WO1999045969A2 - Medicament radioimmunnologique destine au traitement de l'infection a vih-1 - Google Patents

Medicament radioimmunnologique destine au traitement de l'infection a vih-1 Download PDF

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Publication number
WO1999045969A2
WO1999045969A2 PCT/DE1999/000598 DE9900598W WO9945969A2 WO 1999045969 A2 WO1999045969 A2 WO 1999045969A2 DE 9900598 W DE9900598 W DE 9900598W WO 9945969 A2 WO9945969 A2 WO 9945969A2
Authority
WO
WIPO (PCT)
Prior art keywords
hiv
radioimmunoconjugate
radioimmuno
cells
infected
Prior art date
Application number
PCT/DE1999/000598
Other languages
German (de)
English (en)
Other versions
WO1999045969A3 (fr
Inventor
Wolfgang Bergter
Ingrid-Corina Bergter
Original Assignee
Wolfgang Bergter
Bergter Ingrid Corina
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 Wolfgang Bergter, Bergter Ingrid Corina filed Critical Wolfgang Bergter
Priority to JP2000535382A priority Critical patent/JP2002506051A/ja
Priority to EP99919038A priority patent/EP1061959A2/fr
Priority to AU36981/99A priority patent/AU3698199A/en
Publication of WO1999045969A2 publication Critical patent/WO1999045969A2/fr
Publication of WO1999045969A3 publication Critical patent/WO1999045969A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1027—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against receptors, cell-surface antigens or cell-surface determinants
    • A61K51/1039—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody against receptors, cell-surface antigens or cell-surface determinants against T-cell receptors

Definitions

  • Radioimmune drug for the treatment of HIV-1 infection is Radioimmune drug for the treatment of HIV-1 infection.
  • HIV infection leads to a progressive immune deficiency due to loss of the CD4 + T helper cells infected with HIV. If the number of these cells falls below a threshold value of 350 / ⁇ l or if the viral load in the blood exceeds 30,000 RNA copies / ⁇ l, antiretroviral therapy is preferred today with an orally administered combination of three medications consisting of two inhibitors of reverse transcriptase (RTI) and a protease inhibitor (PI). This replicates and slows down the replication of the HI viruses.
  • RTI reverse transcriptase
  • PI protease inhibitor
  • HTV-replicating host cells cannot be eliminated with these agents. HIV infection persists as a life-threatening infection. A cure for HIV infection is still not possible.
  • HIV and HIV-infected cells can be labeled with antibodies, but these do not trigger the desired immune response, which leads to the elimination of the infected cells, because the latter is already compromised by the HIV infection.
  • the body's own cytotoxic immune response, which is disturbed by HIV infection, must therefore be replaced by a targeted, artificially induced death of all HIV-infected cells, if possible.
  • Radionuclides as radioiodine therapy from the treatment of benign and malignant thyroid diseases has been known in Germany for over 50 years as the most important method of nuclear medicine therapy and has proven to be low in side effects. To date, late complications, particularly malignant induction, have not been demonstrated (Moser 1996).
  • MIBG I-labeled meta-iodo-benzyl-guanidine
  • J adioimmunotherapies including 131 J-labeled anti-CEA IgG for colorectal cancer (Blumenthal et al. 1992, Blumenthal 1994), and 131 J-labeled anti-CD20 and anti CD22 antibodies in B cell lymphoma (Kaminski et al 1993, Press et al. 1993, Press et al. 1995, Press et al. 1995).
  • AZ WO 94/04191 AI describes a treatment method for the complete elimination of all cells carrying CD4 receptors, i.e. healthy and HIV-infected cells. Two options are mentioned for this, on the one hand the
  • Radioimmune drugs should be taken after antiretroviral therapy has been used to reduce the viral load, and the possible problems of bone marrow and thyroid damage may be covered by stem cell transplantation and or thyroid medication. This is intended to overcome the disadvantages of the pharmaceuticals and treatment methods described in the abovementioned printed publications and to solve a global health problem which has so far been expanding unhindered.
  • the compound is a human gp41 specific monoclonal antibody with the isotope 131 I into consideration.
  • the retroviral transmembrane glycoprotein gp41 is firmly integrated into the viral and cellular lipid membrane and, unlike the surface protein gpl20, cannot dissociate by shedding from the virus or from the HIV-infected cell.
  • a suitable component of a radioimmunoconjugate and well characterized would be, for example, the human monoclonal antibody 2F5, which binds to a highly conserved epitope which is therefore widespread in the different HTV-1 isolates (Muster et al. 1993).
  • the short half-life of the radionuclides J, P, Y and Sr requires preparation close to the center or rapid transport of the radioimmuno-conjugate
  • the prerequisite for the therapy of HIV patients with short-lived radionuclides is therefore the establishment of specialized interdisciplinary centers, in which, in addition to professional therapy for HIV-infected people (including standard antiretroviral therapy), timely application of the radioimmuno-conjugate is also guaranteed under radiation protection law aspects.
  • a prerequisite for successful therapy is the reduction of the viral load by pretreating the patient with the modern standard triple therapy, as is generally known. This allows a higher dose of the radioimmune drug to be applied to the HIV-infected cells in order to eliminate them. Otherwise the preparation would be trapped by free virus particles and the cytotoxic effect would be reduced.
  • thyroid diagnostics and thyroid blockade must also be carried out according to the known scheme.
  • the radioimmunoconjugate should be administered intravenously. This generally requires hospitalization over several days in order to shield the patient from the environment until the radiation has decayed.
  • the preparation can be administered peripherally or centrally as a bolus, short infusion or continuous therapy over several days with a dose of probably 50 - 300 mCi.
  • the dose is given once or in the form of cycles at intervals of several weeks.
  • the radioimmunoconjugate binds specifically with the help of the monoclonal antibody to an epitope of a retroviral transmembrane or surface glycoprotein (gp41 or gpl20) integrated in the cell wall of the HIV-1 replicating cell. So this at this Cell-fixed radionuclide emits ⁇ -radiation into the surrounding area. In particular, the cell infected with HIV-1 infected with numerous radioimmuno-conjugates is damaged.
  • gp41 or gpl20 retroviral transmembrane or surface glycoprotein
  • the radiation energy of an ⁇ or ⁇ emitter such as m J has a range of up to 40 cell diameters. Malignant transformations of healthy cells as a result of radiation damage are extremely rare and can hardly be recorded statistically. If a healthy cell is damaged, it also loses its ability to divide in most cases and reproductive or programmed cell death (apoptosis) occurs. The radiation of surrounding healthy cells also plays a subordinate role in the radioimmunotherapy of HIV-infected T lymphocytes, since these are predominantly in the circulation and healthy cells therefore only experience radiation exposure for a short time.
  • a third major advantage is that internalization of our radioimmuno-conjugates, in contrast to the antibody-toxin conjugates of WO 91/10742 AI, is not necessary and that radionuclides do not bind unspecifically to healthy cells like toxins.
  • the aim of radioimmunotherapy for HIV infection with the radioimmunoconjugates described in this patent application is the targeted, complete elimination of HTV-1 replicating cells and thus the healing of HIV-infected persons or at least a significant delay in the course of the disease, an improvement in quality of life and a reduction healthcare costs.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Physics & Mathematics (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (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

Les traitements standard de l'infection à VIH présentent des inconvénients. D'une part, les médicaments utilisés actuellement doivent être pris quotidiennement en grande quantité (environ 30 comprimés par jour) à heures précises et à vie et leurs effets indésirables sont nombreux. D'autre part, les médicaments classiques ne font que réduire la réplication des virus si bien que les cellules hôtes infectées par le virus VIH ne sont pas éliminées et que l'infection à VIH n'est pas guérie. L'invention concerne un médicament radioimmunologique constitué d'un anticorps monoclonal et d'un radionucléide destiné à l'élimination in-vitro des cellules répliquant le virus VIH chez des patients infectés par le virus VIH-1 après abaissement de la charge virale par un traitement antirétroviral et éventuellement sous protection d'une transplantation de cellules souches et sous protection médicamenteuse du fonctionnement de la glande thyroïde. Ce médicament radioimmunologique est administré par voie intraveineuse en une fois ou en plusieurs cycles aux patients infectés par le virus VIH-1 et endommage ultérieurement de façon ciblée les cellules hôtes répliquant le virus VIH de telle façon que si possible l'ensemble des cellules hôtes soient éliminées. L'objectif est la guérison de l'infection à VIH ou au moins le ralentissement de la progression de la maladie.
PCT/DE1999/000598 1998-03-08 1999-03-05 Medicament radioimmunnologique destine au traitement de l'infection a vih-1 WO1999045969A2 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP2000535382A JP2002506051A (ja) 1998-03-08 1999-03-05 Ｈｉｖ−１感染を治療するための放射免疫剤
EP99919038A EP1061959A2 (fr) 1998-03-08 1999-03-05 Medicament radioimmunnologique destine au traitement de l'infection a vih-1
AU36981/99A AU3698199A (en) 1998-03-08 1999-03-05 Radioimmuno-pharmacon for treating the hiv-1 infection

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE19809785.9 1998-03-08
DE1998109785 DE19809785C2 (de) 1998-03-08 1998-03-08 Radioimmunpharmakon zur Behandlung der HIV-1-Infektion

Publications (2)

Publication Number Publication Date
WO1999045969A2 true WO1999045969A2 (fr) 1999-09-16
WO1999045969A3 WO1999045969A3 (fr) 2000-02-17

Family

ID=7860044

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DE1999/000598 WO1999045969A2 (fr) 1998-03-08 1999-03-05 Medicament radioimmunnologique destine au traitement de l'infection a vih-1

Country Status (5)

Country Link
EP (1) EP1061959A2 (fr)
JP (1) JP2002506051A (fr)
AU (1) AU3698199A (fr)
DE (1) DE19809785C2 (fr)
WO (1) WO1999045969A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999054954A2 (fr) * 1998-04-15 1999-10-28 Wolfgang Bergter Substances pharmaceutiques radio-immunologiques a base de cd4 destinees au traitement de l'infection par le vih
EP1091763B1 (fr) * 1998-06-29 2003-09-17 Wolfgang Bergter Medicaments antiviraux et antiretroviraux radioimmunologiques a base d'emetteurs de rayonnement alpha et beta
WO2004011633A1 (fr) * 2002-07-29 2004-02-05 Tsinghua University Anticorps dirige contre la souche de type o du vih, lignee cellulaire d'hybridomes produisant cet anticorps et utilisations correspondantes

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0417927A1 (fr) * 1989-08-24 1991-03-20 Immunomedics, Inc. Détection et traitement d'infections en utilisant des immunoconjugués
WO1991010742A1 (fr) * 1990-01-16 1991-07-25 Replgien Corporation Anticorps monoclonal specifique de l'epitope non-immunodominant de l'enveloppe proteinique du vih
WO1994004191A1 (fr) * 1992-08-13 1994-03-03 Antisoma Limited Traitement medical
WO1994007922A1 (fr) * 1992-09-30 1994-04-14 The Scripps Research Institute Anticorps monoclonaux neutralisateurs humains contre le virus de l'immunodeficience humaine

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IE63109B1 (en) * 1986-06-23 1995-03-22 Genetic Systems Corp Human monoclonal antibody to lymphadenopathy-associated virus
CA1339857C (fr) * 1987-05-29 1998-05-05 Cecily Rou-Yun Sun Anticorps monoclonaux qui peuvent se fixer a la proteine gp120 et qui neutralisent le vih-1
JPH04505099A (ja) * 1989-02-28 1992-09-10 ニューヨーク　ユニバーシィティ ヒト免疫不全ウイルスに対するヒトモノクローン抗体
CA2178341A1 (fr) * 1993-10-15 1995-04-20 Eva M. Rakowicz-Szulczynska Detection et traitement des cancers du sein et des cancers gynecologiques

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0417927A1 (fr) * 1989-08-24 1991-03-20 Immunomedics, Inc. Détection et traitement d'infections en utilisant des immunoconjugués
WO1991010742A1 (fr) * 1990-01-16 1991-07-25 Replgien Corporation Anticorps monoclonal specifique de l'epitope non-immunodominant de l'enveloppe proteinique du vih
WO1994004191A1 (fr) * 1992-08-13 1994-03-03 Antisoma Limited Traitement medical
WO1994007922A1 (fr) * 1992-09-30 1994-04-14 The Scripps Research Institute Anticorps monoclonaux neutralisateurs humains contre le virus de l'immunodeficience humaine

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS [Online] DN=120:189253, XP002114952 & OTTEKEN A. ET AL: "Characterization of monoclonal antibodies to the envelope proteins of an immunodeficiency virus of African green monkeys, SIVagmTYO-7" J. MED. PRIMATOL., Bd. 22, Nr. 4, 1993, Seiten 263-268, *
LANCET THE, Bd. 346, 5. August 1995 (1995-08-05), Seiten 336-340, XP002114951 LONDON GB in der Anmeldung erw{hnt *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999054954A2 (fr) * 1998-04-15 1999-10-28 Wolfgang Bergter Substances pharmaceutiques radio-immunologiques a base de cd4 destinees au traitement de l'infection par le vih
WO1999054954A3 (fr) * 1998-04-15 2000-01-20 Wolfgang Bergter Substances pharmaceutiques radio-immunologiques a base de cd4 destinees au traitement de l'infection par le vih
EP1091763B1 (fr) * 1998-06-29 2003-09-17 Wolfgang Bergter Medicaments antiviraux et antiretroviraux radioimmunologiques a base d'emetteurs de rayonnement alpha et beta
WO2004011633A1 (fr) * 2002-07-29 2004-02-05 Tsinghua University Anticorps dirige contre la souche de type o du vih, lignee cellulaire d'hybridomes produisant cet anticorps et utilisations correspondantes

Also Published As

Publication number Publication date
DE19809785C2 (de) 2000-02-10
EP1061959A2 (fr) 2000-12-27
DE19809785A1 (de) 1999-09-09
WO1999045969A3 (fr) 2000-02-17
JP2002506051A (ja) 2002-02-26
AU3698199A (en) 1999-09-27

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