WO1996007915A1 - Test predictif relatif a la resistance a l'hepatite b - Google Patents

Test predictif relatif a la resistance a l'hepatite b Download PDF

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Publication number
WO1996007915A1
WO1996007915A1 PCT/GB1995/002067 GB9502067W WO9607915A1 WO 1996007915 A1 WO1996007915 A1 WO 1996007915A1 GB 9502067 W GB9502067 W GB 9502067W WO 9607915 A1 WO9607915 A1 WO 9607915A1
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WO
WIPO (PCT)
Prior art keywords
hepatitis
hla
drb1
hbv
class
Prior art date
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PCT/GB1995/002067
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English (en)
Inventor
Adrian Vivian Sinton Hill
Mark Richard Thursz
Howard Christopher Thomas
Original Assignee
Imperial College Of Science, Technology & Medicine
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 Imperial College Of Science, Technology & Medicine filed Critical Imperial College Of Science, Technology & Medicine
Priority to JP8509285A priority Critical patent/JPH10505668A/ja
Priority to AU33933/95A priority patent/AU3393395A/en
Priority to EP95930612A priority patent/EP0778948A1/fr
Publication of WO1996007915A1 publication Critical patent/WO1996007915A1/fr
Priority to US09/754,290 priority patent/US20010005507A1/en

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Classifications

    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56966—Animal cells
    • G01N33/56977—HLA or MHC typing
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/576—Immunoassay; Biospecific binding assay; Materials therefor for hepatitis
    • G01N33/5761—Hepatitis B
    • 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
    • A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
    • A61K2039/515—Animal cells
    • A61K2039/5158—Antigen-pulsed cells, e.g. T-cells
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • 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
    • 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

Definitions

  • the present invention relates to a novel method of predicting resistance to Hepatitis B, peptides useful in modifying immune response to Hepatitis B, vaccines against Hepatitis B and methods of treating Hepatitis B.
  • HVB hepatitis B virus
  • Persistent HBV infection predisposes the host to chronic liver disease and hepatocellular carcinoma
  • HBV infection does not appear to be determined by variations in virulence of the virus, and the course of disease may be influenced by the host immune response. Although a proportion of patients with persistent infection have specific immunodeficiency states such as HIV (Krosgaard, K. et al , Hepatology, 7: 37-41, 1987) or agamma-globulinaemia (Hermaszewski, R. A. et al , Q. J. Med. , 86(1): 31-42, 1993), the majority are not otherwise immunocompromised. In West Africa, HBV is transmitted via a horizontal route with young children (under 10 years) acquiring the infection from older siblings or playmates (Marinier, E. et al , West Africa J.
  • HBV related hepatocellular 15 carcinoma is the leading cause of male mortality in adults of working age in The Gambia (Ryder et al, Am. J. Epidemiol . , supra; and Kiire, C. F., Vaccine, 8: 5107- 112, 1990) .
  • class I or class II molecules 25 specific class I or class II molecules.
  • CTL cytotoxic T lymphocytes
  • DRB1*1302 is associated with a reduced risk of cerebral malaria in Gambian children, which may relate to the high frequency of the DRB1*1302-DRB3*0301-DQA1*0102-DQB1*0501 and DRB1*1302-DRB3*0301-DQA1*0102-DQB1*0604 haplotypes in this population (Lepage, V. et al , supra) .
  • the combined haplotype frequency in North Europeans is 4.4% compared with 16.4% in The Gambia (Hill, A. et al , Nature, 352(6336), 595-600, 1991). Malaria and HBV are both important causes of premature mortality in West Africa.
  • HBV HBV related mortalities are common during working life. If recovery from HBV infection were also linked to DRB1*1302, in addition to malaria, HBV would confer a selective advantage on individuals carrying the DRB1*1302 haplotypes in The Gambia.
  • DRw6 which is the serological supertype of DRB1*1302 and DRB1*1301, was identified in two previous studies as potentially protective against persistent HBV infection. Van Hattum et al found DRw6 nearly twice as frequently in North European patients who cleared HBV than in those who failed to eliminate the virus (Van-Hattum, J. et al , supra) . In a study of factors influencing the response of chronic HBV infection to interferon therapy, we found that DRw6 is associated with a favourable response (Scully, L. et al , Hepatology, 12: 1111-17, 1990). However, both these studies were too small to reach statistical significance.
  • the present invention provides a method of identifying resistance to Hepatitis B infection which comprises the step of identifying the presence of HLA- DRB1*1302. Suitably identification is carried out on a sample of blood.
  • the invention provides a convenient method of predicting Hepatitis B resistance in any given individual and hence also allows for predictions to be made concerning the outcome of Hepatitis B infection in individual patients.
  • the method of the present invention further comprises the step of identifying the presence of HLA-DRB1*1301. Again, this is suitably carried out by analysing a blood sample.
  • HLA- DRB1*1302 and/or HLA-DRB1*1301 is/are associated with resistance to Hepatitis B
  • the present invention also provides one or more peptides capable of binding to HLA- DRB1*1302 and/or HLA-DRB1*1301.
  • Such peptides can be used to modify the ability of HLA-DRB1*1302 and/or HLA- DRB1*1301 to elicit an immune response.
  • Such an approach would be useful in immunisation against HBV infection, and in DRB1*1302 and *1301 individuals, who had become persistently infected, would facilitate recovery
  • binding of the one or more modified peptides will result in a reduced immune response. This is particularly advantageous in treating conditions such as fulminant Hepatitis B.
  • the present invention provides a peptide capable of modifying the ability of an HLA to elicit an immune response in response to a Hepatitis B antigen.
  • the peptide is one derived from a Hepatitis B antigen.
  • the peptide can consist only of a particular region known to bind to a particular HLA molecule.
  • a synthetic peptide could be constructed consisting of a binding region and other, non-binding regions.
  • the peptides can be administered in the form of a pharmaceutical formulation, eg. as an intravenous formulation.
  • a pharmaceutical formulation comprising one or more peptides capable of binding to HLA-DRB1*1302 and/or HLA-DRB1*1301, together with one or more pharmaceutically acceptable carriers and/or excipients.
  • the invention also provides a vaccine against Hepatitis B comprising one or more peptides capable of binding to HLA-DRB1*1302 and/or HLA-DRB1*1301.
  • the peptides of the invention also provide other methods of treating Hepatitis B.
  • antigen specific lymphocytes can be generated in vi tro using a peptide of the invention. These can then be administered to a patient suffering from Hepatitis B.
  • the present invention therefore also provides a composition comprising lymphocytes wherein the lymphocytes have been exposed to one or more peptides of the invention.
  • a method of treating Hepatitis B is also provided which comprises the step of administering such a composition to a subject.
  • lymphocytes will either be from the subject being treated or from another with a similar HLA type.
  • FIG T RE 1 shows Hepatitis B exposure and HBsAg carriage rise with age during childhood.
  • FIGURE 2 shows the frequencies of HLA class I serotypes for each group of children and adults.
  • FIGURE 3 shows the class II haplotypes for the children.
  • FIGURE 4 shows the class II haplotypes for the adults
  • FIGURE 5 shows the differential analysis of risk for individual DRB1*1302 Haplotypoes.
  • the subjects were all Gambians living in the area surrounding the capital, Banjul, which is in the western coastal region. Two different populations were recruited for the two stages of the study between 1988 and 1990. In the first stage, children up to 10 years were recruited at the Royal Victoria Hospital, Banjul, and the Medical Research Council Hospital, Fajara, where they had been seen for a variety of conditions unrelated to HBV. The adult population was recruited from healthy male blood donors. Both populations had previously been studied as part of a case-control study of susceptibility to malaria (Hill, A. et al , supra) .
  • Group C who had persistent HBV infection, were Anti-HBc positive and HBsAg positive.
  • Patients in Group C who had IgM antibodies to HBV core antigen, were excluded from the analysis.
  • Individuals who had received vaccination against HBV ( ⁇ 10%) fell into group A and were not therefore included in the analysis of HLA frequencies.
  • In the Adult population there were a total of 260 subjects: 25 in Group A, 195 in Group B and 41 in Group C. The very small number of individuals with HIV antibodies ( ⁇ 1%) were excluded.
  • Plasma samples were taken from all subjects and stored at -20°C.
  • Anti-HBc, Anti-HBc(IgM) and HBsAg status and anti-HBs antibody concentration were determined by ELISA according to the manufacturers instructions (Boehringer Mannheim, Kunststoff, Germany) .
  • Anti-HIV status was determined by Wellcozyme ELISA (Wellcome, Beckenham, UK) and positive results confirmed by Western Blot.
  • HLA Tvpin ⁇ Class I serotyping was performed on approximately half the subjects in each population.
  • Serological MHC class I types were determined by standard microlymphocytotoxicity assays using 180 well characterised antisera on fresh or cryopreserved cells (Rood, J., Van, Manual of Tissue Typing Technisques, Bethesda, Maryland : National Insti tutes of Heal th, 104- 105, 1979) .
  • MHC Class II typing was performed by restriction fragment length polymorphism analysis, as previously described, using the restriction enzymes Tagl and BamHl (Hill et al , supra; and Hill, A. et al , Proc. Na tl . Acad. Sci .
  • HLA class II haplotypes were initially determined using the restriction enzyme Tagl to define restriction fragment length polymorphism (RFLP) haplotype (Hill, A. et al , Proc . Natl . Acad . Sci . USA, supra) .
  • RFLP restriction fragment length polymorphism
  • the RFLP pattern 25-1 which corresponds with the class II haplotypes DRB1*1302-DRB3*0301-DQA1*0102-DQB1*0501 (DRwl3/DQw5) and DRB1*1302-DRB3*0301-DQA1*0102-DQB1*0604 (DRwl3/DQw6) , was found in 26.6% of the children who had cleared HBV infection (Group B) and in 16.2% of the children with persistent HBV infection (Group C) (relative risk 0.53 [95% CI 0.32 - 0.90], p - 0.012), and is therefore associated with a protective effect against persistent HBV carriage.
  • the study clearly shows that the RFLP defined haplotype 25-1 is associated with the ability to clear HBV after infection.
  • the 25-1 haplotype represents two MHC class II haplotypes, DRB1*1302-DRB3*0301-DQA1*0102- DQB1*0501 and DRB1*1302-DRB3*0301-DQA1*0102-DQB1*0604. Further analysis has shown that the two DRB1*1302 haplotypes are both associated with HBV clearance, and it is therefore probable that one or both of the shared HLA- DR alleles are responsible for this association.
  • HLA- DRB1*1302 is only found on the 25-1 RFLP haplotypes, whereas HLA-DRB3*0301 is also found on other RFLP haplotypes in The Gambia. Furthermore, the product of DRB1*1302 is expressed at a higher level than the DRB3 locus product and may thus be of greater functional importance. We conclude that, on the 25-1 haplotype, the DRB1*1302 seems most likely to be of importance in viral clearance.
  • the RFLP haplotype 13-2 which corresponds to the class II haplotype DRB1*1301- DRB3*0101-DQA1*0103-DQB1*0603, is also associated with a degree of resistance to HBV persistence in the population, as suggested by the data on persistently infected children.
  • the DRB1 allele of this haplotype, DRB1*1301 differs from HLA-DRB1*1302 by just a single amino acid substitution.
  • HBV-specific CD4+ helper activity as judged by the proliferative response to HBcAg and HsAg, is markedly reduced in patients with persistent infection in comparison to patients with acute self limiting infection (Ferrari, C. et al , J. Immunol . , supra).
  • the class II molecule is considered to be critical in the development of CD4+ helper T cell responses and therefore differential ability of class II molecules to present antigens may manifest as variability in the level of CD4+ help. This is consistent with the detection of a specific class II association with HBV clearance.
  • HLA B8, SC01, DR3 in Caucasians (Egea, E. et al, J. Exp .
  • HLA-DRB1*1302 HLA-DRB1*1302
  • HBV clearance a higher titre of anti-HBs antibody in individuals with this HLA allele.
  • levels of anti-HBs antibody in adults who had eliminated HBV were not higher amongst those with the HLA-DRB1*1302 allele, suggesting that the provision of extra "help" for the generation of this antibody response is not the critical mechanism in enhanced HBV clearance in carriers of HLA- DRB1*1302.
  • HBV infected hepatocytes can be recognised and destroyed by HLA class I restricted CTL (Mondelli, M. et al , J. Immunol . , 129(6) : 2773-78, 1982; and Pignattelli, M. et al , J. Hepatol . , 4: 15-21, 1987) .
  • HLA class I restricted CTL Mondelli, M. et al , J. Immunol . , 129(6) : 2773-78, 1982; and Pignattelli, M. et al , J. Hepatol . , 4: 15-21, 1987.
  • HBV antigens are presented with comparable efficiency by all the class I molecules found in high frequency in The Gambia.
  • HBV- specific CTL are not readily detectable, which may indicate that the numbers are low or that the CTLs are inactive.
  • DRB1*1302 appears to be associated with a potent protective effect against three important infectious pathogens, but it is not clear how it might exert this effect.
  • Malaria, HBV and HPV are complex pathogens in which there must be hundreds of potential T cell epitopes with variable MHC restriction elements.
  • the occurrence of an MHC association in any of these diseases suggests that there may only be a small number of epitopes to It is therefore conceivable that polymorphisms of the MHC class I and II loci contribute to the variability in outcome from HBV infection.which a protective immune response is mounted.

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Abstract

Procédé d'identification de la résistance à l'hépatite B, ainsi que peptides capables de modifier la réponse immunitaire et procédés de traitement de l'hépatite B.
PCT/GB1995/002067 1994-09-02 1995-09-01 Test predictif relatif a la resistance a l'hepatite b WO1996007915A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
JP8509285A JPH10505668A (ja) 1994-09-02 1995-09-01 Ｂ型肝炎に対する耐性の推定試験
AU33933/95A AU3393395A (en) 1994-09-02 1995-09-01 Predictive test for hepatitis-b resistance
EP95930612A EP0778948A1 (fr) 1994-09-02 1995-09-01 Test predictif relatif a la resistance a l'hepatite b
US09/754,290 US20010005507A1 (en) 1994-09-02 2001-01-05 Predictive test for hepatitis-B resistance

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9417850.6 1994-09-02
GB9417850A GB9417850D0 (en) 1994-09-02 1994-09-02 Predictive test

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WO1996007915A1 true WO1996007915A1 (fr) 1996-03-14

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PCT/GB1995/002067 WO1996007915A1 (fr) 1994-09-02 1995-09-01 Test predictif relatif a la resistance a l'hepatite b

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EP (1) EP0778948A1 (fr)
JP (1) JPH10505668A (fr)
AU (1) AU3393395A (fr)
CA (1) CA2198707A1 (fr)
GB (1) GB9417850D0 (fr)
WO (1) WO1996007915A1 (fr)
ZA (1) ZA957376B (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998002749A1 (fr) * 1996-07-12 1998-01-22 Imperial College Of Science Technology & Medicine Procede permettant de predire la resistance a l'infection provoquee par l'hepatite c
EP0979080A1 (fr) * 1997-01-02 2000-02-16 Thomas Jefferson University Procede de modulation d'une reaction immunitaire chez un mammifere infecte par administration transmuqueuse d'un agent de modulation

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
L. FAINBOIM ET AL.: "Chronic active autoimmune hepatitis in children. Strong association with a particular HLA-DR6 (DRB1*1301) haplotype.", HUMAN IMMUNOLOGY, vol. 41, no. 2, 14 February 1994 (1994-02-14), WASHINGTON DC USA, pages 146-146 - 150 *
M. THURSZ ET AL.: "The MHC class II haplotype DRB1*1302-DRB3*0301-DQA1*0102-DQB1*0501 protects against persistent HBV infection.", JOURNAL OF HEPATOLOGY, vol. 21, no. s1, 7 September 1994 (1994-09-07), COPENHAGEN DK, pages s3 *
M.R. THURSZ ET AL.: "Factors influencing the outcome of infection in HBV and malaria.", HEPATOLOGY, vol. 20, no. 4, 11 November 1994 (1994-11-11), CHICAGO IL USA, pages 297a *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998002749A1 (fr) * 1996-07-12 1998-01-22 Imperial College Of Science Technology & Medicine Procede permettant de predire la resistance a l'infection provoquee par l'hepatite c
EP0979080A1 (fr) * 1997-01-02 2000-02-16 Thomas Jefferson University Procede de modulation d'une reaction immunitaire chez un mammifere infecte par administration transmuqueuse d'un agent de modulation
JP2001507360A (ja) * 1997-01-02 2001-06-05 トマス・ジエフアーソン・ユニバーシテイ 調節剤の経粘膜投与による感染している哺乳類における免疫応答の調節方法
EP0979080A4 (fr) * 1997-01-02 2005-06-01 Univ Jefferson Procede de modulation d'une reaction immunitaire chez un mammifere infecte par administration transmuqueuse d'un agent de modulation

Also Published As

Publication number Publication date
EP0778948A1 (fr) 1997-06-18
JPH10505668A (ja) 1998-06-02
GB9417850D0 (en) 1994-10-26
AU3393395A (en) 1996-03-27
CA2198707A1 (fr) 1996-03-14
ZA957376B (en) 1997-03-03

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