) suggest the transformation of the tumor area into an inflammatory area without any angiogenesis.
Evaluation of immunotherapeutic treatment with DECA 10 At the fifth surgery, on 08/05/2010, the freezing test showed no tumor in the treated area where only a conservative removal of the inflammatory lesion was performed.
Result of immunotherapeutic treatment with DECA 15 The post-surgical anatomopathological examination of 05/05/2010 demonstrated the presence of a palisade granuloma with central necrosis, skin with dense chronic inflammatory infiltrate involving the superscribed foreign body gigantocellular granuloma, absence of residual neoplasia and margins 20 neoplasia-free surgical procedures.
The immunohistochemical examination revealed a complete absence of tumor cells from the tissue surgically removed © previously treated with DECA according to the limits of the available diagnostic techniques (Figure 3). P
W · After the first two applications of the protocol described above, the patient recovered from the immunosuppression found by the normalization and hyperactivation of all points of application of immunotherapy as if she were a normal patient. These results demonstrate the recovery of the T loop and all the cellular immunity of the THI profile of the patient who was overwhelmed by the tumor. Concomitantly, immunotherapy generated an inflammatory process that completely involved the entire tumor lesion, necrotizing it and 10 eliminating it, as shown by ultrasound exams and confirmed by histological examination.
From 07/08/2010 until 11/30/2011 the patient was treated in the same systemic and perilesional way twice a week and recombinant human interleukin 2 at a dose below 15 of the receptor saturation with 600,000 units daily. Since then, she has been receiving the battery of antigens weekly and daily of interleukin 2. Thus, the patient has been tumor-free for 18 months.
Conclusion of the case 20 The evaluated data and the clinical evolution of the patient, to date, strongly suggest that immunotherapy with the immunogenic compositions of the present invention was responsible for the verified elimination of the tumor.
W Example 4: Combating malignant melanoma
N i / Patient data PPC 62-year-old male patient.
Diagnosis Clark and Breslow level II malignant melanoma of 1.25 mm2 diagnosed on 02/02/2011.
Previous treatments In this case, previous treatment was not performed, since immunotherapy using DECA was performed before the oncological surgery of the primary tumor after the application of the 10 informed consent form.
Pre-treatment immunological evaluation with DECA As there was no time for a previous immunological evaluation, due to the need for surgery in the shortest possible time, this evaluation was performed by reading the antigens applied during treatment with DECA.
Treatment with DECA pre-oncological surgery In the preoperative period (10/02/2011 to 17/02/2011) treatment of the patient was initiated on the following basis: 20 · Application, together with the 10 main lymphatic territories, of 1.8 cc of formulation 1 or deca, divided into 2 applications of 0.9 cc.
The margin of 3 to 4 cm of distance to facilitate the reading of the evolution of the treatment with an interval of 4 ± 1 r days.
· Administrations of 2 extra sets of the 1.8 cc DECA composition divided into two 0.9 cc applications for each composition, bypassing the melanoma tumor lesion on the first 5 days of treatment.
"Intratumor application of five DECA compositions of 1.8 cc each, with a final volume of 9.0 cc.
"Application of low doses, at the level of receptor saturation in the concentration of 1 to 2 million units per 10 m2 of body surface located at a distance of 5 cm from the lesion. For the patient, 1 million units per day were used subcutaneously.
Thus, until the date of surgery, 02 sessions of systemic immunotherapy, 01 perilesional and 01 15 intratumor were applied, the latter two being applied on the first day of treatment. This treatment was associated with the daily application of recombinant Hurnan interleukin 2 in the doses and in the form described above.
Result of immunotherapeutic treatment with DECA before 20 cancer surgery In this 8-day period of therapy, the patient responded well to immunological treatment with total regression + of malignant melanoma. The lesion in the part transformed into a tumor evolved with an intense local inflammatory process that
F il ulcerated and disappeared giving way to the inflammatory process described in the surgical anatomopathological exam. It is necessary to mention that the patient presented during this period: episodes of high and low fevers and intense inflammatory homolateral inguinal adenopathy 5.
Conventional surgical cancer treatment Complete excision of the primary tumor with a wide surgical safety margin has been proposed, with intraoperative sentinel lymph node research.
10 Conventional oncological surgery of the primary tumor On 02/18/2011, the patient underwent surgery with complete excision of the tumor lesion with a wide margin of safety, whose investigation of two satellite ganglia was negative for neoplasia. for this reason 15 ganglionic emptying was not performed.
Result of conventional oncological surgery of the primary tumor The anatomopathological examination confirmed the complete regression of the tumor, attesting: 20 "in the skin: inflammatory changes with an area of ulceration covered by fibrino-leukocyte buffer, with granulation tissue with exuberant base.
D mixed inflammatory infiltrate. This infiltrate permeates and extends throughout the epithelium at the edges of this ulcer,
There are also 165 foreign body multinucleated giant cells. The whitish and bulging region described under microscopy corresponds to seborrheic keratosis of the papillomatous type with acanthosis, hyperkeratosis and papillomatosis of the epidermis. The entire skin was submitted to histological examination, with no residual melanocytic neoplasia.
"in sentinel I lymph nodes: extensive fibrosis of the hilar region and sinus and subcapsular histiocytosis without metastatic deposits being identified on morphological examination; 10" in sentinel II lymph nodes: histological findings similar to those described in I, with no metastatic deposits in the morphology.
On this date, the immunohistochemical examination for sentinel lymph nodes I and II revealed the absence of 15 melanoma micrometastases.
The immunohistochemical examination of the primary tumor revealed a complete absence of tumor cells from the tissue surgically removed previously treated with DECA according to the limits of the available diagnostic techniques (Figure 20 4).
Result of treatment with DECA pre-oncological surgery of the primary tumor These data produced by the surgery, within the context and within the limits of the available diagnostic techniques, showed a surprising result for the non-detection of the primary tumor after immunotherapy with DECA.
Treatment with DECA after cancer surgery 5 With this result of complete tumor regression, immunological treatment was continued on the following bases: "Application, along with the 10 main territories, ..l .. W, lymph, 1.8 cc of DECA composition divided into 2
W 0.9 cc applications.
10 "Margin of 3 to 4 cm of distance to facilitate the reading of the evolution of the treatment with interval of 4 + 1 - days.
"Administrations of 2 extra perilesional compositions of 1.8 cc each, with two applications of 0.9 per cc per 15 composition around the large surgical scar without space between them, too, with an interval of 4 ± 1" Daily application of interleukin 2 low-dose human recombinant, at the level of receptor saturation at a concentration of 1 to 2 million units per m2 of body surface 20 located within 5 cm of the surgical scar.
For the patient, 1 million units were used per m2 of body surface per application. m Result of treatment with DECA after surgery »oncology
The surgical area for the removal of the satellite ganglia, in the inguinal region, evolved with the formation of a liquid collection, confirmed on 03/16/2011 by ultrasonography that showed: simple cystic formation of 6.0 x 5.2 x 3.1 cm, 5 with blurring of the adjacent fatty planes and no abnormal vascularization or vascular changes of the tumor type were observed on color Doppler.
P This collection described above evolved with process -.
Local inflammatory H, with reduced size and increased 10 of the inflammatory adenopathy seen on the ultrasound of 03/28/2011. On color Doppler, no abnormal vascularization was observed in this formation. Regarding the examination of 03/16/2011, it can be noted: 1) marked reduction in the formation that previously had a cystic aspect, suggesting 15 significant resorption, organization and favoring the inflammatory / reaction hypothesis (post-surgical collection); it was also observed in the region of the left inguinal ganglia 2) enlarged lymph nodes, preserving a vascularized hilum and of a reactionary aspect, 20 located medially and cranially to the aforementioned formation measuring 1.6xO, 8 cm and 2.4 xl, 7 cm.
Immunological treatment was continued until
W 07/31/2011, whose physical examination revealed complete regression "of the lesions and transformation from intense reactional regional lymphadenopathy to residual reactive regional lymphadenopathy.
On July 5 and 8, 2011, the repetition of PET / CT and soft tissue ultrasonography with colored doppler, 5 of the left leg and left inguinal region, respectively, proved the inflammatory character and the
P complete regression of the lesions, leaving only adenopathy! residual inflammatory reaction. There was also a regression
K of the diffuse increase in metabolic activity in bone marrow 10 of the axial and appendicular skeleton, showing a bone marrow stimulation effect by DECA, in the re-renewal of the immune response, which shows its ability to stimulate and regenerate tissues.
Discussion of the results of treatments with DECA pre 15 and post-conventional cancer surgery This is a case of malignant melanoma of approximately 1 cm that underwent a punctual biopsy without surgical treatment. This tumoral lesion was the target of immunotherapeutic treatment with a battery of 920 antigens associated with reduced doses of human recombinant interleukin 2 described above. This therapy caused an intense inflammatory reaction involving the entire
M lesion leading to necrosis and ulceration of the entire area
R tumor that disappeared in 8 days of treatment.
After this period, the patient underwent surgery and the anatomopathological examination confirmed the replacement of the tumor tissue with an ulceration with total absence of tumor cells involved by an intense inflammatory process with 5 characteristics of foreign body granuloma (Figure 4B).
The anatomopathological examination of two sentinel lymph nodes confirmed the reactive lymphoid hyperplasia with
N! 'An intense sinus and subcapsular histiocytosis, as well as
Ò extensive fibrosis of the hilar region, with no metastatic deposit being identified. The immunohistochemical examination confirmed the finding attesting the absence of micrometastasis in these lymph nodes.
The region from which the satellite lymph nodes were removed evolved with the formation of a liquid collection 15 enveloped in an inflammatory process with an increase in locoregional reactive inflammatory lymphadenitis showing a good immunological reaction. With the continuation of treatment, an intense inflammatory process involved this liquid collection causing its regression and absorption 20 accompanied by the inflammatory reaction of a non-tumoral character in the satellite ganglia.
Ultrasound exams with Doppler and PET-CT. demonstrate the suggested non-tumor inflammatory aspect, "proving the absence of tumor mass. These exams showed that the intense regional lymphatic reaction and the increase in bone marrow activity show an intense and effective anti-tumor immune reaction.
Conclusion of case 5 The data evaluated and the clinical evolution of the patient, so far, strongly suggest that immunotherapy m using the compositions of the present invention, as unique! treatment used before cancer oncology surgery primary, was responsible for the observed elimination of the tumor in 8 days.
Example 5: Combating advanced microtubular gastric adenocarcinoma with peritoneal carcinomatosis intra-abdominal lymphatic metastatic dissemination Patient data 15 Male patient R - M, 72 years old.
K Diagnosis Advanced microtubular gastric adenocarcinoma with peritoneal carcinomatosis and intra-abdominal lymphatic metastatic spread.
20 Exams performed a. Conventional upper digestive endoscopy and anatomopathological. The upper digestive endoscopy of 06/12/2008 demonstrated "neoplasia of an advanced and stenosing gastric antrum,
confirmed by anatomopathological examination of 06/13/2008 the biopsy anatomopathological showed: b. Imaging conventional On 06/20/2008 tomography of abdomen and 5 pelvis was performed for preoperative staging of gastric neoplasia whose conclusion was advanced gastric neoplasia with peritoneal carcinomatosis by dissemination of extensive lymphatic eag "continuity in multiple lymphatic territories 7 measuring 4 with the largest of them (figure 5, Al - A3).
C. Post-surgical immunological evaluation The first consultation was carried out after surgery on 07/23/2008 and the conventional exams and the immunological evaluation on 07/24/2008.
Conventional exams showed mild microcytic anemia 15 (Hb = 11.7 g / dL (VN = 13 to 18 g / dL, HT = 37.1% (VN = 40 to 54%) and VCM = 70 U3 (VN = 80 at 97 U3) and hyperplaquetemia (755,000 (VN = 150,000 to 450,0OO / mm3)), lymphocytosis (9.10O / mm3 (VN = 4,000 to 11.OOO/mm3), hyperglycemia (155 mg / dL (VN = up to 99 mg / dL), high ESR 20 110 mm / h, high uric acid (7.3 mg / dL (VN = up to 7.0 mg / dL), high CRP (0.6 mg / dL whose VN is up to 0.5 mg / dL), alpha-1 high acid glycoprotein (141 mg / dL (VN = up to 140. mg / dL) and high amylase with 170 U / L (VN = 25 to 125 U / L).
the immunological evaluation was performed after surgery with the following tests in vitro (blood tests) and in vivo (primary and secondary hypersensitivity).
The in vitro tests consisted of; t-dependent immunoglobulin dosage that are borderline 5 for maximum normal values (Ig A 324 (VN = 82 to 453), Ig G 1476 (VN = 751 to 1560), Ig M 200 (VN = 46 to 304) and & Ig and 61.89 (VRN = up to 100)), negative RAST for all
And tests, beta-2 microglobulin 2496 (VN = until 2030)
P immunophenotyping of normal total CD3 + T lymphocytes, with 10 normal CD4 + cells (43.3% (845 / mm3) NV = 27 to 57% (560 to 2700 / mm3)), CD8 + decreased in absolute and relative values (242 / mm3 VN = 14 to 34% (330 to 1400 / mm3) and a high CD4 + / CD8 + ratio (3.49 VN = 0.98 to 3.24).
In vivo tests: 15 "delayed primary hypersensitivity: performed with 0.5% and 2% DNCB skin patches.
"secondary delayed hypersensitivity.
The results showed: "primary hypersensitivity was shown to be abolished.
20 "delayed systemic secondary hypersensitivity was shown to be decreased from 0 / + to +++++ for intracellular antigens and decreased by + / ++ for other antigens, at a distance from the tumor. In the pericicatricial area, all antigens showed abolished reactions 0 / + for intracellular antigens and 0 / + in +++++ for other antigens.
These in vivo and in vitro examinations revealed an important immunosuppression of the 5 Thl profile cellular immune system, primary and secondary, local and systemic, which is responsible for antitumor immunity and elimination of tumor cells and a tumor escape mechanism, by & < profile Th2, with an antibody response rather than a bad cellular response. Primary immunosuppression with loss of T loop integrity and without the possibility of developing a new T response, combined with the breakdown of cellular immunity of the THI profile responsible for anti-tumor immunity and the predominance of the escape antibody response rather than the cellular one , showed a compromised immune system, 15 overwhelmed by the tumor, with no chance of containing the disease on its own.
d. Diagnostic conclusion Advanced advanced microtubular gastric adenocarcinoma with peritoneal carcinomatosis by dissemination 20 by contiguity and extensive lymphatic metastatic dissemination in multiple lymphatic territories measuring 4 cm the largest of them.
Treatment e. Conventional surgical
The treatment carried out (on 11/07/2008) was partial gastrectomy with reconstruction in palliative b2 with partial lymphadenectomy. 'The anatomopathological examination of the gastrectomy and 5 partial and palliative lymphadenectomy of 11/07/2008 showed extensive remaining advanced neoplastic disease.
f. Conventional chemotherapy and radiotherapy 6 "As it is an advanced gastric carcinoma with peritoneal carcinomatosis and intra-IO abdominal lymphatic dissemination with no possibility of cure by surgery and chemotherapy, radiotherapy associated with non-curative chemotherapy with 5-fluoracil and taxotere was proposed in 21-day cycles to control tumor mass and improve both quality of life and patient survival.
15 This chemotherapy treatment was carried out from 08/14/2008 to 12/26/2008. The 25 radiotherapy sessions started on 10/10/2008 and ended on 11/13/2008.
gr. Treatment with DECA For the above reasons, an association of 20 immunotherapy with palliative chemotherapy has been proposed to improve the patient's condition and possible beneficial results of this pharmacological association.
Immunotherapy was performed one week (two q applications of DECA) before the start of chemotherapy and
[175 followed in the second and third weeks after the first week and each 21-day chemotherapy cycle. In this way, chemotherapy remained uninterrupted, whereas immunological therapy was carried out for a period of 52 weeks with an interval of 1 week.
The DECA protocol was performed as follows: · Application of 1.8 cc of the DECA composition divided into b two applications of 0.9 cc along the 10 main 4 lymphatic territories.
10 3 to 4 cm margin of distance to facilitate reading the evolution of the treatment with an interval of 4 + 1 days.
"From the evaluation of the fourth application, when all responses normalized, becoming 15 hyperergic.
0 Recombinant human interleukin 2 at low doses, at the level of receptor saturation at a concentration of 1 to 2 million units per m2 of body surface for the patient at 600,000 units applied daily 20 next to the surgical scar.
H. Treatment results i. Conventional. Conventional isolated (surgical) treatment was "carried out in a palliative manner to resolve the patient's gastric obstruction.
ii. Deca treatment associated with chemotherapy The patient normalized the primary delayed hypersensitivity tests in one month and secondary delayed hypersensitivity 5 in two weeks demonstrating a recovery of the T-loop cellular response. Within two weeks, the signs and symptoms of inflammation and infection disappear. and systemic. · K After six months of treatment for DECA and chemotherapy 10 associates (started, respectively, on 06/08/2008 14/08/2008) the patient was reevaluated. After six months (02/09/2009) of associated immunological and chemotherapy treatment there was: "significant reduction in the majority of adbdominal lymphadenopathy 15;" significant reduction in the signs of carcinomatosis.
"complete remission of immunosuppression with positivity, after 4 weeks of treatment, of the reading of the delayed secondary hypersensitivity showing a positive reaction of 3 + / 4 + in 5+ for the 9 antigens previously tolerated. The delayed primary hypersensitivity previously abolished became positive, too, after 1 month of
P treatment.
'After 9 months (05/13/2009) of treatment described above
, there was: "reduction of lymph node enlargement of the celiac trunk from 2.0 to 1.6 cm to 1.4 cm without other lymph node enlargements (Figure 5, B2 - B3).
5 0 attenuation of the fibrocicatrial aspect showing disappearance of the signs of carcinomatosis (Figure 5, BI).
"left pleural effusion unchanged. e After 1 year and 2 months (10/03/2009) of treatment
W described above: 10 · Significant reduction in left pleural effusion; "reduction of lymph node enlargement of the celiac trunk from 1.4 cm to 1.3 cm without other lymph node enlargements" Attenuation of fibrocicatory changes in the surgical store.
15 After 1 year and 8 months (04/13/2010) of treatment described above, there was: "Resolution of the left pleural effusion.
"unchanged celiac trunk lymph node enlargement (Figure 5, C2).
20 After 1 year and 11 months (7/31/2010) of treatment described above, there was: "reduction of lymph node enlargement of the celiac trunk from 1.3» cm to 1.1 cm without other lymph nodes.
0 "Complete disappearance of liver nodules;
After 2 years and 4 months (18/02/2011) of treatment described above, there was: 0 Chest without changes.
0 Maintenance of lymph nodes of the celiac trunk measuring 5 1.1 cm.
Conclusion of the case Association of radio, chemo and immunotherapies carried out from August to December 2008 brought: complete remission of immunosuppression and significant reduction in both carcinomatosis and lymphadenomegaly of the upper abdomen. The liver nodules and enlarged lymph nodes of the celiac trunk remained, presenting the largest 1.6 cm.
From this evaluation, immunotherapy was exclusively instituted until February 2012. As a result of this treatment, it is possible to observe: complete remission of suspected liver nodules, disappearance of the signs of carcinomatosis and significant reduction of lymph nodes from 2.0 to 1.6 cm to 1 , 1 cm.
These data strongly suggest that immunotherapy was effective as an adjunct to radio and chemotherapy and, when applied alone, it was effective for inducing and maintaining tumor remission after 3 years and 6 months of treatment (Figure 5, Cl, C3) .
Example 6: Combating a multiple inflammatory pseudotumor related to human herpes virus type VIII.
Patient data Patient A - D, 40 years old, female.
Diagnosis 5 Multiple inflammatory pseudotumor related to human herpes virus type viii.
+ Clinical history a. Clinical summary u In a consultation on 06/04/2006, he had a history of 10 afternoon fever (between 37.5 and 37.8 ° C), headache, tiredness and dyspnea on small efforts. On clinical examination, the patient was feverish, adynamic a little prostrate, with sparse snores in both lungs and important hepatosplenomegaly.
B. Conventional blood tests performed Laboratory tests on 10/05/2006 showed an infectious / inflammatory condition to clarify: ESR = 41 mm (VN = <10 mm), CRP = 3.83 mg / dL (VN = <0.50 mg / mL), 20 alpha-1 acid glycoprotein = 1.66 mg / dL (VN = 50 to 120 rng / dL), Ca2 + hypocalcernia = 7.4 rrig / dL (VN = 8.6 to 10.3 mg / dL), mild platelet count with platelets 143.00O / mm3 (VN = 150,000 to 450,0OO / mm3), proteinuria 0.66 g. On 10/05/2006, serological research was negative for the following etiological agents: Toxoplasmosis, Dengue, Brucellosis, HIV, viral hepatitis: A, B and C; Paracoccus spp, Histoplasma spp., Direct antigen screening by PCR was negative for Criptococcus spp and Histoplasrna spp.
5 Serologies showed previous infection for Cytomegalovirus, EBV (mononucleosis) and Rubella. While the search for herpes virus was positive Ig m. This pathology is related to herpes virus type VIII and the cross-reaction between this type with I and II suggests infection by human serotype VIII.
Conventional imaging The chest tomography of 10/9/2006 revealed: multiple bilateral pulmonary nodules of up to 3.0 cm, an irregular tumor-like area of 5.0 cm in the left apex, 15 air bronchogram on the right and a nodule in LMD adhered to the pleura (Figure 6A). Contemporary abdomen tomography confirmed an important hepatosplenomegaly, with multiple ganglia across the root of the mesentery, liver nodules and a splenic nodule. A picture of maxillary sinusitis and edema and nasal fossa hypertrophy was also found.
Anatomopathological patients The anatomopathological examination was complex, showing an inflammatory process with a large amount of histiocytes. The exam was sent to a lung specialist. The anatomopathological analysis was the diagnosis of a rare pathology: inflammatory pseudotumor.
Immunological evaluation 5 The immunological evaluation was carried out on 10/05/2006 with the following tests in vitro (blood tests) and in vivo (primary and secondary hypersensitivity). e The in vitro tests presented the following conjuncture and clinical: normal immunoglobulin (Ig G, Ig A, Ig E) 10, total complement and C3 and C4 according to normality standards, total CD3 + T lymphocyte immunophenotyping with decreased in absolute number (715 / mm3 - minimum normal value = 1035 / mm3) showing T lymphopenia, with normal CD4 + cells (54% (551 / mm3) VN = 35 15 to 62% (535 to 2580 / mm3)), CD8 + decreased in absolute values (163 / mrn3 VN = 17 to 43% (255 to 1720 / mm3) and a high CD4 + / CD8 + ratio (3.4 VN = 0.9 to 2.6).
These results showed normal humoral and complement system immunity, however, non-reactive, that is, 20 not involved in the immune response of the ongoing infection. Immunophenotyping demonstrated T lymphopenia and an ongoing T response due to the high CD4 + / CD8 + 'ratio (predominance of helper cells over suppressor / cytotoxic cells). The infectious agent caused a polarization for a THI cell type response.
In vivo tests: "delayed primary hypersensitivity: performed with skin patches" of 0.5% DNCB and 2 "o.
5 "secondary delayed hypersensitivity.
The results showed: <"primary hypersensitivity proved to be abolished.
"Systemic secondary delayed hypersensitivity m was shown to be decreased.
10 The conclusion of the irrlunological evaluation: in vivo and in vitro tests showed that the infectious agent caused a polarization for a THI-type cellular T response.
This response proved to be ineffective with lymphopenia and rupture of the T loop due to the abolition of delayed primary hypersensitivity 15 indicating an inability to perform a new primary response, as well as decreased delayed secondary hypersensitivity showing impaired cellular memory and effector loop.
Conclusion diagnoses 20 Multiple inflammatory pseudotumor (associated and related to herpes hurnan virus type VIII) with associated T immunosuppression.
Conventional Treatment Surgical intervention is a form of
[183 effective treatment and etiology is related to herpes virus VIII which explains the cross-reaction with that of IgM positive for herpes virus I and II. Relapse cases are described in case after surgical removal. In this case, in 5 that there are multiple pulmonary, abdominal (at the root of the mesentery) and hepatosplenomegaly nodules, with systemic inflammatory condition, hypocalcemia, similar reports were not found in the scientific literature. Thus, surgery cannot be curative. It is possible to infer that the 10 important immunosuppression T observed may have contributed to the multiple and unusual form of a rare pathology.
Treatment with DECA Due to the immunosuppression found and the impossibility of surgical treatment (due to the 15 multiple foci), with free and informed consent, it was decided to treat this immunosuppression with DECA, for a period of approximately 2 months, after which the patient would be reassessed. The protocol consisted of: "Application of 3 1.8 cc 20 DECA compositions divided into 2 applications of 0.9 cc per composition, on the abdomen and two 1.8 cc DECA compositions divided into 2 applications of 0.9 cc by composition, respectively one in each right and left upper limb with 0.9 cc in the arm and 0.9 cc in the forearm bilaterally next to the 10 main lymphatic territories.
3 to 4 cm margin of distance to facilitate reading the evolution of the treatment in an interval of 7 ± 2 days.
5 "Daily applications of recombinant human interleukin 2 at low doses, at a level of receptor saturation at a concentration of 1 to 2 million units per m2 of body surface. For the patient, 600 thousand units were used subcutaneously once a day in the abdomen.
i. Treatment results i. Conventional In this case, there were no therapeutic alternatives, since surgical treatment would not be effective in view of the multiple manifestations of the disease, ii. Treatment with DECA The patient normalized the primary delayed hypersensitivity tests in one month and secondary delayed hypersensitivity tests in two weeks demonstrating a recovery of the cellular T-loop response. Within two weeks, the signs and symptoms of systemic inflammation and infection disappeared.
After two months of treatment, the patient was reassessed. On physical examination, the patient did not show signs of infection or inflammation and hepatosplenomegaly regressed. Computed tomography of the chest and abdomen performed on 11/12/2006 showed: "In the lungs: faint ground-glass opacities in the sutures of the right apex (surgical sequelae), disappearance of multiple sparse nodular opacities 5 in both lungs (complete remission of the pulmonary infectious and inflammatory process) and complete regression of the right hilar lymph node (Figure 6B). »" In the abdomen: complete remission of the hepatosplenomegaly, and significant reduction of the 10 lymph nodes of the mesentery root.
Conclusion of the case After the treatment period (10/15/2006 to 11/12/2006) with DECA there was: complete regression of hepatosplenomegaly, multiple pulmonary and abdominal nodules with normailization of mesenterial lymph nodes, as well as clinical symptoms of inflammation and systemic infection in the 11/12/2006 exams. There was also complete remission of immunosuppression with the positivation, after 2 weeks of treatment, of the delayed hypersensitivity reading 20 showing a positive reaction of 3 + / 4 + in 5+. The primary delayed hypersensitivity before abolished became positive after 1 month of treatment. These results showed a complete remission: clinical, laboratory and image of the inflammatory pseudotumor, as well as the immunosuppression presented by the patient through the proposed treatment employed. The patient has been without signs of the disease or has relapsed for 5 years and 3 months Example 7: Fighting a Gleason grade 7 5 (4 + 3) acinar adenocarcinoma. Stage T2a localized adenocarcinoma of the prostate.
k Patient data Patient O - S, 69 years old, male. »Initial diagnosis 10 Gleason grade 7 (4 + 3) acinar prostatic adenocarcinoma whose staging is T2a.
Idenfication and summary of clinical history He showed an increase in PSA 20, with a biopsy revealing Gleason grade 7 (4 + 3) acinar adenocarcinoma and 15 stage T2- It is noteworthy that the patient had allergic rhinitis as a comorbidity.
Conventional treatment proposed and performed Total prostatectomy as a form of curative surgery for localized disease (restricted to the prostate). It was carried out on 20 February 18, 2010 without complications.
Result of the conventional treatment performed and final diagnosis The final diagnosis through the anatornopathological examination describes the disease with locoregional spread by
[187 Gleason grade 9 (4 + 5) adenocarcinoma of the gleason with TNM 2002 pT3bNO staging, affecting 22% of the glandular volume (tumor volume of 11.2 Cc) and located in both lobes of the gland. The left seminal vesicle and periprostatic fat 5 infiltrated by the neoplasm, but the iliac lymph nodes and bladder neck were free of neoplasia.
Final conclusion: ineffective surgical treatment, since tumor mass remained in the periprostatic region 10, compromising the possibility of proposed cure. The proposed treatment was radiotherapy in 2 months and oncological segment every 6 months for 5 years.
Immunological assessment prior to treatment with
DECA 15 In the first consultation, held on 03/09/2010, the patient requested an immunological evaluation and the possibility of immunotherapy to contain the disease before the radiotherapy that would be performed in 2 months.
In the oncological laboratory evaluation of 03/10/2010, 20 PSA of 0.15 compatible with residual neoplasia status by non-effective prostatectomy were performed (Figure 7).
The previous immunological evaluation demonstrated by the blood tests of 03/10/2010 showed: "Cellular THI profile compatible with a good antitumor response when presenting antibodies at the lower limit of normal: Ig G 977 mg / dL (VN = 600 to 1500) ; Ig A 233 mg / dL (VN = 50 to 400 mg / dL); Ig m 112 5 mg / dL (VN = 50 to 300 mg / dL) albumin 3.67 g / cy (3.50 to 4.85 g / dL), the gamma globulin 0.97 g / dL (NV = 0.74 to 1.75 g / dL). «" Correct phenotypically normal T loop
V CD4 + 846 / mm3; 10 o CD8 + 504 / mm3; o CD4 + // CD8 + 1.7 ratio.
· Moderate allergy assessment: Ig E 204 mg / dL (VN = less than 100 mg / dL); o Specified IgE for dust 1.5 mg / dL 15 (moderate class 2); "Positive autoimmunity assessment for the following markers: the nuclear FAN> 1/640; the nucleolar FAN> 1/640; 20 In vivo evaluation (primary and secondary delayed hypersensitivity tests) was not performed due to the short time remaining for immunotherapy before radiotherapy.
Conclusion based on in vitro exams:
1. humoral immunity, complement system and t-loop were phenotypically normal and without apparent immunodeficiencies; 5 2. THI cell profile conducive to a good response with immunotherapy;
3. Functional tests not performed, as no in vivo tests were performed. % Treatment proposed with DECA 10 Treatment with DECA consisted of: · Application of 1.8 cc of the DECA composition divided into two applications of 0.9 cc along the 10 main lymphatic territories.
3 to 4 cm margin of distance to facilitate the reading of the treatment evolution with an interval of 4 ± 1 days.
"Administration of 6 DECA compositions of 1.8 cc each divided into two applications of 0.9cc each perilesional bypassing in the following regions: upper and lower 20 of the right and left inguinal segment totaling 4 compositions in these regions, as well as a suprapubic composition and the other composition in the lower abdomen (inframbilical).
0 Recombinant human interleukin 2 at low doses, at the level of receptor saturation at a concentration of 1 to 2 million units per m2 of body surface located in the region of the extra DECA s. Thus, on the days of the application of the antigen, after the million daily subcutaneous units 5 in the regions indicated above.
Thus, until the date of radiotherapy, the patient's free and informed consent was chosen for the 0 immunotherapeutic treatment that started on 03/11/2010 with 0 the first partial reassessment scheduled for 03/04/2010.
10 First partial result of the proposed treatment with
DECA After 4 weeks of treatment, PSA became undetectable (Figure 7), indicating a complete remission induced by immunotherapy, which is apparently capable of eliminating or significantly reducing the tumor mass. due to the current state of the art, it is not possible to differentiate complete eradication of tumor mass from minimal residual disease showing that the proposed treatment with DECA has shown a surprising effect.
20 On this occasion (03/04/2010) it was possible to verify: Ig G 1070 mg / dL (VN = 600 to 1500); o Ig A 248 mg / dL (VN = 50 to 400 mg / dL); Ig M 129 mg / dL (NV = 50 to 300 mg / dL); o Total complement system without significant changes (280 on 03/10/2010 to 281 erri 04/03/2010); This maintenance of the complement system can also be seen in C3 (from 117 to 115) and C4 (76 to 71); 5 · albumin 3.21 g / dL (3.50 to 4.85 g / dL); · Globulin range 1.00 g / dL (NV = 0.74 to 1.75 g / dL).
· CD4 + 1,075 / mm3; 4 · CD8 + 537mm3;
W · CD4 + // CD8 + 2.0 ratio.
10 · Ig E 165 mg / dL (VN = less than 100 mg / dL); the nuclear FAN> 1/320; "Nuclear ANA> 1/320; In vivo evaluation (secondary delayed hypersensitivity tests) demonstrated 15 · in the first application: · antigens administered remotely from the tumor area with a score of + / ++ for all antigens; · in the region of DECAS close to the residual tumor area, the reaction was decreased, presenting a score of + / ++ in 20 +++++ attesting to tumor immunosuppression.
"in the second application: · antigens administered remotely from the turnoral area became hyperergic with a score of +++ / ++++ for all antigens;
r 192 "in the DECAS region close to the residual tumor area normalized and started to present a score of ++ / +++ in +++++ attesting to a reversal of immunosuppression caused by the residual tumor mass.
5 "in the third application (beginning of the second week of treatment C @" the antigens administered remotely from the tumor area became more hyperergic with a score of
M ++++ / +++++ for all antigens; 10 "in the DECAS region close to the residual tumor area reached the same activity level (from ++++ / +++++) attesting to a complete reversal of loco-regional immunosuppression of the residual mass.
These reactions continued to be hypergly until the date of the reevaluation of the fourth week (03/04/2010).
Completion of the first partial result of the proposed treatment with DECA The patient initially had preserved systemic immunity with the cellular Thl profile. This cellular Thl 20 profile was compromised in the regions close to the tumor with a low reactive T loop attesting to the loco-regional immunosuppression of the tumor.
Immunotherapy made secondary delayed hypersensitivity hyperergic in all territories at a distance from the tumor after the second application of DECA and reversed loco-regional immunosuppression that became hyperergic like the others.
Blood tests corroborated with the functional analysis of the t loop showing an increase in the absolute and relative number of CD4 + / helper cells and an increase in the CD4 + // CD8 + ratio attesting to the mobilization of CD4 + cells, at the systemic level with which they restored immunity patient's cell phone. Blood tests also demonstrated a specific action of the DECA composition, exclusively on cellular immunity, since the antibodies and the complement system remained unchanged in this first phase of treatment.
In parallel, other antiallergic and autoimmune benefits were observed: "decrease in Ig E class antibodies accompanied by complete clinical remission of allergic rhinitis manifested in the patient as a comorbidity suggesting an antiallergic action of the proposed DECA treatment.
"Significant reduction in the ANA score from 1/640 to 1/320 showing a probable regression of the tendency to autoimmunity; Final result of the proposed treatment with DECA prior to radiotherapy
On April 27, 2010, the second partial reassessment was performed when the patient had painful hyperglycemic reactions (all with +++++). In view of the undetectable PSA result and remained so until February 2012.
5 The immunological treatment that started on 03/11/2010 continued until 06/10/2010 (the eve of radiotherapy) totaling 90 days, emphasizing that the
Complete remission of the tumor mass was achieved after 4
W weeks and reversal of immunosuppression in 2 weeks.
10 Results of treatment with DECA Due to the complete remission of a patient with Gleason grade 9 (4 + 5) prostatic adenocarcinoma and pT3bNo surgical staging with post-surgical residual tumor mass, in 4 weeks, it can be inferred that these 15 results are surprising in relation to the state of the art that points these cases as difficult to reverse.
It is also possible to infer that in that first month of treatment, immunotherapy with DECA demonstrated a potential antiallergic capacity (reduction of Ig E 20 associated with complete remission of allergic rhinitis) and a regression of the tendency to autoimmunity (evidenced by the reduction of the titration by half antibodies against nuclear elements).
Conclusion of the case
These data strongly suggest that immunotherapeutic treatment with DECA, in the condition of pharmacological monotherapy adopted while awaiting the beginning of radiotherapy, was effective in the complete remission of the remaining locoregional turner 5 (in 4 weeks) of the prostatectomy backed by the conversion of the levels of PSA until it is undetectable, representing, therefore, eradication of the tumor mass *, since the current state of the art does not * make it possible to differentiate complete eradication of the tumor mass 10 from minimal residual disease.
In addition, complete clinical remission of allergic rhinitis and improvement in ANA levels were observed (probably improving the tendency of autoimmunity).
Example 8: Combating septicemia 15 Patient data Patient j - P 58 years old male.
Main diagnosis Septicemia.
Secondary diagnoses 20 Polytrauma with: "Complex wounds infected with significant tissue loss of approximately 40 cm.
"Extensive infected tissue necrosis with indication of amputation of the left lower limb.
0 Grade IIIB exposed fracture infected with left femur osteomyelitis with lateral exposure.
0 Open, infected cutaneous contusion wounds with no possibility of suturing in the left arm, left dorsum 5 and right lateral malleolar region.
Identification and summary of clinical history On January 12, 2011, he was admitted to the Intensive Care Center of Hospital das Clinicas in Teresópolis
W Constantino Otaviano, sliding victim with open fracture 10 of left femur grade III b with exposure of the lateral face and medial cut-contusion wound 40 cm long that in depth communicated with the exposure of the lateral face. Cut-blunt wound on the left arm, dorsal region of the left foot and right lateral malleolar region 15. He evolved in 24 hours with a septic condition with microbiological identification of Pseudomona aeroginosa.
Conventional treatment proposed and performed Placement of external fixator in the femur, in the emergency, with administration of clindamycin, vancornicin and cefepime 20 associated with daily surgical debridement.
Result of conventional treatment performed Initially, the septic condition improved, followed by the evolution of the infection of the left lower limb with an extensive area of muscle necrosis with a high risk of amputation. After 15 days of hospitalization, he developed sepsis with feverish episodes of 39 ° C, profound anemia (receiving transfusion) and exchange of antimicrobials for Tazocim. The patient was transferred to an aerial mobile ICU to São 5 Paulo with medical supervision.
The conclusion of conventional treatment showed recurrence of sepsis and increased necrosis of the left lower limb with an indication of amputation.
Proposed treatment with DECA associated with conventional surgical treatment The patient was admitted to the ICU of Hospital Alernão Oswaldo Cruz for debridement and application of treatment with DECA which took the following form: · Application of 1.8 cc of the DECA composition divided into 2 applications of 0 , 9 cc per composition with the 10 main lymphatic territories.
3 to 4 cm margin of distance to facilitate reading the evolution of the treatment with an interval of 4 ± 1 days. These applications were performed together with surgical debridement (on average 1 to 2 times a week).
· Administration of 36 extra perilesional compositions of 01.8 cc cc of each DECA divided into two applications of 0.9 cc per composition bypassing the following open lesions without the possibility of suture: left inguinal region, lateral aspect of the left thigh, anterior aspect of the left thigh and medial aspect of the left thigh, dorsum of the left foot and lateral malleolar region of the right leg.
"Recombinant human interleukin 2 in low 5 doses, at the level of receptor saturation at a concentration of 1 to 2 million units per m2 of body surface located in the region of the extra DECA s. For the patient, 3 million subcutaneous units were used. left thigh or left inguinal region.
· In the exposed regions, 15 DECA compositions of 1.8 cc each were applied to infiltrate the exposed raw areas.
0 This extensive immunotherapy was always applied in the operating room on days of surgical cleaning and debridement under general anesthesia.
In this way, the first phase of immunotherapy started on 01/29/2011 and ended on 03/19/2011 totaling 9 applications of DECA in periods that varied from one to two times a week, since it followed the cleaning schedule and debridement in the operating room (due to severity, pain and the high risk of infection due to the extensive exposure of internal tissues in bloody areas).
Result of the proposed treatment with DECA associated with surgical malnutrition and antibiotic therapy Initial assessment 199 of the patient's wounds in the operating room on 01/29/2011 demonstrated all hemorrhagic wounds with numerous clots, with extensive area of necrosis and foul-smelling purulent secretion. After surgical cleaning, tissue 5 continued to be winey with a poor overall appearance without any appearance of healthy granulation tissue.
According to the description, immunotherapy with DECA was applied in these areas. It is interesting to mention that on this occasion, cultures of internal secretions and 10 of tissue fragments were performed.
After 24 hours, the first evaluation of surgical treatment associated with immunotherapy with DECA was carried out, which showed: reddish lesions, with the appearance of healthy granulation tissue, with few necrotic areas, with scarce secretion, with a fetid odor and without active bleeding.
The lesions were cleaned and immunotherapy was applied with DECA as indicated above. On that occasion, Tazocim antibiotic therapy was switched to Meronem, Cubicin and Rifampicin pending the result of the cultures.
On 01/02/2011, the result of the wound cultures and peripheral blood and central catheter showed: · in the wound of the left thigh the isolation of multiresistant Pseudomonas aeroginosa, multidrug-resistant Acinetobacter baunnamii and sensitive only to Polymyxin B and multiresistant Proteus mirabíles.
0 in the peripheral blood and in the central catheter the isolation of multi-resistant Acinetobacter baunnamii and 5 sensitive only to Polymyxin B.
Conclusion: these results demonstrated that the bad evolution of the left leg injuries led to a new
Sespse episode with Acinetobacter baunnamii and that for
V being multidrug-resistant and sensitive only to Polymyxin B, 10 did not respond to treatment with intravenous Tazocim. On the other hand, it strongly suggests a beneficial action of the composition deca together with surgical treatment in the local and systemic protection against this infection, since there was an improvement in the systemic infection and injuries before the application of polymyxin B capable of neutralizing this agent etiological.
On that day, Meronem was exchanged for 20,000 Ul / kg in two daily administrations of Polymyxin B without altering the other medications.
20 On 02/03/2011, the remission of the septic condition was verified with the therapeutic association of antibiotic therapy, surgical cleaning and immunotherapy with DECA, which made it possible to transfer the ICU to the infirmary from that date.
r 201 On 02/06/2011, due to the toxicity of the administration of PQiimixina B and the other antimicrobials, the patient presented a picture of acute renal failure with oliguria. As a consequence in the period between 02/06/2011 and 5 02/15/2011 (12 days) the administration of these antimicrobials was suspended and Limezolid (Zyvox) was introduced to protect against staphicococcal hospital contamination. On 02/15/2011, the complete remission of renal failure presented by the patient was observed. In that 10 12-day period, relying only on the therapeutic association of surgical cleaning, prophylactic antibiotic therapy and immunotherapy with DECA, the patient presented an excellent evolution of the general infectious condition and of the wounds, being, after this period, able to remove the external fixator, cleaning surgery and introduction of an internal nail to fix the fracture focus in surgery performed on 02/17/2011. Thus, in this period, in conjunction with orthopedic surgery, there was a significant reduction in bloody areas without skin with extensive tissue regeneration and without new infections.
The patient was discharged on 15/03/2011 with complete healing of the infection of all complex wounds and injuries, including osteomyelitis. The patient was discharged without using antibiotic therapy.
Conclusion of the case The existence of a severe generalized infection and a complex wound contaminated by multidrug-resistant Acinetobacter baunnamii and sensitive only to Polymyxin B, which was controlled without specific antibiotic therapy with wide evolution to cure sepsis, of all exposed lesions, of osteornielitis strongly suggest a decisive role for ¢ immunotherapy with DECA, associated with surgical cleaning and
W antibiotic therapy, to cure the clinical condition, in a relatively short time.
Table 2. Result of the association of immunotherapy with DECA, antibiotic therapy and surgical cleaning for sepsis and severe infection of complex wounds.
Result of the association of cultures pre-immunotherapy, 15 treatment of infected regions antibiotic therapy and immunological surgical cleaning (29/01/2011) (15/03/2011) Pseudomonas aeroginosa multidrug resistant, Acinetobacter Thigh injury Absence of signs of left baumannii multidrug resistant and sensitive infection Aztreonam and Polymyxin B only Acinetobacter baumannii 20 Absence of signs of multidrug-resistant peripheral blood and infection sensitive only to Aztreonam and
.J, 203 Polymyxin B Acinetobacter baumanníí multiresistant and Absence of signs of central catheter sensitive only to infection Aztreonam and Polymyxin B 5 In summary, the clinical cases presented here demonstrate that diseases and illnesses considered to be of high degree of complexity and obscure to very bad prognosis «When analyzed by knowledge of the state of the art,
W were fought differently, more advantageously or more efficiently through the use of the compositions of the present invention.

权利要求:
Claims (11)
[1]
1. Immunogenic composition for modulation of the immune system characterized by comprising a therapeutically effective amount of two or more antigenic agents, natural or synthetic, which have molecular patterns associated with pathogens (PAMPS) and / or molecular patterns associated with danger (DAMPS) selected from the group consisting of: (a) antigenic agents with molecular patterns associated with bacteria, (b) antigenic agents with molecular patterns associated with viruses; (c) antigenic agents with molecular patterns associated with fungi and yeasts; (d) antigenic agents with molecular patterns associated with protozoa; (e) antigenic agents with molecular patterns associated with helminths and / or (f) antigenic agents with molecular patterns associated with prions and one or more physiologically acceptable vehicles, excipients, diluents or solvents.
[2]
2. Composition according to claim 1, characterized by the fact that antigenic agents are selected from at least three or four of the groups (a), (b), (c), (d), (e) and (f).
[3]
Composition according to either of Claims 1 or 2, characterized in that: (i) antigenic agents with molecular patterns associated with bacteria are selected from antigenic agents with molecular patterns associated with bacteria belonging to the genera Staphylococcus, Streptococcus,
Enterococcus, Corynebacterium, Bacillus, Listeria,
Clostridium, Mycobacterium, Actinomyces, Nocardia,
Escherichia, Proteus, Klebsiella, Serratia, Enterobacter,
Salmonella, Shigella, Pseudomonas, Burkholderia,
Stenotrophomonas, Acinetobacter, Vibrio, Campylobacter,
Helicobacter, Bacteroides, Neisseria, Moraxella,
Haemophilus, Bordetella, Brucella, Francisella,
Pasteurella, Yersinia, Legionella, Gardnerella, Treponema,
Leptospira, Borrella, Mycoplasmas, Rickettsiae and Chlamydiae;
(ii) antigenic agents with molecular patterns associated with viruses are selected from antigenic agents with molecular patterns associated with viruses belonging to the Adenoviridae, Arenaviridae,
Bunyaviridae, Coronaviridae, Filoviridae, Flaviviridae,
Hepadnaviridae, Delta virus, Caliciviridae, Herpesviridae,
Orthomyxoviridae, Papovaviridae, Paramyxoviridae,
Parvoviridae, Picornaviridae, Poliovirus, Poxyviridae,
Reoviridae, Retroviridae, Rhabdoviridae and Togaviridae;
(iii) antigenic agents with molecular patterns associated with fungi and yeasts are selected from antigenic agents with molecular patterns associated with fungi and yeasts belonging to the genera Sporothrix, Aspergillus,
Blastomyces, Candida, Coccidioides, Cryptococcus,
. 1 3/11 Histoplasma, and Pneumocystis; or, (iv) antigenic agents with molecular patterns associated with protozoa are selected from antigenic agents with molecular patterns associated with protozoa belonging to the genera Cryptosporidium, Ciclospora, Entamoeba, Naegleria, Giardia, Leishmania, Plasmodium, Toxoplasma, Trichomonas, Trypanosoma, Microspor and Isospora; or (v) antigenic agents with molecular patterns associated with helminths are selected from antigenic agents with molecular patterns associated with trematode, cestode and nematode helminths.
[4]
Composition according to any one of claims 1 to 3, characterized by the fact that the antigenic agents contain protein, polysaccharide, lipid and / or synthetic compounds that mimic protein, polysaccharide and / or lipid molecules; optionally in which the immunoactive protein molecules have enzymatic activity; and optionally, in which the immunoactive protein molecules act as kinases, phosphatases, streptokinases and streptodornases.
[5]
5. Composition according to any one of claims 1 to 4, characterized by the fact that
.. 4/11 comprise 0, 001-500 micrograms per ml of each immunogenic agent.
[6]
Composition according to any one of claims 1 to 5, characterized in that it comprises from 4 to 20 antigenic agents selected from the group consisting of antigenic agents derived from dornase, yeast, oidiomycin, purified protein derivative of the Koch bacillus (PPD) , prions, streptokinases, Streptococcus toxoid, Diphtheria toxoid, Tetanus toxoid, Koch's crude tuberculin, inactivated lysates of Ascaris lumbricoides, Aspergillus spp., Aspergillus flavus, Aspergillus fumigatus, Aspergillus sp. parapsilosis, Chlamydia spp., Chlamydia pneumonia and, Chlamydia psi ttaci, Chlamydia trachomatis, Cryptosporidium spp., dermatophytes, Entamoeba hystolitica, Enterobius vermicularis, Enterococcus faecalis, Epidermophyton floccosum, Escherchiapischisum, Microscope, . ' Mycobacterium bovis, Mycobacterium leprae, Mycobacterium tuberculosis, Neisseria gonorrhoeae, human papillomavirus, Palio virus, Proteus spp., Proteus mirabilis, Proteus penerii, Proteus vulgaris, Salmonella spp. , Salmonella bongori, Salmonella enterica, Serratia spp., Serratia liquefaciens, Serratia marcescens, Shigella spp., Shigella flexneri, Shigella sonnei,
I_
1
5/11
Staphylococcus spp., Staphylococcus aureus, Staphylococcus epidermidis, Strongyloides stercoralis, Streptococcus spp.,
Streptococcus bovis, Streptococcus of the viridans group,
Streptococcus equinus, Streptococcus pneumonia and,
Streptococcus pyogenes, Toxoplasma gondii, Trichomonas vaginalis, trichophytin, Trichophyton spp., Trichophyton rubrum, Trichophyton tonsurans, Trichophyton mentagrophytes, yellow fever virus, hepatitis virus
B, rubella virus, Varicella zoster virus, smallpox virus, mumps virus, measles virus, herpetic virus and vaccine virus or synthetic analogues that have molecular patterns associated with pathogens
(PAMPs) and / or molecular patterns associated with danger
(DAMPS) associated with these antigenic agents;
optionally, wherein the immunogenic composition comprises inactivated lysate of Mycobacterium bovis, purified protein derivative of Koch's bacillus, inactivated lysate of
Staphylococcus aureus, inactivated lysate of Staphylococcus epidermidis, inactivated lysate of Streptococcus pyogenes,
inactivated lysate of Streptococcus pneumoniae, inactivated lysate of Enterococcus faecalis, streptokinase / dornase,
inactivated lysate of Candida albicans, inactivated lysate of
Candida glabra ta, inactivated lysate of Epidermophyton floccosum, inactivated lysate of Microsporum cannis, inactivated lysate of Trichophyton mentagrophytes variety interdigitale, inactivated lysate of Escherichia coli enteropathogenic, inactivated lysate of Salmonella bongori,
inactivated lysate of Salmonella enterica and inactivated lysate of underground Salmonella, optionally, wherein the immunogenic composition comprises 0.001-1 ng / ml of inactivated lysate of Mycobacterium bovis, 0.001-1 ng / ml of purified protein derivative of Koch's bacillus, 0. 1 to 100 µg / ml of inactivated lysate of Staphylococcus aureus, 0.1 to 100 µg / ml of inactivated lysate Staphylococcus epidermidis; 0.1 to 100 µg / ml of inactivated lysate of Streptococcus pyogenes; 0.1 to
100 µg / mL of inactivated lysate of Streptococcus pneumoniae;
0.1 to 100 µg / mL of inactivated lysate Enterococcus faecalis,
O, 01 to 10 µg / ml of streptokinase, O, 01 to 10 µg / ml of dornase; 0.1 to 100 µg / mL of inactivated lysate of Candida albicans; O, 1 to 100 µg / ml of inactivated lysate of Candida glabra ta, 0.1 to 100 µg / ml of inactivated lysate
Epidermophyton floccosum; 0.1 to 100 µg / ml of inactivated lysate of Microsporum cannis, 0.1 to 100 µg / ml of inactivated lysate of Trichophyton mentagrophytes variety interdigitale; 0.1 to 100 µg / mL of inactivated lysate
Enteropathogenic Escherichia coli; 0.1 to 100 µg / ml of inactivated Salmonella bongori lysate, 0.1 to 100 µg / ml of inactivated Salmonella enterica lysate and 0.1 to 100 µg / ml of inactivated Salmonella subterranea lysate.
[7]
Composition according to any one of claims 1 to 6, characterized in that it additionally comprises cytokines and / or chemokines; optionally comprising GM-CSF, IL-2, IL4, IL5, IL7, IL12, IL15, IL21 and / or gamma interferon, preferably IL-2.
[8]
8. Composition according to any of claims 1 to 7, characterized by the fact that: (i) the antigenic agents are encapsulated in the form of capsules, microparticles, nanoparticles, dragees, or liposomes, and I or (ii) it is presented as a solid, liquid or gel; and / or (iii) the administration in human or animal can be oral, intradermal, parenteral, subcutaneous, intravenous, intrarnuscular, as well as through the nasal and / or oral mucosa.
[9]
9. Use of an immunogenic composition as defined in any of claims 1 to 8, characterized by the fact that it is for preparing a drug or vaccine for modulating the immune system.
[10]
10. Use of an immunogenic composition as defined in any of claims 1 to 8 characterized by the fact that it is for the preparation of a medicine for:
(a) induce cell regeneration, tissue regeneration, organ regeneration and regeneration of organic systems, such as the circulatory system, nervous system and endocrine system in an animal; or
(b) restoring the immune response in an animal, in which the use comprises the following steps:
i) to administer systemically and / or locally to the animal a therapeutically effective amount of one or more immunogenic compositions as defined in any one of claims 1 to 8;
ii) ensuring contact of one or more immunogenic compositions, applied in step "ili with the animal's dendritic cells or other APC cells;
iii) optionally, administer the prosthetic agents, such as vitamins in the place or region where the disease to be treated occurs, in order to strengthen the metabolism and, consequently, the animal's immune system,
and iv) optionally, administer other specific medications or treatments;
or,
(c) to prevent or treat infectious diseases,
autoimmune diseases, allergic diseases, inflammations,
arthritis, inflammatory diseases, transplant rejection,
diseases caused by vascular disorders, diseases caused by hemorrhagic or ischemic cardiovascular accidents, ischemia, myocardial infarction and hemorrhage that leads to tissue destruction, heart, kidney, respiratory or liver failure, cancer, tumors and malignant and benign neoplasms in an animal .
[11]
11. Use, according to claim 1 / characterized by the fact that: (i) diseases or conditions may be systemic and localized lupus erythematosus, rheumatoid arthritis, polyarteritis nodosa, poliomyositis, and progressive dermatomyositis, systemic progressive sclerosis, diffuse scleroderma , glomerulonephritis, myasthenia gravis, Sjogren's syndrome, Hashimoto's disease, Graves' disease, hypoparathyroidism adrenaline, pernicious anemia, diabetes, multiple sclerosis, demyelinating diseases, uveitis, pemphigus, pemphigoid cirrhosis, ulcerative colitis, myocardial syndrome, enteritis respiratory distress in adults, local manifestations of drug reactions, atopic dermatitis, childhood eczema, contact dermatitis, psoriasis, lichen planus, allergic enteropathies, bronchial asthma, transplant rejection, post-streptococcal diseases with cardiac, renal and joint manifestations of fever rheumatic and other related manifestations, various and multiple forms of cancer, such as carcinomas, adenocarcinomas, melanomas, sarcomas, malignant astrocytomas, hepatomas, hypernefromas, lymphomas and melanomas, among others; or (ii) infectious diseases can be of viral, bacterial, fungal or parasitic origin, optionally, in which: (a) viral diseases are caused by the following viruses: HIV, hepatitis virus, herpes virus, rhabdovirus, rubella, smallpox virus, poxvirus, paramyxovirus, and morbillivirus; or, (b) diseases of bacterial origin are caused by the following bacteria: Pneumococcus, Staphylococcus, Bacillus, Streptococcus, Meningococcus, Gonococcus, Escherichia, Klebsiella, Proteus, Pseudomonas, Salmonella, Shigella, Haemophilus, Yersinia, Listeria, Vibrio Clostridium, Chlamydia Mycobacterium, Helicobacter, and Treponema; or, (c) diseases of fungal origin are caused by the following fungi: Candida, Aspergillus, Cryptococcus neoformans and / or fungi that cause superficial and deep mycoses; (d) diseases of parasitic origin are caused by the following parasites: Trypanosoma, Schistosoma, Leishmania, amoebas and tapeworm.
12. Use according to either claim or 11, characterized in that the drug optionally comprises one or more cytokines and / or
11/11 chemokines.
13. Use according to claim 12, characterized by the fact that the drug optionally comprises GM-CSF, IL-2, IL4, IL5, IL 7, IL12, ILl 5, IL21 and / or gamma interferon, preferably IL2.
14. Use according to any of claims 10 to 13, characterized by the fact that it is associated with antibiotic therapy, chemotherapy, radiation therapy, therapy with antibodies and antisera, the use of hormones, cytokines, chemokines, neurohormones, peptides , antivirals, phytotherapics, vitamin supplementation, supplementation with other cofactors or prosthetic agents, cell or tissue transplants, therapeutic or prophylactic vaccination techniques, gene therapy, surgery and homeopathy.
15. Use according to any one of claims 10 to 14, characterized by the fact that the animal is a mammal.
,, 1/7 --- vehicle -.- Deca-o-Deca + IL2 M '9000 I
A -o E 7500
E 6000
E .3 4500 o ~ 3000 § 1500 o> o .......... *., ~.! ':.! L. •. ":., * P <0.05 t 7 10 13 16 19 22 25 Days after inoculation of cells. B16F10 · 28 Start of treatments -e-Vehicle - + - Deca -o- Deca + IL2 33500 28500 B 23500 o -o 18500 o 13500 e Q) E 8500 · u IJ) 3500 ~ ü -15o8 * p <0.05. ---, .t 7 10 13 16 19 Days after inoculation of cells 816F1 22 25 o 28 Start of treatments · Figure 1
· "". '""' -: "Vehicle ..., ... DECA..". ' : '- · DEÇA_. + IL02:.
~~ - ~ -rr ------, · ·· L.L ;:; · [. • - ~. . ~ ----: 1) th .. .. - · "$. 100] 80% · n1: E 60 -" . ~ ---- ~~ -i: ... .. 50% ~ ..5 40 • 33; 3% · O (/) 20 * p <o · .os o - O. 3 6 · 9 12 · 15 18. : 21: 24 2nd ° 30 Days _after · cell inoculation. "816F1 O Figure 2.
,,
3/7
"··· e ... ::. ~, ·
J: 5 ... r -----
Figure 3
. ••. 1,: '.. f • • I. ~! . ,, .., ~ - / .. • "- •.; ..>.,:. •. •:, '.'. ' . •.. •• ..,.:. ••• •. • '. ·.' · •. 1 "~, .6, ·. •• ~:. ~ · .. .. ·. •, ~ j - ~ •••• •. ; :: -. · ·.
. ~ -t, '<·'. ·. ::. -! . • "'' •. ·. •. '. · ~ ~ ....". ': J. , ; · · '- ~ ...: .. - ...:,. O -::-:....... .. '. .- - ... ·· .. · ~ ·. ·· .. ·· '· · ..; ,,'.,., '•. r O ,. . . . . ~., .. •,. • '.. •. • ··: •. , •. . - <.. •. , .. · .-:, "..:.:. ~" '°'! .: ... · t ;. . ,. •. . ·; ~~ i ~ r -. ,, • ..._. . .. • • r. - · -; ~: - ... • •. ! • ••• '·., · .. •' ". · ' E _J Figure 4
Figure · S
• • '1 •• 6/7 · - ~ - ~ · - ~ · - ~ - · ~ •••••. - · ~ <. í •. .
11.
'· O ~ - l, r ·' -.... . r-. ·. .
Figure 6
(· 'F'
.. 7/7
0.16 PSA levels of: patient O - S pre, not valid and 0.15. · .. post-immunotherapy treatment: - ::. . .. 0, -14
O. '1i ·
0.1 ·
. 0.08
0.06
0.04
0.02 o · ·. : o o o 'o 1. •. • •••. ·. •:• ... , 1 . • · 1., 3/1/10 5/1/10 7/1/10. 9/1/10 11/1/10 1/1/11 3/1/11. 5/1/11 7/1/11 9/1/11 1/1 / Ú
·. -: Figu ~ a, 7
-W "~~ -."
L $ Summary of the Invention Patent for: "IMMUNOGENIC COMPOSITION FOR MODULATION OF THE IMMUNE SYSTEM AND ITS USE, METHOD OF TREATING AND PREVENTING DISEASES, METHOD FOR INDUCING
CELL REGENERATION AND METHOD FOR RECONDUCTION OF RESPONSE 5 IMMUNE ".
The present invention relates to immunogenic compositions for modulating the immune system which comprise a therapeutically effective amount of two
W ¢ or more immunoactive antigenic agents that have 10 pathogen-associated molecular patterns (PAMPS) and / or hazard-associated molecular patterns (DAMPS) and one or more of a physiologically acceptable vehicle, excipient, diluent or solvent. The immunogenic compositions of the present invention are used in the manufacture of 15 drugs for the prevention and / or treatment of and in the prevention and / or treatment of infectious diseases, autoimmune diseases, allergic diseases, inflammations, arthritis, inflammatory diseases, transplant rejection, diseases caused for vascular disorders, diseases caused by 20 hemorrhagic or ischemic cardiovascular accidents, ischemia, infarction and hemorrhages that lead to tissue destruction, heart, kidney, respiratory or liver failure, cancer, tumors and malignant and benign neoplasms.
The present invention also relates to methods for inducing
¢ k 2 cell regeneration, tissue regeneration, organ regeneration and regeneration of organic systems, such as the circulatory system, the nervous system and the endocrine system. Finally, the present invention relates to 5 methods for renewing the immune response in an animal, particularly humans.
Q
P y.

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法律状态:
2020-11-24| B06F| Objections, documents and/or translations needed after an examination request according [chapter 6.6 patent gazette]|

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BRPI1100857-1A|BRPI1100857A2|2011-03-18|2011-03-18|immunomodulatory agent and combinations thereof, their use and immunotherapeutic method for real time recontextualization, reprogramming and rebuilding of the immune system|

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