WO2008011884A1 - Nouvel immunomodulateur - Google Patents

Nouvel immunomodulateur Download PDF

Info

Publication number
WO2008011884A1
WO2008011884A1 PCT/EC2006/000006 EC2006000006W WO2008011884A1 WO 2008011884 A1 WO2008011884 A1 WO 2008011884A1 EC 2006000006 W EC2006000006 W EC 2006000006W WO 2008011884 A1 WO2008011884 A1 WO 2008011884A1
Authority
WO
WIPO (PCT)
Prior art keywords
million
immunomodulator
strains
phenol
streptococus
Prior art date
Application number
PCT/EC2006/000006
Other languages
English (en)
Spanish (es)
Other versions
WO2008011884A8 (fr
Inventor
Angel Dr. Ramirez Castro
Original Assignee
Ramirez Castro Angel Dr
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ramirez Castro Angel Dr filed Critical Ramirez Castro Angel Dr
Priority to PCT/EC2006/000006 priority Critical patent/WO2008011884A1/fr
Publication of WO2008011884A1 publication Critical patent/WO2008011884A1/fr
Publication of WO2008011884A8 publication Critical patent/WO2008011884A8/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/74—Bacteria
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators

Definitions

  • the present invention is related to a new immunomodulator derived from inactivated bacteria that serves to induce an immune response in diseases related to the lack of cellular immune response and specifically related to T lymphocytes.
  • the present invention entails technical advantages in relation to products of similar constitution, for example, it is a biological product composed of the characteristic mixture of 7 pure strains of bacteria, genetically classified by the ATCC of the United States of America, unlike previous products composed of 10 strains of inactive bacteria, which, since they are not genetically classified, are nonspecific, an aspect that is overcome by this invention by having specific strains each with its code acquired from the ATCC.
  • the proposed invention is not limited to the treatment of chronic bronchitis, its complications and bronchial asthma of bacterial origin, but is indicated for the treatment of chronic infectious and inflammatory diseases related to cellular immunology failures.
  • CMH Major Histocompatibility Complex
  • TH 1 or TH2 type of lymphocyte line it uses
  • this invention activates the antigen presenting cells and through them the T 1 lymphocyte line is not only effective against bacterial infectious diseases but also against viruses (HIV), intracellular parasites (Toxoplasmosis gondii), fungi, tumors and abnormal immune reactions (chronic inflammation).
  • viruses HIV
  • Toxoplasmosis gondii intracellular parasites
  • fungi tumors and abnormal immune reactions (chronic inflammation).
  • both the DNA (gene), as well as the proteins and membrane residues of a mixture of bacteria of the Mycobacterium, Rhidococcus, Corynebacterium, Listeria, or E. coli species promote response immune system where the apoptosis (programmed cell death) of the malignant cells or the destruction of molecules that promote the progression of the disease with inflammation and / or chronic infections occurs.
  • the total inactivation of the bacteria genes used tells us that it is the membrane proteins that act as the initial stimulus and these are favorably selected by the Major Histocompatibility Complex.
  • Atherosclerosis is a chronic inflammatory disease of the endothelium that leads to its destruction, but as indicated in WO / 2006/048628, the administration of enteric bacteria such as Lactobacillus Spp, Bifidobacteria Spp.Streptococcus, and E. coli can counteract the disease.
  • enteric bacteria such as Lactobacillus Spp, Bifidobacteria Spp.Streptococcus, and E. coli can counteract the disease.
  • the present invention is distinguished by being a macromolecule constituted by other bacterial strains, its administration is subcutaneously (safer) and not only inflammation of the vascular endothelium but also epithelial tissue cells.
  • Bacterial proteins alone or fused can be injected subcutaneously and constitute a specific immune antigen, which is what WO / 2006/007366 refers to where a bacterial exotoxin protein treats, prevents or inhibits the action of an enterotoxigenic E. coli infection .
  • the proposed invention is not really a vaccine because it does not form immunoglobulins, therefore it is not useful for disease prevention, but it is a heterologous immunomodulator that is used for the treatment of chronic infectious and inflammatory diseases including certain tumor diseases.
  • bacterial polysaccharide antigens an immune response related to T cells that recover patients infected by bacteria (Streptoccocus, Meningococcus, Pneumococcus, H. influenzae) or by virus (Poliovirus, Encephalomyocarditis, Influenza) is induced.
  • bacteria Streptoccocus, Meningococcus, Pneumococcus, H. influenzae
  • virus Polyovirus, Encephalomyocarditis, Influenza
  • the present formula not only uses bacterial polysaccharides as antigens, but also the complete and intact membrane of 7 bacterial strains.
  • the mixture of inactivated bacteria constitutes a potent antigen that slows or stimulates the immune system becoming a potent immunomodulator as mentioned in WO / 2004/096270.
  • the clinical indications also depend on the bacterial strains that are used.
  • the present application is differentiated by the method of inactivation of bacteria (via phenol to
  • Antigen presenting cells are inflammatory cells that will initially be neutrophils and subsequently macrophages, dendritic cells and lymphocytes. The conglomeration of these cells constitutes an inflammatory focus, which must resolve the immune system and does so through the major histocompatibility complex that the antigen presenting cells possess, which pass the identity (the epitope) to the lymphocyte receptors T, until reaching the suppressor T cell, modulator or TH3, who will give the final warning of having finished the inflammatory process, which means that acute inflammation is an effective immune defense mechanism.
  • the acute inflammatory process has a beginning and an end; on the other hand, the chronic inflammatory process as its name indicates active indefinitely for both chronic inflammation is an immune failure and an aggression.
  • anti-inflammatory drugs is frequent continuously and often accompanied by antibiotics, antiviral, antifungal, antiparasitic, antiallergic or antitumor agents, as the case may be, which do not always have the desired effect, due to the resistance of germs to these medications.
  • the present invention overcomes these limitations based on the repetitive stimulation of the immune system until it becomes competent against germs.
  • the immunomodulator consists of the mixture of seven pure bacterial strains, genetically characterized, grown and harvested under known techniques, measuring the optical density in a spectrophotometer calibrated to 600 nrm, washing them in double-distilled and autoclaved water three times to remove contaminants.
  • the inactivation process is done using 4% phenol, which will cause the inactivation of the genes but keeping the surface molecules intact, after removing the 4% phenol, the amounts in millions per milliliter of each bacterial strain are calculated , which is then mixed and resuspended in 0.20% phenol that would have the characteristic of being a preservative.
  • the result of this solution gives a concentration per milliliter of 50 million streptococus pneumoniae; 40 million streptococus pyogenes: 500 million Stafilococus aureus; 40 million Haemophilus influenzae; 250 million Pseudomona aeruginosa; 40 million Klebsiella pneumoniae and 80 million Micrococus species.
  • Conservative agent max. 0.25 of phenol and finally the measurement of the optical density that should be around 0.600 nm is made.
  • the compound is originated in a mixture of inactivated bacteria (between Gram. Positive and Gram. Negative), which are equivalent to being “anesthetized”, but integral, that when injected subcutaneously are captured by antigen presenting cells (CPA) of the skin (macrophages, Langerhans cells, dendritic cells, B lymphocytes) which trap them and remove the identity through the Major Histocompatibility Complex (CMH) to present to the T h lymphocyte receptor (helper), the same that produces cytokines (IL-2, FNT alpha and gamma INF) that activate the proliferation and specialized response of Th1 lymphocytes are TCD4 and / or TCD8 (also through cytokines) so that they specifically and definitively act against the infecting antigens.
  • CPA antigen presenting cells
  • CMH Major Histocompatibility Complex
  • helper T h lymphocyte receptor
  • TCD4 and / or TCD8 also through cytokines
  • the product of this mixture was subjected to multiple cultures (in vivo tests) and the bacteria did not develop until 15 days, which indicates the effective inactivation of the bacteria and the null possibility of their pathogenicity.
  • the local response at the immunomodulator inoculation site was the same as the therapeutic dose was injected, than the 1,200 times higher concentration. Injected this product subcutaneously should normally produce an erythematous area that begins its appearance the day after inoculation and lasts approximately 48 hours. This kind of answer discovered Robert Koch in 1895 calling it "infection allergy" and that is what is now known as a delayed type IV or simply cellular delayed hypersensitivity immune response.
  • First to fifth dose 0.1 / 0.3 / 0.5 / 0.7 / 0.9 / mi, after a week of rest it is injected 5 times 1 mi. Both initial and booster doses should be applied every four days.
  • the immunological explanation is the following: it is known that an antigen of more than 600,000 daltons of molecular weight (macromolecule) when injected subcutaneously takes time to dissolve and therefore the cells of the immune system have enough time to process the antigen and remove the epitopes or epitopes that represent the macromolecule; This is what antigen presenting cells do through the Major Histocompatibility Complex.
  • This information is transferred to the T lymphocyte receptors at the level of the lymph nodes so that through Interleukin-1, Tumor Necrosis Factor-alpha and Interferon range reach TH1 lymphocytes, who upon receiving the stimulus proliferate and activate their genes to give a specific response against the infecting microorganism.
  • this signal may reach the suppressor, modulator or TH3 T lymphocyte that is responsible for terminating the chronic inflammation after eliminating the infection (see Figure 1a and 1b).
  • Fig. 1st After trauma, inflammatory cells accumulate consisting of macrophages, T lymphocytes and B lymphocytes.
  • Fig. 1.b The cellular detritus or microorganisms are captured by the Antigen Presenting Cell (CPA) and processed by means of the Major Histocompatibility Complex and presented to the Th lymphocyte (LTh), which produces lnterleukin-2 (IL- 2), Tumor Necrosis Factor- ⁇ (FTN- ⁇ ) and Interferon- ⁇ (INF-Y) so that Th 1 or CD4 Lymphocytes proliferate and specialize, which will send stimuli to Th3 Lymphocyte (LTh3), suppressor or moderator that through lnterleukin-10 (IL-10) and lnterleukin-12 (IL-12) will send the signal of completion of the inflammatory process by blocking IL-2, FNT- ⁇ and INF- ⁇
  • Fig. 2 After injecting into the skin a dose of inactivated bacteria, these are captured, processed and identified by the Major Histocompatibility Complex of the Antigen Presenting Cell (CPA), which will identify the epitopes and pass the signal through cytokines to the helper or helper (LTh), which will express the lnterleukin-2 cytokines (IL-2), Tumor Necrosis Factor - ⁇ (FNT- ⁇ ) and Interferon
  • CCA Antigen Presenting Cell
  • LTh helper or helper
  • IL-2 lnterleukin-2 cytokines
  • FNT- ⁇ Tumor Necrosis Factor - ⁇
  • IL-2 induces the proliferation and specialization of ThL lymphocytes
  • IL-2 also activates anti-HIV immune response genes that are expressed through the production of anti-HIV protein that upon entering Ia circulation will reach the shock organs to control HIV virulence; therefore, the TCD4 lymphocyte index rises with a tendency to normality and HIV virulence is canceled.

Landscapes

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

Abstract

L'invention concerne un immunomodulateur composé de sept espèces de bactéries entières désactivées et conservées dans du phénol. Lesdites espèces sont: Streptococcus pneumoniae, Streptococcus pyogenes, Staphycoccus aureus, Haemophilus influenza, Pseudomonas aeruginosa, Klebsiella pneumoniae et Micrococcus spp. L'immunomodulateur est utilisé dans le traitement de maladies chroniques associées à des immunodéficiences ou une immunodépression de la lignée cellulaire.
PCT/EC2006/000006 2006-07-27 2006-07-27 Nouvel immunomodulateur WO2008011884A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EC2006/000006 WO2008011884A1 (fr) 2006-07-27 2006-07-27 Nouvel immunomodulateur

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EC2006/000006 WO2008011884A1 (fr) 2006-07-27 2006-07-27 Nouvel immunomodulateur

Publications (2)

Publication Number Publication Date
WO2008011884A1 true WO2008011884A1 (fr) 2008-01-31
WO2008011884A8 WO2008011884A8 (fr) 2008-03-13

Family

ID=38981157

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EC2006/000006 WO2008011884A1 (fr) 2006-07-27 2006-07-27 Nouvel immunomodulateur

Country Status (1)

Country Link
WO (1) WO2008011884A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016176380A1 (fr) * 2015-04-28 2016-11-03 The Procter & Gamble Company Compositions comprenant des micrococcus non viables entiers pour améliorer la santé de la peau

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2179067T3 (es) * 1993-03-31 2003-01-16 Fernand Torossian Complejo inmunomodulador anti-sida.
WO2004096270A1 (fr) * 2003-04-30 2004-11-11 Medi Service S.R.L. Composition immunomodulatrice contenant une fraction de particules de lysats mecaniques bacteriens
WO2005120560A1 (fr) * 2004-06-07 2005-12-22 Harold David Gunn Compositions bacteriennes pour le traitement d'un cancer

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2179067T3 (es) * 1993-03-31 2003-01-16 Fernand Torossian Complejo inmunomodulador anti-sida.
WO2004096270A1 (fr) * 2003-04-30 2004-11-11 Medi Service S.R.L. Composition immunomodulatrice contenant une fraction de particules de lysats mecaniques bacteriens
WO2005120560A1 (fr) * 2004-06-07 2005-12-22 Harold David Gunn Compositions bacteriennes pour le traitement d'un cancer

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
"BIOL", VACUNA ANTIPIOGENA POLIVALENTE, Retrieved from the Internet <URL:http://www.e-bio.com.ar/prodvacunaantipiogena.htm> *
"Vacuna broncopulmonar", VACUNAS LIOFILIZADAS CASASCO, Retrieved from the Internet <URL:http://www.casasco.com/info_amp/vac_bronc_amp.htm> *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016176380A1 (fr) * 2015-04-28 2016-11-03 The Procter & Gamble Company Compositions comprenant des micrococcus non viables entiers pour améliorer la santé de la peau
US9913800B2 (en) 2015-04-28 2018-03-13 The Procter & Gamble Company Compositions and methods for improving skin health

Also Published As

Publication number Publication date
WO2008011884A8 (fr) 2008-03-13

Similar Documents

Publication Publication Date Title
Jabbal-Gill et al. Chitosan-based delivery systems for mucosal vaccines
Nanjappa et al. Vaccine immunity against fungal infections
US20080014281A1 (en) Chitin Micro-Particles As An Adjuvant
KR101312308B1 (ko) 폴리이노신산-폴리시티딜산 기초 보조제를 포함하는 점막면역원성 물질
Kitiyodom et al. The potential of mucoadhesive polymer in enhancing efficacy of direct immersion vaccination against Flavobacterium columnare infection in tilapia
ES2352780B2 (es) Lipopolisacárido de ochrobactrum intermedium contra la sepsis.
Petrunov et al. The role of immunostimulants in immunotherapy and immunoprophylaxis
CN1674935B (zh) 含有CpG或寡/多核苷酸以及毒素或肠毒素的双功能组合物
US8709448B2 (en) Anti-infective agents and uses thereof
CN103096923A (zh) 新型免疫佐剂化合物及其用途
Sahu et al. Encapsulation of recombinant MOMP in extended-releasing PLGA 85: 15 nanoparticles confer protective immunity against a Chlamydia muridarum genital challenge and re-challenge
Patil et al. Alpha-D-glucan-based vaccine adjuvants: Current status and future perspectives
WO2008011884A1 (fr) Nouvel immunomodulateur
US9056094B2 (en) Adjuvant
RU2011120168A (ru) Вакцина mycobacterium tuberculosis
Hunter et al. The role of IL12 in toxoplasmosis
Kim et al. Vaccination of rock bream, Oplegnathus fasciatus (Temminck & Schlegel), using a recombinant major capsid protein of fish iridovirus.
Tahamtan et al. An overview of different types of immune stimulating adjuvants and their application
Reza Efficacy Of A Liposomal Aspergillus Protein Vaccine Containing Different Immunomodulatory Adjuvants To Prevent Pulmonary Aspergillosis In Mice And Chickens
RU2796973C2 (ru) Интраназальная вакцина, индуцирующая клеточно-опосредованный иммунитет
US20240148864A1 (en) Polysaccharide adjuvants for virus vaccines
CN101347616A (zh) 一种新型安全的jy免疫佐剂系统的组方及其应用
Latifynia et al. Measurement of Serum Levels of Interleukin 17 and 23 in the Immune System with Different Amounts of Spleens White Pulp Size after Inoculation of New Leishmania Vaccine in Susceptible Mice
Smith et al. Group B meningococcal outer membrane protein vaccine promote potent anti-viral effect
Davis Immunomodulators

Legal Events

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

Ref document number: 06761884

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

NENP Non-entry into the national phase

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 06761884

Country of ref document: EP

Kind code of ref document: A1