EP1432418A1 - Traitement des infections par le virus de l'hepatite b avec des anticorps monoclonaux humains - Google Patents

Traitement des infections par le virus de l'hepatite b avec des anticorps monoclonaux humains

Info

Publication number
EP1432418A1
EP1432418A1 EP01978778A EP01978778A EP1432418A1 EP 1432418 A1 EP1432418 A1 EP 1432418A1 EP 01978778 A EP01978778 A EP 01978778A EP 01978778 A EP01978778 A EP 01978778A EP 1432418 A1 EP1432418 A1 EP 1432418A1
Authority
EP
European Patent Office
Prior art keywords
pharmaceutical composition
treatment
hbv
composition according
hepatitis
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP01978778A
Other languages
German (de)
English (en)
Inventor
Shlomo Dagan
Rachel Eren
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
XTL Biopharmaceuticals Ltd
Original Assignee
XTL Biopharmaceuticals Ltd
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 XTL Biopharmaceuticals Ltd filed Critical XTL Biopharmaceuticals Ltd
Publication of EP1432418A1 publication Critical patent/EP1432418A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K39/42—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum viral
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man

Definitions

  • the present invention concerns a pharmaceutical composition for the treatment or prevention of hepatitis B infection comprising a mixture of two human monoclonal antibodies.
  • HCC hepatocellular carcinoma
  • plasma-derived polyclonal antibodies are limited because these preparations have variable activity, limited availability and there are potential hazards for the transmission of infectious agents.
  • mAbs monoclonal antibodies
  • HBsAg hepatitis B surface antigen
  • a pharmaceutical composition comprising a combination of two, fully human, high-affinity monoclonal antibodies directed against different epitopes of hepatitis B virus surface antigen (HBsAg).
  • HBsAg hepatitis B virus surface antigen
  • VTT composition comprising as an active ingredient a mixture of the human monoclonal antibody 19.79.5 as well as fragments thereof retaining the antigen binding characteristics of the antibodies, and the human monoclonal antibody 17.1.41 as well as fragments thereof retaining the antigen binding characteristics of the antibodies together with a pharmaceutically acceptable carrier.
  • Antibody 19.79.5 is secreted by the hybridoma cell line deposited in the European Collection of Cell Cultures (ECACC) under Accession No. 96052168, and antibody 17.1.41 secreted by the hybridoma cell line deposited in the ECACC under Accession No. 96052169.
  • Antibodies 19.79.5 and 17.1.41 are further characterized by their sequence disclosed in PCT/IL97/00184 and PCT/IL97/00183. Fragments retaining the antigen binding characteristics of the antibodies may be, for example, Fab or F(ab) fragments obtained by digestion of the whole antibody with various enzymes as known and described extensively in the art. The antigenic characteristics of an antibody are determined by testing the binding of an antibody to a certain antigenic determinant using standard assays such as RIA, ELISA, or FACS analysis. Further aspects of the present invention are various prophylactic and therapeutic uses of the antibody mixture.
  • the pharmaceutical composition comprising the antibody mixture may be used for the treatment of chronic Hepatitis B patients by administering to such a patient a therapeutically effective amount of the mixture of antibodies or fragments thereof capable of binding to the HBVsAg being an amount effective in alleviating the symptoms of the HBV infection or reducing the number of circulating viral particles in an individual.
  • Means to assess alleviation of symptoms of HBV infection may include as a non limiting example measurement of liver functions by determining levels of the enzyme alanine aminotransferase (ALT) or by measuring sero conversion namely disappearance of the HBeAg or by examining liver biopsies and determining the level of tissue fibrosis by methods well known in the art.
  • the number of circulating viral particles can be determined for example by measuring HBV DNA levels using PCR or by detecting HBsAg levels in the blood.
  • the pharmaceutical composition is given in a dose ranging from 0.26 mg to 80 mg. Preferably 10 mg or 40 mg. In a preferred embodiment of the present invention the pharmaceutical composition comprises an approximate ratio of 1 :3 between antibodies 19.79.5 and 17.1.41 respectively.
  • the pharmaceutical composition of the invention may optionally also comprise a carrier selected from any of the carriers known in the art.
  • a carrier is a liposome.
  • the pharmaceutical composition of the invention may also comprise various diluents and adjuvants known per se.
  • the composition of the invention may be administered by a variety of administration modes including intra venous, intra muscular and subcutaneous administration.
  • the pharmaceutical composition of the invention may be administered in combination with other anti-viral agents.
  • agents may include, as a non-limiting example: interferons, anti hepatitis B monoclonal antibodies, anti hepatitis B polyclonal antibodies, nucleoside analogues, inhibitors of DNA polymerase and therapeutic vaccines.
  • the antibodies may be given simultaneously with the anti viral agent or sequentially either before or after treatment with the anti viral agent.
  • the pharmaceutical composition of the invention may also be used, for example as a prophylactic treatment of neonates born to HBV infected mothers or of healthcare workers exposed to the virus or of liver transplant recipients to eliminate possible recurrent HBV infection of the transplanted liver.
  • Figure 1 HBsAg and HBV-DNA serum levels of two patients infused with a single dose the HBV-Ab XT mixture.
  • the HBV-Ab XTL mixture was administered at time point 0. The time range is not to scale.
  • Figure 2 HBsAg and HBV-DNA serum levels in four patients administered with multiple infusions of the HBV-Ab mixture.
  • the HBV-Ab mixture was administered at time points (days) 0, 8,15 and 22; arrows indicate administration time.
  • Figure 3 HBsAg and anti-HBsAg antibody serum levels in four patients administered with multiple infusions of the HBV-Ab mixture.
  • the HBV-Ab mixture was administered at time points (days) 0, 8,15 and 22; arrows indicate administration time.
  • D patient no. 301, dose 4 x 80 mg.
  • HBsAg levels were determined by a modified automated immunoassay (IMX system, Abbott GmbH Diagnostika) using a purified HBsAg preparation (Bio-Hep-B, Biotechnology General, Ness-Ziona, Israel) as standard.
  • Anti-HBs levels were determined by AUSAB RIA and compared to a WHO reference for anti-HBs.
  • a reference serum for anti-HBs was obtained from CLB, Red Cross Blood Transfusion Service, the Netherlands.
  • HBV-DNA levels in patients' serum were analyzed by HBV-DNA PCR using the Amplicor HBV Monitor 1 " 1 Test (Hoffman-La Roche Inc., Roche Diagnostics, Branchburg, N.J., USA) according to the manufacturers' instructions.
  • Each dose of HB V-Ab XTL is prepared by diluting the two antibodies 19.79.5 and 17.1.41 in 250 ml normal saline solution in an approximate ratio of 1 :3 between the antibodies respectively (i.e. for each mg of antibody 19.79.5 approximately 3 mg of antibody 17.1.41 are added).
  • HBV-Ab XTL was first tested in a dose escalation (single-dose) phase IA study in patients with otherwise untreated chronic Hepatitis B infection (Galun et al., 2000 Hepatology 32 (4 Pt.2): p221A). A total of 15 patients were enrolled in the study and each received a single dose of HBV-Ab x L . The doses ranging between 0.26 to 40 5 mg. The dosing levels, were based on the molar ratio of antibody to antigen (Ab:Ag) (Table 1). HBV-Ab XTL was administered as intravenous infusions over 2-8 hours.
  • HBsAg and HBV-DNA levels were detectable shortly after infusion initiation but was only observed in patients receiving antibodies with a high Ab:Ag ratio.
  • Ab:Ag molar ratio of 1 :2 HBsAg levels decreased to undetectable levels and then started to increase 24 hr after initiation of the infusion, reaching pre-treatments levels only eight days after the infusion ( Figure 1).
  • HBV- DNA levels also decreased after the initiation of the HBV-Ab XTL infusion and reached pre-treatment levels one day later.
  • the reduction in HBV-DNA levels was between one to three orders of magnitude. The most common adverse event reported was mild myalgia observed in six patients (40%).
  • HBsAg levels decreased to undetectable levels immediately after administration and returned back almost to the original levels prior to the next infusion. A similar pattern was observed following each administration resulting in a trend of progressive decrease in HBsAg levels during repeated administration. At 24 hours following injection, HBsAg levels were still undetectable in one patient but started to increase in the other 2 patients. Similarly, upon infusion HBV-DNA levels decreased by 3 logs and a progressive decline was observed with every administration. These levels remained undetectable for 24 hours after every infusion (Figure 2).
  • the second cohort of patients received four weekly infusions of 20 mg of HBV- AB XTL each ( Figure 2B). A similar pattern of reduction of HBsAg levels to undetectable limit was also observed in these three patients. HBV-DNA levels have also dropped by one to four logs.
  • the third cohort received four weekly infusions of 40 mg of HBV-AB XTL and the forth cohort received four weekly infusions of 80 mg of HBV-AB X1 L , each. These administrations showed similar effects on HBsAg and HBV-DNA dynamics ( Figure 2 C, D). In all cases HBV-DNA decreased significantly, and HBsAg levels were reduced to undetectable levels immediately following infusion.
  • HBV-Ab is given in combination with lamivudine.
  • Lamivudine is given in a dose of 100 mg/day (The recommended dose of lamivudine for treatment of chronic hepatitis B virus infection)
  • HBV-Ab XTL is given intravenously either as a 10 mg or 40 mg dose.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Immunology (AREA)
  • Virology (AREA)
  • Epidemiology (AREA)
  • Communicable Diseases (AREA)
  • Mycology (AREA)
  • Microbiology (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Oncology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention se rapporte à une composition pharmaceutique servant au traitement ou à la prévention des infections par le virus de l'hépatite B et comprenant un mélange 1/3 de deux anticorps monoclonaux anti-HBsAg totalement humains 19.79.5 et 17.1.41. Cette invention décrit également des modes préférés d'administration d'une telle composition. Cette composition pharmaceutique peut être administrée en monothérapie ou associée à d'autres agents antiviraux.
EP01978778A 2001-10-04 2001-10-04 Traitement des infections par le virus de l'hepatite b avec des anticorps monoclonaux humains Withdrawn EP1432418A1 (fr)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IL2001/000927 WO2003028722A1 (fr) 2001-10-04 2001-10-04 Traitement des infections par le virus de l'hepatite b avec des anticorps monoclonaux humains

Publications (1)

Publication Number Publication Date
EP1432418A1 true EP1432418A1 (fr) 2004-06-30

Family

ID=11043099

Family Applications (1)

Application Number Title Priority Date Filing Date
EP01978778A Withdrawn EP1432418A1 (fr) 2001-10-04 2001-10-04 Traitement des infections par le virus de l'hepatite b avec des anticorps monoclonaux humains

Country Status (7)

Country Link
EP (1) EP1432418A1 (fr)
JP (1) JP2005505582A (fr)
KR (1) KR20040048935A (fr)
CN (1) CN1558763A (fr)
CA (1) CA2462427A1 (fr)
IL (1) IL161138A0 (fr)
WO (1) WO2003028722A1 (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9292111B2 (en) 1998-01-26 2016-03-22 Apple Inc. Gesturing with a multipoint sensing device
US8479122B2 (en) 2004-07-30 2013-07-02 Apple Inc. Gestures for touch sensitive input devices
CA2594922A1 (fr) * 2005-01-14 2006-07-20 The Government Of The United States Of America, As Represented By The Se Cretary, Department Of Health And Human Services Anticorps monoclonaux se liant avec le virus de l'hepatite b ou le neutralisant
US7785595B2 (en) 2005-04-18 2010-08-31 Yeda Research And Development Company Limited Stabilized anti-hepatitis B (HBV) antibody formulations
KR20090056537A (ko) * 2007-11-30 2009-06-03 주식회사 녹십자 Ｂ형 간염 바이러스 중화능을 갖는 항체를 유효성분으로포함하는 ｂ형 간염 바이러스 감염의 예방 또는 치료용조성물
CN102757492A (zh) * 2011-04-26 2012-10-31 中国人民解放军第二军医大学 全人乙肝表面蛋白单克隆抗体及其在制备预防hbv感染药物中的用途
KR101771309B1 (ko) * 2015-07-24 2017-08-24 재단법인 목암생명과학연구소 B형 간염 바이러스의 ｃｃｃＤＮＡ 형성 억제용 약학 조성물
CN105001325A (zh) * 2015-07-31 2015-10-28 北京泰诺迪生物科技有限公司 一种全人源抗乙肝病毒中和抗体及其制备方法与应用
WO2017114812A1 (fr) * 2015-12-29 2017-07-06 F. Hoffmann-La Roche Ag Traitement combiné avec un inhibiteur de hbsag et un interféron
EP3519443A4 (fr) * 2016-09-30 2020-06-10 Baylor College of Medicine Thérapie par récepteurs d'antigène chimériques présentant une cytotoxicité réduite pour maladie virale

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL118625A0 (en) * 1996-06-11 1996-10-16 Xtl Biopharmaceuticals Limited Anti HBV antibodies
IL118626A0 (en) * 1996-06-11 1996-10-16 Xtl Biopharmaceuticals Limited Anti HBV antibody
EP0893124A1 (fr) * 1997-07-24 1999-01-27 Roche Diagnostics GmbH Préparations pharmaceutiques combinées comprenant des anticorps monoclonaux humains pour le traitement de l'hépatite B et une substance virostatique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03028722A1 *

Also Published As

Publication number Publication date
CA2462427A1 (fr) 2003-04-10
JP2005505582A (ja) 2005-02-24
IL161138A0 (en) 2004-08-31
KR20040048935A (ko) 2004-06-10
CN1558763A (zh) 2004-12-29
WO2003028722A1 (fr) 2003-04-10

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