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WO2008104133A1 - Thérapie combinée pour le traitement de l'hépatite b chronique - Google Patents

Thérapie combinée pour le traitement de l'hépatite b chronique Download PDF

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Publication number
WO2008104133A1
WO2008104133A1 PCT/CU2008/000001 CU2008000001W WO2008104133A1 WO 2008104133 A1 WO2008104133 A1 WO 2008104133A1 CU 2008000001 W CU2008000001 W CU 2008000001W WO 2008104133 A1 WO2008104133 A1 WO 2008104133A1
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Prior art keywords
treatment
antiviral
hbv
protein
patients
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Ceased
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PCT/CU2008/000001
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English (en)
Spanish (es)
Inventor
Julio César AGUILAR RUBIDO
Eduardo PENTÓN ARIAS
Verena Lucila MUZIO GONZÁLEZ
Gerardo Enrique GUILLÉN NIETO
Sonia Gonzalez Blanco
Raimundo UBIETA GÓMEZ
Luis Saturnino Herrera Martinez
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Centro de Ingenieria Genetica y Biotecnologia CIGB
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Centro de Ingenieria Genetica y Biotecnologia CIGB
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Publication of WO2008104133A1 publication Critical patent/WO2008104133A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A61K39/29—Hepatitis virus
    • A61K39/292—Serum hepatitis virus, hepatitis B virus, e.g. Australia antigen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/162—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/39—Medicinal preparations containing antigens or antibodies characterised by the immunostimulating additives, e.g. chemical adjuvants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2730/00—Reverse transcribing DNA viruses
    • C12N2730/00011—Details
    • C12N2730/10011—Hepadnaviridae
    • C12N2730/10111—Orthohepadnavirus, e.g. hepatitis B virus
    • C12N2730/10134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention is related to the field of biotechnology and the pharmaceutical industry, in particular to the field of treatments against chronic diseases, specifically against the chronic infection caused by the Hepatitis B Virus (HBV).
  • HBV Hepatitis B Virus
  • the World Health Organization (WHO) 1 places HBV infection among the top 10 causes of death in the world.
  • WHO World Health Organization
  • CH liver cirrhosis
  • CHC hepatocellular carcinoma
  • HBC chronic Hepatitis B
  • HBV can cause both acute infection and chronic infection. The evolution of this disease depends on the virus-host interaction and in particular on the maturity of the host's immune system.
  • Acute infection occurs in a self-limited manner, the virus is eliminated from the blood and liver and lasting immunity develops.
  • This immunity is characterized by the presence of antibodies against the surface antigen of Hepatitis B (HBsAg) 1 although some patients who recover never develop antibodies against this antigen, or subsequently produce them. These patients generally do not require medical intervention (Lok AS. Hepatology 2004; 39 (3): 857-861).
  • HBV infection requires the detection of serum HBsAg on 2 occasions with an interval of 6 months or more.
  • serum HBsAg serum HBsAg
  • the sustained presence of the virus and its interaction with the immune system leads to an increase in serum liver enzyme levels. These may be persistently or intermittently elevated and be associated with different degrees of alteration in liver histology (Fattovich et al. Semin Liver Dis 2003; 23 (1): 47-58).
  • Interferon (IFN) alpha has been used for the treatment of HBC for more than 15 years.
  • pegylated IFN has been approved, which has superior characteristics.
  • a product line based on the inhibition of the enzyme deoxyribonucleic acid (DNA) - viral polymerase has been developed. They are Lamivudine, Adefovir Dipivoxil, Entecavir and Telbivudine. Many other antivirals are in development, so far these four have been approved by regulatory entities worldwide.
  • the non-pegylated IFN has some limitations, including its adverse effects, which decrease the permanence of the patients in treatment; its lower efficacy in patients with high viral load and the increase in transaminase levels in a percentage of those treated, which leads to complications in patients with low transaminase levels since it is not recommended in cirrhotic patients (Hoofnagle JH, et al .N Engl J Med. 1997; 336: 347-356).
  • Pegylated IFN is a conjugate of IFN alpha 2a and polyethylene glycol. This new molecule has a longer half-life in blood and is administered once a week, conferring greater efficacy and a better safety profile (Marcellin P. et al. N Eng J Med. 2004; 351: 1206-1217).
  • its low efficacy approximately 30%
  • the high price of this treatment approximately USD16,000
  • Lamivudine was the first nucleus analogue (t) approved for use in the treatment of HBC. Subsequently, Adefovir Dipivoxil, Entecavir and, very recently, Telbivudine have been approved. These antivirals are from the family of nucleus analogs (t) gone. They produce a strong reduction in viral load, associated with a high percentage of normalization of transaminases, as well as improvement in histological parameters. The fundamental problem of antivirals consists in the relative ease with which escape mutants appear and the need for prolonged treatment for several years, given the high rate of viral relapse.
  • Entecavir which has shown in its strong capacity to control its distinctive viral load, produces very few mutants, however this antiviral is less effective in patients refractory to Lamivudine (Colonno R, et al. AASLD 2005. Abstract 962) .
  • this drug like the rest of the antiviral drugs, is not able to keep the viral load controlled in a sustained way when administered for a period of 6 months.
  • Antiviral treatments are currently evolving into combined therapeutic strategies, which constitute exclusive alternatives of developed countries and whose primary objective is to suppress viral load to the maximum, reducing the possibility of occurrence of viral mutants and viral relapses (Peters M, et al. Gastroenterology 2004; 126: 91-101).
  • the main problem of the immunotherapeutic strategy is that during the chronic HBV infection it has been possible to verify a poor or non-existent response of effector T and B cells, as well as functional deficiencies of the professional presenting cell subgroups.
  • patients who develop acute infection show a strong, polyclonal and multispecific cytotoxic and helper response against envelope, nucleocapsid and polymerase proteins (Webster GJ, et al. J Virol 2004; 78: 5707-5719).
  • the levels of Th 1 type cytokines secreted by peripheral blood lymphocytes stimulated with the different viral antigens is very poor, which does not occur during the acute infection (Penna A, et al. Hepatology 1997; 25: 1022-1027).
  • An aspect that supports the feasibility of developing a therapeutic vaccine is the fact that those patients who recover spontaneously from HBC (10-15% of the total), or those who respond to treatment with IFN alpha, are able to develop responses cytotoxic agents of similar intensity to that found in patients who develop acute infection (Rehermann B, et al. J Clin Invest 1996; 97: 1655-1665). Additionally, an increase in the levels of CD4 and CD8 + cellular response was demonstrated in patients treated with Lamivudine, suggesting that it is possible to induce an immune response in these patients (Boni C, et al. Hepatology 2001; 33: 963-971; Boni C , et al. J Hepatol 2003; 39: 595-605).
  • GenHevac B did not favor the immune response against the vaccine antigen in those patients who did not respond to a first vaccine treatment (Couillin I, et al. J Infect Dis 1999; 180: 15-26) .
  • the children were infected pe r nata I mind and their viral load was at very high levels, as in this type of patients in the immunotolerance phase (Dikici B 1 ⁇ al. Pediatr Infect Dis J. 2003; 22: 345-349).
  • the vaccine was administered orally, three times a week, for 5-6 months.
  • the viral load decreased significantly in 36% of patients, associated with seroconversion to anti-HBeAg in 26% of patients. Most of them showed histological improvement.
  • NK cells were increased in the patients studied (Godfrey Dl 1 et al. Immunol Today 2000; 21: 573-83; Safadi R 1 et al. Am J Gastroenterol 2003; 98: 2505-2515).
  • This vaccine was evaluated in combination with Lamivudine antiviral treatment in 15 patients. As a control group, 57 patients received Lamivudine alone.
  • the scientific community recognizes that the goal of the treatment of HBC is the appearance of anti-HBsAg antibody levels as the culmination of a process that is initiated by virological control, followed by the reduction or normalization of transaminases, the decrease or normalization of the levels of inflammation and fibrosis in the liver and the HBeAg / anti-HBeAg seroconversion in patients positive to said antigen.
  • the frequency of appearance of "protective" titles of anti-HBsAg antibodies is so low (usually less than 3% with the best treatments) and frequently so outdated in time (several months after the viral load is normalized ) that it is impossible for medical practice to use this marker as a success variable in current treatments. Therefore, this goal, although unexpected, is the best scenario in the treatment of chronic infection with Hepatitis B Virus.
  • a quarter aspect which is to achieve the appearance of anti-HBsAg antibody response levels in a time less than 6 months, - period of time for which there is no therapy currently capable of achieving it - would concentrate the antiviral treatment at the time in which the risk-benefit balance is completely displaced in the sense of benefit, preventing the treatment from inducing a proportion of cases of mutants that not only have a reported natural history similar to the wild virus, but also implies the decrease of the possibilities future therapies (it is known that patients with mutants to lamivudine are reduced their ability to benefit from treatment with Entecavir).
  • a fifth aspect is, therefore, the ability of the new treatment to increase the slope of viral disappearance and the percentage of patients who manage to reduce the viral load in undetectable levels in the first 12 and 24 weeks of the study, this aspect is known with certainty which will prevent the emergence of mutants in the future.
  • This invention solves the aforementioned problems, through the use of an immunopreparate of proteoliposomal nature comprising the "S" protein of HBV obtained by immunoaffinity for the preparation of a pharmaceutical composition for the treatment of patients with HBC, by a method consisting in the administration of the immunopreparate comprising the "S" protein in association with an effective amount of an antiviral with inhibitory activity of HBV replication, characterized in that the antiviral treatment is performed in a time equal to or less than 6 months.
  • the treatment of patients with the therapeutic strategy described, of administration of the immunopreparation comprising the "S" protein in association with different antiviral drugs results in higher levels of efficacy than those obtained with conventional treatments.
  • used as control of the study in terms of a clinically significant therapeutic response, characterized by a decrease in viral load below 10,000 copies per mL of serum, normalization of transaminases and improvement in histological damage rates.
  • the effectiveness of the new treatment object of the present invention is inextricably associated with the unique characteristics of the immunopreparate of proteoliposomal nature comprising the "S" protein of HBV obtained by immunoaffinity, in terms of its ability to subvert the tolerance of B-cells specific for HBsAg 1 and produce an antibody response that is associated with the reduction of the viral load and the therapeutic activity of this product, which is reflected in the normalization of the transaminases and the improvement in the liver histology of the patients. Additionally, no escape mutants are produced, an aspect that was significantly higher in the case of patients who received antiviral treatment only.
  • an antiviral with inhibitory activity of HBV replication for the preparation of a pharmaceutical composition for the treatment of patients with HBC, by a method consisting of the administration of an effective amount of the antiviral in association with an immunopreparate of proteoliposomal nature comprising the "S" protein of HBV obtained by immunoaffinity, characterized in that the antiviral treatment is performed in a time equal to or less than 6 months.
  • This treatment results in the strengthening of the immunological properties of the immunopreparate, according to the results of the clinical experience.
  • Another aspect of the invention is the use of the immunopreparation of a proteoliposomal nature comprising the "S" protein of the HBV envelope obtained by immunoaffinity and an antiviral with inhibitory activity of the HBV replication for the preparation of a pharmaceutical composition for the treatment of patients with HBC, by means of a method that consists of the administration of the immunopreparation comprising the "S" protein in association with an effective amount.
  • an antiviral with HBV replication inhibitory activity characterized in that both products are administered in association with patients with HBC to induce a therapeutic response at a time equal to or less than 6 months of antiviral treatment.
  • compositions of the present invention comprising the immunopreparate based on the "S" protein of the HBV envelope, obtained by immunoaffinity, and an antiviral with inhibitory activity of HBV replication, induces a therapeutic response in a time equal to or less than 6 months of antiviral treatment characterized by an increase in antibody levels against HBV surface antigen.
  • the immunopreparation comprising the "S" protein of the HBV envelope is characterized in that the proteoliposome is purified and selected by immunoaffinity.
  • the "S" protein of the HBV envelope is an immunopreparate of proteoliposomal nature between 20 nm and 200 nm in diameter.
  • the proteoliposomal immunopreparation comprising the "S" protein of the HBV envelope is administered intramuscularly.
  • Other equally effective routes of administration are subcutaneous, intradermal, intranasal and oral. Variations, such as those related to the routes of administration and the amount of the active pharmaceutical ingredients present in both compositions, are widely known to persons versed in this branch of the technique.
  • the protein "S" of the wrapping HBV obtained as recombinant protein which forms particles between 20 nm and 200 nm in diameter, may be associated with homologous antigens or heterologous possess activity 'antigenic or adjuvant.
  • homologous antigens that can be associated with the "S" protein of the HBV envelope are the nucleocapsid antigen and the proteins encoded by the pre-S regions of said virus.
  • the heterologous antigens that can be associated with the "S" protein of the HBV envelope are antigens of other pathogens included in the group of chronic viral infections, such as the human immunodeficiency virus (in English "Human Immunodeficiency Virus” , abbreviated HIV), Hepatitis C virus (HCV), human papillomavirus, among others.
  • the antiviral belongs to the group of viral polymerase inhibitors used for the treatment of HBC, among which are Lamivudine, Adefovir, Entecavir and Telbivudine.
  • effective amount of the antiviral is understood as a dose ranging from 0.5 to 500 mg of antiviral per day, according to the antiviral used.
  • the immunopreparation comprising the "S" protein of the HBV envelope, obtained by immunoaffinity, together with a non-nucleoside compound with reducing activity of the HBV replication for the generation of a therapeutic response against the HBC.
  • Another object of the present invention is a method to increase the levels of antibodies in HBC 1 patients by administering a proteoliposomal immunopreparate comprising the "S" protein of the HBV envelope, obtained by immunoaffinity, in association with an antiviral belonging to the group of viral polymerase inhibitors used for the treatment of HBC in a period equal to or less than 6 months of antiviral treatment.
  • IP immunopreparation
  • the dose and frequency of administration of each drug is reflected in Table 2. There were no significant differences between the groups regarding the proportion of patients of the different races.
  • Table 2 Main characteristics of the study and aspects related to the age, sex and race of the subjects involved in the study for each treatment group.
  • aB / N / M Percentage of patients of the white, black and mestizo race.
  • IPA and IPB immunopreparations
  • the IPA immunopreparation was based only on the HBV S protein, purified by immunoaffinity
  • the IPB immunopreparation was based on the same S complexed protein in a proteoliposomal composition in conjunction with the HBV nucleocapsid antigen (C antigen).
  • C antigen HBV nucleocapsid antigen
  • Table 4 Main characteristics of the study, aspects related to the age, sex and race of the subjects involved in the study for each treatment group.

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  • Gastroenterology & Hepatology (AREA)
  • Communicable Diseases (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
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  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne l'utilisation d'une immunopréparation protéoliposomale faisant intervenir la protéine « S » du virus de l'hépatite B (VHB) obtenue par immuno-affinité en vue de la préparation d'une composition pharmaceutique pour le traitement de malades atteints de l'hépatite B chronique au moyen d'une méthode d'administration de l'immunopréparation en association avec une quantité efficace d'un antivirus enrayant la réplication du VHB, qui est caractérisé en ce que le traitement antiviral s'effectue en un temps égal ou inférieur à six mois. L'administration des deux médicaments associés se traduit par des niveaux d'efficacité supérieurs à ceux obtenus avec les traitements traditionnels en termes de réponse thérapeutique cliniquement significative, elle est caractérisée par une diminution de la charge virale en dessous des 10'000 copies par mL de sérum, par la normalisation des transaminases et améliorations des indices de dommages histologiques. En raison du temps nécessaire à l'administration des deux médicaments associés, on supprime l'apparition de mutants d'échappement aux antiviraux.
PCT/CU2008/000001 2007-02-28 2008-02-27 Thérapie combinée pour le traitement de l'hépatite b chronique Ceased WO2008104133A1 (fr)

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CU2007-0050 2007-02-28
CU20070050 2007-02-28

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WO2008104133A1 true WO2008104133A1 (fr) 2008-09-04

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011038701A1 (fr) * 2009-09-29 2011-04-07 Centro De Ingeniería Genética Y Biotecnología Formulation d'antigènes du virus de l'hépatite b utilisée pour la stimulation cellulaire suivie de l'immunisation thérapeutique

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CN1364644A (zh) * 2002-02-05 2002-08-21 北京多米诺医药研究所 免疫性脂质体治疗性乙肝疫苗及其制备方法

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CN1364644A (zh) * 2002-02-05 2002-08-21 北京多米诺医药研究所 免疫性脂质体治疗性乙肝疫苗及其制备方法

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011038701A1 (fr) * 2009-09-29 2011-04-07 Centro De Ingeniería Genética Y Biotecnología Formulation d'antigènes du virus de l'hépatite b utilisée pour la stimulation cellulaire suivie de l'immunisation thérapeutique
CN102665687A (zh) * 2009-09-29 2012-09-12 遗传工程与生物技术中心 用于细胞刺激随后进行治疗性免疫的乙肝病毒抗原制剂

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