WO1994026784A1 - Compositions d'anticorps contre l'antigene de surface de l'hepatite b - Google Patents

Compositions d'anticorps contre l'antigene de surface de l'hepatite b Download PDF

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Publication number
WO1994026784A1
WO1994026784A1 PCT/NL1994/000102 NL9400102W WO9426784A1 WO 1994026784 A1 WO1994026784 A1 WO 1994026784A1 NL 9400102 W NL9400102 W NL 9400102W WO 9426784 A1 WO9426784 A1 WO 9426784A1
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WO
WIPO (PCT)
Prior art keywords
mab
hepatitis
human monoclonal
monoclonal antibody
surface antigen
Prior art date
Application number
PCT/NL1994/000102
Other languages
English (en)
Inventor
Willem Pieter Zeijlemaker
Elisabeth Antonia Maria Stricker
Engelbertus Jozef Maria Al
Original Assignee
Stichting Centraal Laboratorium Van De Bloedtransfusiedienst Van Het Nederlandse Rode Kruis
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Application filed by Stichting Centraal Laboratorium Van De Bloedtransfusiedienst Van Het Nederlandse Rode Kruis filed Critical Stichting Centraal Laboratorium Van De Bloedtransfusiedienst Van Het Nederlandse Rode Kruis
Priority to JP6525268A priority Critical patent/JPH08509974A/ja
Priority to EP94917185A priority patent/EP0698042A1/fr
Publication of WO1994026784A1 publication Critical patent/WO1994026784A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
    • C07K16/082—Hepadnaviridae, e.g. hepatitis B virus
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention is in the field of therapeutic compositions for use with patients having chronic hepatitis B and relates in particular to pharmaceutical compositions comprising antibodies against the hepatitis B surface antigen (HBsAg) , which compositions are useful e.g. to prevent re-infection of liver cells in chronic hepatitis B patients after liver transplantation.
  • HBsAg hepatitis B surface antigen
  • Hepatitis B is an infectious disease, progressing in distinct phases.
  • the Hepatitis B virus replicates actively. This phase is characterized by liver damage, probably caused by immune reactivity against virus-infected liver cells. Once the immune reactivity develops sufficiently, active virus replication subsides.
  • the second phase virus latency
  • fragments of the virus can still be detected in the blood, but inflammation of the liver gradually declines.
  • hepatitis B virus is no longer detectable in the blood; at the same time, serum antibodies directed against surface antigens of the virus can be demonstrated.
  • phase 1 In patients with chronic hepatitis B, transition from phase 1 to phase 2, or from phase 2 to phase 3 is delayed, and the hepatitis virus itself or virus fragments can be detected in the blood.
  • phase 1 there is a persistent inflammation of the liver with a risk of liver cirrhosis, which may lead to liver malfunction or liver carcinoma.
  • the blood of such patients is highly infectious.
  • liver transplantation has become available as a possible therapeutic modality in advanced liver disease caused by hepatitis B virus, providing a chance for long-term survival of more than 50%.
  • Antibodies against the hepatitis B surface antigen have been proven very effective in the prevention of hepatitis B virus infection in individuals without earlier exposure to the virus. Such antibodies may result from active vaccination or can be passively administered. However, immunization with hepatitis B vaccine or administration of anti HBs antibodies has no clear effect in patients with chronic hepatitis B.
  • the antibodies first have to neutralize the surface antigen of the hepatitis B virus, after which a level of at least 100 International Units (IU) per liter must be maintained in the serum. Therefore, for the initial neutralization about 50,000 to 100,000 I ⁇ are required and to maintain a sufficient level during a year, at least another 100,000 IU are required.
  • Polyclonal human anti HBs antibody preparations are prepared from pooled plasma of immunized donors. These preparations are available in relatively small amounts and costly, resulting in the overall cost of treatment of from ⁇ LG 50,000.- to ⁇ LG 100,000.- per patient. Beside this, it would be virtually impossible to obtain sufficient amounts of antibody in order to maintain in the patients adequate antibody levels to prevent re-infection of a transplanted liver.
  • monoclonal antibodies are nearly always directed against a single antigenic epitope, in contrast to "classical" polyclonal antisera, which contain a mixture of antibodies, recognizing many different epitopes .
  • polyclonal antisera are better equipped to deal with the possible modifications of the virus as compared to the use of a single monoclonal antibody. It may be possible to circumvent this drawback by using a mixture of monoclonal antibodies, provided however that suitable antibodies are available which recognize different epitopes.
  • European patent application EP-A 0038642 discloses monoclonal antibodies against hepatitis B surface antigen which are secreted by the hybridoma cell lines RF-HBs-1, RF-HBs-2, and RF-HBs- .
  • the monoclonal antibody secreted by the cell line RF-HBs-1 is said to recognize an epitope which is common to the ad and ay subtypes of HBsAg and is different from the epitopes recognised by the RF-HBs- 2 and RF-HBs-4 antibodies.
  • the antibodies are claimed to have therapeutic, prophylactic, and diagnostic uses in respect of hepatitis B virus infections and said to be useful for purifying hepatitis B surface antigen. They may be used in combination with eachother. It is not claimed nor suggested that a mixture of these monoclonal antibodies could neutralize hepatitis B virus almost as efficiently as a polyclonal antiserum.
  • Said known antibodies are mouse monoclonal antibodies produced by hybridomas resulting from the fusion of spleen cells from suitably immunized Balb/c mice and a mouse myeloma cell line. Therapeutic use of such mouse monoclonal antibodies is expected to result in an inhibitory immune response after parental application. Further- more, said known antibodies recognize only one of the subtypes of hepatitis B. This is particularly undesirable with an eye on neutralization of escape mutants, which are less likely to occur in the case of two antibodies reactive with the same subtype.
  • Figure I shows the results of AUSRIA inhibition experiments carried out for polyclonal anti HBs antiserum (HBIg)
  • Figure II shows the results of AUSRIA inhibition experiments carried out for human monoclonal antibody MAb 4-7B;
  • Figure III shows the results of AUSRIA inhibition experiments carried out for human monoclonal antibody MAb 9H9
  • Figure IV shows the results of AUSRIA inhibition experiments carried out for a 1:1 mixture of human monoclonal antibodies MAb 9H9 and MAb 4-7B (on the basis of weight) ;
  • Figure V shows the results of AUSRIA inhibition experiments carried out for a 10:1 mixture of human monoclonal antibodies MAb 9H9 and MAb 4-7B (on the basis of weight)
  • Figure VI shows the results of AUSRIA inhibition experiments carried out for a 1:10 mixture of human monoclonal antibodies MAb 9H9 and MAb 4-7B (on the basis of weight) .
  • Human monoclonal antibodies against HBs have been developed by immortalization of antibody-producing cells from HBs- immune individuals. Human monoclonal antibodies having specificity for different epitopes have been obtained. The antibodies can be obtained in high amounts and are relatively inexpensive. It has been shown that a well-chosen combination of at least two of said human monoclonal antibodies recognizing different epitopes will effectively inhibit the binding of polyclonal human anti-HBsAg antibodies. In view thereof, such a combination promises to be a suitable alternative for the use of a polyclonal antiserum in the treatment of chronic Hepatitis B patients.
  • This invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising antibodies against hepatitis B surface antigen and a pharmaceutically acceptable carrier or diluent, wherein said antibodies comprise at least two different human monoclonal antibodies.
  • said human monoclonal antibodies include a first human monoclonal antibody and a second human monoclonal antibody, wherein binding of said first human monoclonal antibody to hepatitis B surface antigen causes less than 50% inhibition of binding of said second human monoclonal antibody to said hepatitis B surface antigen, and binding of said second human monoclonal antibody to hepatitis B surface antigen causes less than 50% inhibition of binding of said first human monoclonal antibody to said hepatitis B surface antigen.
  • one of said human monoclonal antibodies binds to a linear epitope of hepatitis B surface antigen and another human monoclonal antibody binds to a conformational epitope of hepatitis B surface antigen.
  • the human monoclonal antibody binding to a linear epitope of hepatitis B surface antigen is MAb 4-7B (deposited under the Budapest Treaty with the European Collection of Animal Cell Cultures on 10 December 1992, deposit number ECACC 92121016) and the human monoclonal antibody binding to a conformational epitope of hepatitis B surface antigen is MAb 9H9 (deposited under the Budapest Treaty with the European Collection of Animal Cell Cultures on 10 December 1992, deposit number ECACC 92121015) .
  • This invention provides the above pharmaceutical composition for use in the treatment of chronic hepatitis B patients.
  • the invention also provides a human monoclonal antibody against hepatitis B surface antigen for use in the treatment of chronic hepatitis B patients, in particular MAb 4-7B (ECACC 92121016) or MAb 9H9 (ECACC 92121015) .
  • the invention provides the use of a human monoclonal antibody against hepatitis B surface antigen for preparing a pharmaceutical composition for the treatment of chronic hepatitis B patients, more in particular use of human monoclonal antibodies MAb 4-7B (ECACC 92121016) and MAb 9H9 (ECACC 92121015) for that purpose.
  • the present invention also provides a process of producing a human monoclonal antibody against hepatitis B surface antigen, said process comprising culturing cells which produce monoclonal anti ⁇ body MAb 4-7B (ECACC 92121016), or cells which produce monoclonal antibody MAb 9H9 (ECACC 92121015) , and optionally recovering the monoclonal antibody produced.
  • said cells are cultured in vitro in a nutrient medium therefor and the antibody produced is recovered from the culture supernatant.
  • said cells are from the deposited cell line MAb 4-7B (ECACC 92121016), or from the deposited cell line MAb 9H9 (ECACC 92121015), or are hybrid cells derived from any one of said deposited cell lines by fusion with a murine myeloma cell line, or are recombinant cells transformed with nucleic acid encoding any one of monoclonal antibodies MAb 4-7B (ECACC 92121016) and MAb 9H9 (ECACC 92121015) such as to allow expression thereof.
  • HuMAb-anti-HBs were prepared as follows: Peripheral blood lymphocytes were isolated from volunteer plasmapheresis donors who had high titres of serum antibodies against HBs. The B lymphocytes were isolated and infected with Epstein-Barr virus, resulting in the transformation and immortalization of antibody-producing cells. By repeated sub-culture of the immortalized cells, monoclonal cell lines (i.e. genetically identical) were isolated. Such cell lines continuously secrete HuMAb-anti-HBs. Large amounts of these antibodies are readily obtained from the supernatant of these cells when cultured in-vitro.
  • the properties of two of the HuMAb-anti-HBs prepared in accordance with Example 1 are described herein in some detail.
  • the two HuMAb- anti-HBs are designated herein as CLB-Hu-HBsAg-1 (MAb 4-7B) and CLB-Hu-HBsAg-4 (MAb 9H9) . ?.1 Sner.ificitv of MAh 4-7R and MAb 9H9
  • the antibodies were tested in a radio- immunoprecipitation assay: the antibodies were coupled to a solid phase, which was then incubated with radioactive, 125 I-labelled HBs proteins (obtained from Abbott Laboratories, Chicago, ILL,
  • Percentage binding refers to the binding of the labeled monoclonal antibody after pre-incubation with an excess of unlabeled antibody, and expressed relative to the percentage in the absence of unlabeled antibody (the latter value being taken as 100%) .
  • MAb 4-7B and MAb 9H9 are indeed directed against different epitopes, which is consistent with the data mentioned earlier (i.e. MAb 4-7B recognizes a linear epitope and MAb 9H9 a conformation-dependent epitope) .
  • HBsAg was incubated with antibody MAb 4-7B, antibody MAb 9H9 or with mixtures containing known concentrations of both antibodies.
  • a polyclonal anti-HBs antiserum was tested in parallel.
  • Residual HBs-immunoreactivity was tested in the AUSRIA assay (test kits obtained from Abbott Laboratories) .
  • the principle of the AUSRIA is as follows: beads coated with polyclonal (guinea pig) anti-HBsAg antibodies are incubated with the plasma from a hepatitis B patient, which contains HBs, overnight at ambient temperature. After washing, known quantities of MAb 4-7B, MAb 9H9 or a mixture of both antibodies were added and incubated for 1 hour at 45°C. Then, without washing, the beads were incubated with 125 I-labelled polyclonal (human) anti-HBsAg antibodies for 3 hours at 45°C. Finally the binding of the labeled antibodies was measured and the capacity of the HuMAbs to inhibit the binding of the 125 I-labeled conjugate was calculated. The results of these experiments are shown in Tables I-VI and Figures I-VI .
  • a mixture of both 4-7B and 9H9 antibodies is able to fully neutralize Dane particles as well as HBsAg.
  • a mixture of MAb 4-7B and MAb 9H9 provides a suitable preparation as an alternative for the treatment of chronic Hepatitis B patients circumventing the drawbacks of the "classical" treatment with a polyclonal preparation.
  • the present invention has been described with particular reference to specific cell lines producing the two monoclonal antibodies 4-7B and 9H9.
  • alternative cell lines producing antibodies with the same or similar binding specificities can be generated, e.g. to improve antibody production methods. These alternative cell lines can be generated in several ways.
  • the producing cell line 4-7B or 9H9 can be fused with another cell line (e.g. a mouse myeloma).
  • the resulting new cell line may be selected for improved growth and/or antibody producing characteristics.
  • the thus made new cell line will produce the very same antibody as the parent cell line 4-7B or 9H9.
  • the genetic material can be extracted from either of the two cell lines 4-7B and 9H9 in order to isolate the genes encoding the antibodies.
  • These isolated genes (or parts of the isolated genes) can be used to transform another cell line into a cell line producing proteins with similar HBsAg binding specificities as 4-7B or 9H9 antibodies.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Biochemistry (AREA)
  • Immunology (AREA)
  • Oncology (AREA)
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  • Genetics & Genomics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Composition comprenant au moins deux anticorps monoclonaux humains différents contre l'antigène de surface de l'hépatite B. Combinaison d'un anticorps monoclonal humain se fixant à un déterminant antigénique linéaire, par exemple MAb 4-7B, et d'un anticorps monoclonal humain se fixant à un déterminant antigénique de conformation, par exemple MAb 9H9. Cette composition est efficace dans le traitement de patients atteints d'hépatite B chronique, notamment ceux dont le foie a été transplanté, afin d'empêcher une réinfection.
PCT/NL1994/000102 1993-05-10 1994-05-09 Compositions d'anticorps contre l'antigene de surface de l'hepatite b WO1994026784A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
JP6525268A JPH08509974A (ja) 1993-05-10 1994-05-09 Ｂ型肝炎表面抗原に対する抗体の組成物
EP94917185A EP0698042A1 (fr) 1993-05-10 1994-05-09 Compositions d'anticorps contre l'antigene de surface de l'hepatite b

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Application Number Priority Date Filing Date Title
EP93201315 1993-05-10
EP93201315.4 1993-05-10

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997047654A1 (fr) * 1996-06-11 1997-12-18 Yeda Research And Development Co. Ltd. Anticorps monoclonaux humains se fixant sur l'antigene de surface de l'hepatite b
WO1997047653A1 (fr) * 1996-06-11 1997-12-18 Xtl Biopharmaceuticals Limited Anticorps monoclonal humain dirige contre l'antigene de surface du virus de l'hepatite b
EP2501723A1 (fr) * 2009-11-19 2012-09-26 Agency For Science, Technology And Research Anticorps spécifique du virus de l'hépatite b, et utilisations de cet anticorps

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0038642A1 (fr) * 1980-04-09 1981-10-28 National Research Development Corporation Anticorps monoclonal contre l'hépatite B et sa production, hybridome produisant l'anticorps monoclonal et compositions le contenant, culture de l'hybridome et production de l'anticorps monoclonal pour usage en tant qu'agent anti-viral contre l'hépatite B et dans l'isolement de l'antigene de surface de l'hépatite B à partir d'un échantillon
EP0235805A2 (fr) * 1986-03-04 1987-09-09 The Royal Free Hospital School Of Medicine Immunosuppression
WO1994011495A1 (fr) * 1992-11-06 1994-05-26 Sandoz, Ltd. Production d'anticorps monoclonaux humains actifs contre l'antigene de surface de l'hepatite b

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0038642A1 (fr) * 1980-04-09 1981-10-28 National Research Development Corporation Anticorps monoclonal contre l'hépatite B et sa production, hybridome produisant l'anticorps monoclonal et compositions le contenant, culture de l'hybridome et production de l'anticorps monoclonal pour usage en tant qu'agent anti-viral contre l'hépatite B et dans l'isolement de l'antigene de surface de l'hépatite B à partir d'un échantillon
EP0235805A2 (fr) * 1986-03-04 1987-09-09 The Royal Free Hospital School Of Medicine Immunosuppression
WO1994011495A1 (fr) * 1992-11-06 1994-05-26 Sandoz, Ltd. Production d'anticorps monoclonaux humains actifs contre l'antigene de surface de l'hepatite b

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 106, no. 11, 16 March 1987, Columbus, Ohio, US; abstract no. 82808p, R. L: CERIANI ET AL: "Experimental immunotherapy of human breast carcinomas implanted in nude mice with a mixture of monoclonal antibodies against human milk fat globule components" *
CHEMICAL ABSTRACTS, vol. 99, no. 19, 7 November 1983, Columbus, Ohio, US; abstract no. 156566u, R. W. MOYLE ET AL: "A circular antibody-antigen complex is responsible for increased affinity shown by mixtures of monoclonal antibodies to human chorionic gonadotropin" *
DATABASE WPI Week 9422, Derwent World Patents Index; AN 94-183497 *

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1997047654A1 (fr) * 1996-06-11 1997-12-18 Yeda Research And Development Co. Ltd. Anticorps monoclonaux humains se fixant sur l'antigene de surface de l'hepatite b
WO1997047653A1 (fr) * 1996-06-11 1997-12-18 Xtl Biopharmaceuticals Limited Anticorps monoclonal humain dirige contre l'antigene de surface du virus de l'hepatite b
US6146629A (en) * 1996-06-11 2000-11-14 Xtl Biopharmaceuticals Limited Human monoclonal antibody against Hepatitis B virus surface antigen (HBVsAg)
US6254867B1 (en) 1996-06-11 2001-07-03 Yeda Research & Development Co. Ltd Human monoclonal antibodies to the hepatitis B surface antigen
USRE39586E1 (en) * 1996-06-11 2007-04-24 Xtl Biopharmaceuticals Limited Human monoclonal antibody against Hepatitis B virus surface antigen (HBVSAG)
USRE40831E1 (en) 1996-06-11 2009-07-07 Yeda Research And Development Co., Ltd. Human monoclonal antibodies to the hepatitis B surface antigen
EP2501723A1 (fr) * 2009-11-19 2012-09-26 Agency For Science, Technology And Research Anticorps spécifique du virus de l'hépatite b, et utilisations de cet anticorps
EP2501723A4 (fr) * 2009-11-19 2013-04-17 Agency Science Tech & Res Anticorps spécifique du virus de l'hépatite b, et utilisations de cet anticorps
US9334317B2 (en) 2009-11-19 2016-05-10 Agency For Science, Technology And Research Hepatitis B virus specific antibody and uses thereof

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EP0698042A1 (fr) 1996-02-28
CA2162370A1 (fr) 1994-11-24
JPH08509974A (ja) 1996-10-22

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