WO2003028722A1 - Treatment of hepatitis b virus infection with human monoclonal antibodies - Google Patents
Treatment of hepatitis b virus infection with human monoclonal antibodies Download PDFInfo
- Publication number
- WO2003028722A1 WO2003028722A1 PCT/IL2001/000927 IL0100927W WO03028722A1 WO 2003028722 A1 WO2003028722 A1 WO 2003028722A1 IL 0100927 W IL0100927 W IL 0100927W WO 03028722 A1 WO03028722 A1 WO 03028722A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- treatment
- hbv
- composition according
- hepatitis
- Prior art date
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.
Abstract
Description
Claims
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2003532054A JP2005505582A (en) | 2001-10-04 | 2001-10-04 | Treatment of hepatitis B virus infection with human monoclonal antibodies |
CA002462427A CA2462427A1 (en) | 2001-10-04 | 2001-10-04 | Treatment of hepatitis b virus infection with human monoclonal antibodies |
IL16113801A IL161138A0 (en) | 2001-10-04 | 2001-10-04 | Treatment of hepatitis b virus infection with human monoclonal antibodies |
CNA018236928A CN1558763A (en) | 2001-10-04 | 2001-10-04 | Treatment of hepatitis B virus infection with human monoclonal antibodies |
KR10-2004-7004987A KR20040048935A (en) | 2001-10-04 | 2001-10-04 | Treatment of hepatitis B virus infection with human monoclonal antibodies |
EP01978778A EP1432418A1 (en) | 2001-10-04 | 2001-10-04 | Treatment of hepatitis b virus infection with human monoclonal antibodies |
PCT/IL2001/000927 WO2003028722A1 (en) | 2001-10-04 | 2001-10-04 | Treatment of hepatitis b virus infection with human monoclonal antibodies |
US11/056,186 US20050260195A1 (en) | 2001-10-04 | 2005-02-14 | Treatment of hepatitis B virus infection with human monoclonal antibodies |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
PCT/IL2001/000927 WO2003028722A1 (en) | 2001-10-04 | 2001-10-04 | Treatment of hepatitis b virus infection with human monoclonal antibodies |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/056,186 Continuation-In-Part US20050260195A1 (en) | 2001-10-04 | 2005-02-14 | Treatment of hepatitis B virus infection with human monoclonal antibodies |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2003028722A1 true WO2003028722A1 (en) | 2003-04-10 |
Family
ID=11043099
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/IL2001/000927 WO2003028722A1 (en) | 2001-10-04 | 2001-10-04 | Treatment of hepatitis b virus infection with human monoclonal antibodies |
Country Status (7)
Country | Link |
---|---|
EP (1) | EP1432418A1 (en) |
JP (1) | JP2005505582A (en) |
KR (1) | KR20040048935A (en) |
CN (1) | CN1558763A (en) |
CA (1) | CA2462427A1 (en) |
IL (1) | IL161138A0 (en) |
WO (1) | WO2003028722A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006076640A1 (en) * | 2005-01-14 | 2006-07-20 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Monoclonal antibodies that bind or neutralize hepatitis b virus |
WO2006112838A1 (en) * | 2005-04-18 | 2006-10-26 | Xtl Biopharmaceuticals Ltd. | Stabilized anti-hepatitis b (hbv) antibody formulations |
WO2009069917A1 (en) * | 2007-11-30 | 2009-06-04 | Green Cross Corporation | Use of human antibody capable of neutralizing hepatitis b virus for the prevention or treatment of hepatitis b virus infection |
US9292111B2 (en) | 1998-01-26 | 2016-03-22 | Apple Inc. | Gesturing with a multipoint sensing device |
US9348458B2 (en) | 2004-07-30 | 2016-05-24 | Apple Inc. | Gestures for touch sensitive input devices |
WO2017114812A1 (en) * | 2015-12-29 | 2017-07-06 | F. Hoffmann-La Roche Ag | Combination therapy of an hbsag inhibitor and an interferon |
CN108136009A (en) * | 2015-07-24 | 2018-06-08 | 财团法人牧岩生命科学研究所 | For the pharmaceutical composition for preventing the cccDNA of hepatitis type B virus from being formed |
US11219646B2 (en) * | 2016-09-30 | 2022-01-11 | Baylor College Of Medicine | Chimeric antigen receptor therapy with reduced cytotoxicity for viral disease |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102757492A (en) * | 2011-04-26 | 2012-10-31 | 中国人民解放军第二军医大学 | Holistic hepatitis B surface protein monoclonal antibodies and application thereof to preparation of medicines for preventing HBV (hepatitis B virus) infection |
CN105001325A (en) * | 2015-07-31 | 2015-10-28 | 北京泰诺迪生物科技有限公司 | Total-humanized anti-hepatitis B virus neutralizing antibody and preparing method and application thereof |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997047653A1 (en) * | 1996-06-11 | 1997-12-18 | Xtl Biopharmaceuticals Limited | Human monoclonal antibody against hepatitis b virus surface antigen (hbvsag) |
WO1997047654A1 (en) * | 1996-06-11 | 1997-12-18 | Yeda Research And Development Co. Ltd. | Human monoclonal antibodies to the hepatitis b surface antigen |
WO1999004814A1 (en) * | 1997-07-24 | 1999-02-04 | Roche Diagnostics Gmbh | Combined pharmaceutical preparations containing human monoclonal antibodies for treating chronic hepatitis b |
-
2001
- 2001-10-04 KR KR10-2004-7004987A patent/KR20040048935A/en not_active Application Discontinuation
- 2001-10-04 EP EP01978778A patent/EP1432418A1/en not_active Withdrawn
- 2001-10-04 IL IL16113801A patent/IL161138A0/en unknown
- 2001-10-04 CA CA002462427A patent/CA2462427A1/en not_active Abandoned
- 2001-10-04 WO PCT/IL2001/000927 patent/WO2003028722A1/en not_active Application Discontinuation
- 2001-10-04 JP JP2003532054A patent/JP2005505582A/en active Pending
- 2001-10-04 CN CNA018236928A patent/CN1558763A/en active Pending
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1997047653A1 (en) * | 1996-06-11 | 1997-12-18 | Xtl Biopharmaceuticals Limited | Human monoclonal antibody against hepatitis b virus surface antigen (hbvsag) |
WO1997047654A1 (en) * | 1996-06-11 | 1997-12-18 | Yeda Research And Development Co. Ltd. | Human monoclonal antibodies to the hepatitis b surface antigen |
WO1999004814A1 (en) * | 1997-07-24 | 1999-02-04 | Roche Diagnostics Gmbh | Combined pharmaceutical preparations containing human monoclonal antibodies for treating chronic hepatitis b |
Non-Patent Citations (3)
Title |
---|
R. EREN ET AL.: "Human monoclonal antibodies specific to hepatitis B virus generated in a human/mouse radiation chimera: the Trimera system.", IMMUNOLOGY, vol. 93, no. 2, February 1998 (1998-02-01), Oxford, GB, pages 154 - 161, XP002200770 * |
R. EREN ET AL.: "Preclinical evaluation of two human anti-hepatitis B virus (HBV) monoclonal antibodies in the HBV-trimera mouse model and in HBV chronic carrier chimpanzee.", HEPATOLOGY, vol. 32, no. 3, September 2000 (2000-09-01), Baltimore, MD, USA, pages 588 - 596, XP008003967 * |
R. HEIJTINK ET AL.: "In vivo activity of a mixture of two human monoclonal antibodies (anti-HBs) in a chronic hepatitis B virus carrier chimpanzee.", JOURNAL OF GENERAL VIROLOGY, vol. 80, no. 6, June 1999 (1999-06-01), Cambridge, GB, pages 1529 - 1535, XP002200771 * |
Cited By (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9292111B2 (en) | 1998-01-26 | 2016-03-22 | Apple Inc. | Gesturing with a multipoint sensing device |
US9348458B2 (en) | 2004-07-30 | 2016-05-24 | Apple Inc. | Gestures for touch sensitive input devices |
WO2006076640A1 (en) * | 2005-01-14 | 2006-07-20 | The Government Of The United States Of America, As Represented By The Secretary, Department Of Health And Human Services | Monoclonal antibodies that bind or neutralize hepatitis b virus |
WO2006112838A1 (en) * | 2005-04-18 | 2006-10-26 | Xtl Biopharmaceuticals Ltd. | Stabilized anti-hepatitis b (hbv) antibody formulations |
US7785595B2 (en) | 2005-04-18 | 2010-08-31 | Yeda Research And Development Company Limited | Stabilized anti-hepatitis B (HBV) antibody formulations |
AU2005330672B2 (en) * | 2005-04-18 | 2011-07-28 | Yeda Research And Development Company Limited | Stabilized anti-hepatitis B (HBV) antibody formulations |
US8580256B2 (en) | 2005-04-18 | 2013-11-12 | Yeda Reseach and Development Company Limited | Stabilized anti-hepatitis B (HBV) antibody formulations |
WO2009069917A1 (en) * | 2007-11-30 | 2009-06-04 | Green Cross Corporation | Use of human antibody capable of neutralizing hepatitis b virus for the prevention or treatment of hepatitis b virus infection |
CN108136009A (en) * | 2015-07-24 | 2018-06-08 | 财团法人牧岩生命科学研究所 | For the pharmaceutical composition for preventing the cccDNA of hepatitis type B virus from being formed |
WO2017114812A1 (en) * | 2015-12-29 | 2017-07-06 | F. Hoffmann-La Roche Ag | Combination therapy of an hbsag inhibitor and an interferon |
US11219646B2 (en) * | 2016-09-30 | 2022-01-11 | Baylor College Of Medicine | Chimeric antigen receptor therapy with reduced cytotoxicity for viral disease |
Also Published As
Publication number | Publication date |
---|---|
IL161138A0 (en) | 2004-08-31 |
EP1432418A1 (en) | 2004-06-30 |
KR20040048935A (en) | 2004-06-10 |
CA2462427A1 (en) | 2003-04-10 |
CN1558763A (en) | 2004-12-29 |
JP2005505582A (en) | 2005-02-24 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Galun et al. | Clinical evaluation (phase I) of a combination of two human monoclonal antibodies to HBV: safety and antiviral properties | |
Shah et al. | Spectrum of hepatitis B and renal involvement | |
Liang et al. | Present and future therapies of hepatitis B: from discovery to cure | |
Zhang et al. | Prolonged suppression of HBV in mice by a novel antibody that targets a unique epitope on hepatitis B surface antigen | |
Lo et al. | Failure of hepatitis B vaccination in patients receiving lamivudine prophylaxis after liver transplantation for chronic hepatitis B | |
Eren et al. | Preclinical evaluation of two human anti–hepatitis B virus (HBV) monoclonal antibodies in the HBV‐trimera mouse model and in HBV chronic carrier chimpanzees | |
Elewa et al. | Treatment of hepatitis B virus-associated nephropathy | |
US20170260257A1 (en) | Antibody composition for prevention or treatment of mutant hepatitis b virus infection | |
Nevens et al. | Treatment of decompensated viral hepatitis B‐induced cirrhosis with low doses of interferon alpha | |
CHANG | Chronic hepatitis virus infection in children | |
WO2003028722A1 (en) | Treatment of hepatitis b virus infection with human monoclonal antibodies | |
Finkenstedt et al. | Lactose absorption, milk consumption, and fasting blood glucose concentrations in women with idiopathic osteoporosis. | |
US20050260195A1 (en) | Treatment of hepatitis B virus infection with human monoclonal antibodies | |
EP2224943A1 (en) | Use of human antibody capable of neutralizing hepatitis b virus for the prevention or treatment of hepatitis b virus infection | |
Cotonat et al. | Pilot study of combination therapy with ribavirin and interferon alfa for the retreatment of chronic hepatitis B e antibody-positive patients | |
Akiyama et al. | Effects of cyclosporin A on hepatitis C virus infection in bone marrow transplant patients | |
JP2022542035A (en) | Methods of treating HBV infection using anti-PRE-S1 HBV antibodies | |
Wagner et al. | Failure of vaccination against hepatitis B with Gen HB-Vax-D in immunosuppressed heart transplant recipients | |
Burm et al. | A human monoclonal antibody against HBsAg for the prevention and treatment of chronic HBV and HDV infection | |
Mehrabi et al. | The role of HBIg as hepatitis B reinfection prophylaxis following liver transplantation | |
AU2002210869A1 (en) | Treatment of hepatitis B virus infection with human monoclonal antibodies | |
Perrillo | The management of chronic hepatitis B | |
Heijtink et al. | Administration of a human monoclonal antibody (TUVIRUMAB) to chronic hepatitis B patients pre‐treated with lamivudine: monitoring of serum TUVIRUMAB in immune complexes | |
Chang | Treatment of chronic hepatitis C virus infection in children | |
Shapiro et al. | Remission of nephrotic syndrome of HBV-associated membranous glomerulopathy following treatment with interferon |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BY BZ CA CH CN CO CR CU CZ DE DM DZ EC EE ES FI GB GD GE GH HR HU ID IL IN IS JP KE KG KP KR LC LK LR LS LT LU LV MA MD MG MN MW MX MZ NO NZ PH PL PT RO SD SE SG SI SK SL TJ TM TR TT TZ UG US UZ VN YU ZA |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): GH GM KE LS MW MZ SD SL SZ UG ZW AM AZ BY KG KZ MD TJ TM AT BE CH CY DE DK ES FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GQ GW MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 161138 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 846/DELNP/2004 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2003532054 Country of ref document: JP Ref document number: 2462427 Country of ref document: CA Ref document number: 1020047004987 Country of ref document: KR |
|
WWE | Wipo information: entry into national phase |
Ref document number: 20018236928 Country of ref document: CN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2002210869 Country of ref document: AU Ref document number: 2001978778 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 2001978778 Country of ref document: EP |
|
WWW | Wipo information: withdrawn in national office |
Ref document number: 2001978778 Country of ref document: EP |