WO1995024904A1 - Inhibition synergique d'infections par vih-1 au moyen d'un inhibiteur de transcriptase inverse de nucleosides et d'anticorps anti vih-1 - Google Patents

Inhibition synergique d'infections par vih-1 au moyen d'un inhibiteur de transcriptase inverse de nucleosides et d'anticorps anti vih-1 Download PDF

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Publication number
WO1995024904A1
WO1995024904A1 PCT/US1995/003169 US9503169W WO9524904A1 WO 1995024904 A1 WO1995024904 A1 WO 1995024904A1 US 9503169 W US9503169 W US 9503169W WO 9524904 A1 WO9524904 A1 WO 9524904A1
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WIPO (PCT)
Prior art keywords
hiv
antibodies
infection
aids
composition
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Application number
PCT/US1995/003169
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English (en)
Inventor
Michael S. C. Fung
Nancy T. Chang
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Tanox Biosystems, Inc.
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Publication date
Application filed by Tanox Biosystems, Inc. filed Critical Tanox Biosystems, Inc.
Priority to AU21196/95A priority Critical patent/AU2119695A/en
Publication of WO1995024904A1 publication Critical patent/WO1995024904A1/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
    • C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
    • C07K16/1036—Retroviridae, e.g. leukemia viruses
    • C07K16/1045—Lentiviridae, e.g. HIV, FIV, SIV
    • C07K16/1063—Lentiviridae, e.g. HIV, FIV, SIV env, e.g. gp41, gp110/120, gp160, V3, PND, CD4 binding site
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to treatment of HIV-1 infection
  • HIV-1 the virus which causes AIDS — have been suggested for both treating and preventing HIV-1 infection.
  • Most neutralizing anti-HIV-1 antibodies target specific regions of the envelope glycoproteins gpl20 and gp41. Some of these regions are the principal neutralizing determinant in the V3 region, the C4 region, the V2 loop, and the CD4-binding domain.
  • Monoclonal antibodies which target the principal neutralizing deterrninant (“PND”) have been shown to protect from infection in animal models.
  • T cells with the virus.
  • the T cells are critical to the proper functioning of the immune system. When HIV-1 infects human T cells, it ultimately destroys these cells by lysing them. As the number of T cells declines, the victim's immune system is increasingly compromised, and opportunistic infections and tumors which are characteristic of AIDS result. The invariable outcome of the infection is the death of the victim, usually as a direct result of one or more of these complications.
  • nucleoside reverse transcriptase inhibitors including ZidovudineTM (also known as “AZT”), dideoxyinosine (“ddl”), and dideoxycytidine (“ddC”) are approved for use in treatment of HIV-disease. There are also indications, particularly for AZT, that these inhibitors can prevent infection of newborn whose mothers are HIV-1 seropositive. This mode of infection is known as vertical transmission.
  • Anti-HIV monoclonal antibodies are also intended for use in preventing vertical transmission, or otherwise protecting persons who are exposed to the virus. Such exposure can occur, for example, when a hospital worker is accidentally punctured with an HTV-1 contaminated needle or other sharp object, or through unprotected sexual contact with an infected person.
  • Adrninisterrng anti-HTV monoclonal antibodies to inhibit progression of disease or to prevent infection is known as passive immunization.
  • the invention includes the use of nucleoside reverse transcriptase inhibitors, preferably AZT, in combination with one or more neutralizing anti-HIV-1 antibodies, to treat or prevent
  • AIDS-439 is a genetically engineered chimeric mouse/human monoclonal antibody with human IgGl constant regions and variable regions corresponding to the murine monoclonal antibody BAT123.
  • a transfectoma cell line producing AIDS-439 is on deposit at the American Type Culture Collection ("ATCC"), 12301 Parklawn Drive, Rockville
  • a hybridoma cell line producing BAT123 is on deposit at the ATCC under Accession Number HB 10438.
  • neutralizing anti-HIV-1 antibodies polyclonal and monoclonal, can also be used to assay a biological fluid sample for HrV-1 virions or for HTV-1 -infected cells, or to quantify the concentration of HIV-1 or of infected cells, present in a biological fluid. This is useful for diagnosis of HIV-1 infection and detection of HIV-1 contamination in a culture or another sample.
  • These antibodies can be used in standard assay formats, such as the ELJSA format or the immunofluorescence format described below.
  • the invention includes the use of nucleoside reverse transcriptase inhibitors, preferably AZT, in combination with neutralizing anti-HTV-1 antibodies, to treat or prevent HTV-1 infection.
  • nucleoside reverse transcriptase inhibitors are AZT, ddl, and ddC.
  • the dosage ranges for these inhibitors are all readily available from the pharmacopeias, as these products are approved for sale. The recommended dosages should be used when practicing the invention, although other dosages which do not result in toxicity and which result in synergistic neutralization are also acceptable.
  • the neutralizing anti-HIV-1 antibodies for use in the invention are preferably those targeting the PND, the C4 region, the V2 loop, or the CD4-binding domain.
  • a number of such antibodies are known and available.
  • AIDS-439 targets the PND.
  • G3-519, G3-508 and G45-60 (the cells lines producing them are on deposit at the ATCC under Accession Numbers HB 10747, HB 10748, and HB 10749, respectively) target the C4 region.
  • BAT 085, G3-136 and G3-4 (the cell lines producing them are on deposit at the ATCC under Accession Numbers HB 11118, HB 10932, and HB 10733, respectively) target the V2 loop.
  • There are also a number of other monoclonal antibodies which target these same regions, or otherwise neutralize HIV-1, and which can be used in the invention.
  • the recommended dosage for the monoclonal antibodies can be estimated based on in vitro studies and animal model studies. To perform this extrapolation, one determines the dosage in animal models (such as the hu-PBL-SCID mouse) which is effective in protecting the animals from HTV-l infection, when they are administered the same dose of HIV-1. Then one multiplies this dosage by the ratio of the mass of the human over that of the animal. This provides the initial estimate of the dosage
  • Example 1 Protection of hu-PBL-SCID Mice from Infection A study was made of me ability of two monoclonal antibodies of the invention, BAT123 and AIDS-439, to protect hu- PBL-SCID mice from infection by HIV-1. The protocol for this study was as follows.
  • SCID mice were reconstituted by intraperitoneal (i.p.) injection of 2 x 10 7 human peripheral blood lymphocytes (PBL).
  • PBL peripheral blood lymphocytes
  • mice were checked for human immunoglobulin.
  • PBL-SCLD mice were required to show a human immunoglobulin level of at least 10 ⁇ g/ml in their sera.
  • mice for use in the study were divided into three groups with six mice in each group.
  • One group was a control group, and received tl.. irrelevant immunoglobulin PNTU.
  • AIDS-439 All antibodies were injected i.p. at a dose of 40 mg/kg of animal weight.
  • me animals were inoculated i.p. with HIV-1 IIIB , at a dose adequate to infect at least 80% of the animals, as calculated based on a prior virus titration in otiier hu-PBL-SCID mice. This dosage is 10 times die dosage needed to infect 50% of me animals.
  • Serum samples were taken from me animals at selected intervals in order to study me pharmacokinetics of me injected antibodies. The animals were sacrificed three weeks after inoculation and their spleen cells and peritoneal lavage were cultured for HIV-l for four weeks. Cells from me peritoneal lavage and spleen cells were analyzed for HTV-l infection by co- cultivation, and only spleen cells were analyzed by PCR.
  • BAT123 and AIDS-439 showed any HTV-l infection.
  • Five out of the six control mice showed infection of their spleen cells as determined by co-cultivation, and two of the five showed infection by PCR. Only one control animal showed infection of me cells from me peritoneal lavage.
  • a range of the same dosages of AIDS-439 (40 mg/kg of animal weight) could be used in humans, in beginning me determination of the appropriate dosage to use. The same procedure could be used to determine me appropriate dosage of other anti-HTV-l antibodies.
  • Example II Safety and Tolerability of ATDS-439
  • AIDS patients were screened from the closely monitored AIDS patients at the University Hospital of Zurich. Twelve male AIDS patients selected were above age 18. Each had CD4 + lymphocyte counts of 10-230/mm 3 with proven viremia at CDC stage IV clinical status, i ⁇ ., up to 3 opportunistic Cl or C2 type infections wim a life expectancy of at least 6 months. All patients were wimdrawn from AZT treatment four to six weeks before the trial began.
  • HIV-l antigenemic positive by HIV-l antigen assays and tissue culture infectious dose (TCID) assays.
  • TCID tissue culture infectious dose
  • the 12 selected patients were carefully evaluated, beginning 6-8 weeks before the trial. Monitoring and recording activities for each patient included a medical history, clinical examination, and various laboratory tests, including hematology, clinical chemistry, general immunology, HIV antigen test, HIV-l viremia, special immunology, and urinalysis.
  • HIV-l antigenemia was monitored by me Abbott HTV Ag test and HTV viremia was monitored by tissue culture for TCID, PCR, and branched DNA amplification techniques.
  • the pharmacokinetics of AIDS-439 were:
  • CD4 + , CD3 + ,and CD8 + cells from peripheral blood were enumerated with use of specific monoclonal antibody reagents and flow cytometry. All laboratory work complied with good clinical practices.
  • Clinical and laboratory analysis data in combination wim the weekly physical examinations were the basis for review of the clinical status of each patient throughout the trial. Good tolerability was defined as lack of subjective or objective symptoms following administration of AIDS-439.
  • AIDS-439 was well tolerated, even up to a cumulative dose of 1,425 mg over 170 days. However, one patient reported tiredness at an interim stage in the trial. Among the patients receiving the highest dose of AIDS-439 (Group 3), all of mem showed stabilization of body weight and all survived for me entire 170 day trial period. This indicates mat AIDS-439 can be safely administered at a dose up to at least 200 mg per administration, cumulatively over several weeks. Such dosages can be used in me present invention. The same protocol detailed above can be used to determine the safe and effective dosage of otiier anti-HIV antibodies. In summary, one uses several different dosages in various patients and monitors their reaction and their clinical response over a period of time.
  • Example ELI Synergy in Inhibition of HTV-l Infection by a Combination of AZT and AIDS-439
  • the following is an analysis of the inhibition of HIV-l TTTR infection of CEM-SS cells (a human T cell line) by a combination of AZT and AIDS-439. Progressively increasing dosages of
  • AIDS-439 and AZT were added to a culture of CEM-SS cells, a human T cell line known to be subject to HTV-l infection.
  • An infectivity assay was men perfo ⁇ ' ;d on me CEM-SS cells, using the method of Nara, P. et al., AIDS Res. Human Retroviruses
  • Example TV Use of Antibodies for Detection or Quantitation of HTV-l Virions or Infected Cells
  • anti-HIV-1 antibodies monoclonal and polyclonal, can be used for detection or quantitation of HIV-l virions or infected cells.
  • a protocol for carrying this out is
  • the antibodies of me invention can be immobilized on inert solid matrices or magnetic beads, either directly or indirectly through a cross-linking agent or a specific binding agent (e.g. protein A, goat anti-mouse IgG, or goat anti-human IgG).
  • a cross-linking agent or a specific binding agent e.g. protein A, goat anti-mouse IgG, or goat anti-human IgG.
  • the biological fluid test samples are then incubated wim the antibody-coated matrices.
  • HIV-l virions or gpl20 reactive with the antibodies will bind to me matrices.
  • the bound virions or gpl20 can men be detected wim either monoclonal or polyclonal anti-HTV-1 antibodies, which can men be reacted wim enzyme-linked secondary detecting antibodies for quantitation based on color reaction.
  • the captured virions can be detected by otiier means, ejg. fluorescence, chemil
  • the monoclonal antibodies of the invention can be used to detect and to quantitate the HTV-l -infected cells in patient blood samples by direct or indirect immunofluorescence procedures.
  • the protocol is well-known by tiiose skilled in me art, and is described specifically in U.S. Application Serial No. 07/950,571.

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Abstract

L'invention concerne une composition à base d'inhibiteurs de transcriptase inverse de nucléosides, de préférence l'AZT, combinée à des anticorps neutralisant anti-VIH-1, qui sert au traitement ou à la prévention d'infections par VIH-1. On peut utiliser des anticorps polyclonaux ou monoclonaux ciblant un domaine neutralisant de gp120, tel que la région V3, la région C4, la boucle V2 ou le domaine de fixation de CD4. Les anticorps préférés sont ceux qui ciblent le déterminant neutralisant principal de la région V3. L'anticorps monoclonal anti-gp120 qui fait l'objet d'une préférence particulière est AIDS-439. On a découvert que cette composition exerce un effet synergique sur la neutralisation de l'infection par VIH-1.
PCT/US1995/003169 1994-03-16 1995-03-14 Inhibition synergique d'infections par vih-1 au moyen d'un inhibiteur de transcriptase inverse de nucleosides et d'anticorps anti vih-1 WO1995024904A1 (fr)

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AU21196/95A AU2119695A (en) 1994-03-16 1995-03-14 Synergistic inhibition of hiv-1 infection using a nucleoside reverse transcriptase inhibitor and anti-hiv-1 antibodies

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US21483794A 1994-03-16 1994-03-16
US08/214,837 1994-03-16

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO2001034177A2 (fr) * 1999-11-08 2001-05-17 The Government Of The United States Of America, A S Represented By The Secretary, Department Of Hea Lth & Human Services, The National Institutes Of Health Procede pour le traitement d'une infection virale a l'aide d'antagonistes du facteur stimulant la proliferation de macrophages
WO2002059154A2 (fr) * 2001-01-26 2002-08-01 Abgenix, Inc. Utilisation de souris transgenique pour isoler efficacement de nouveaux anticorps monoclonaux humains a activite de neutralisation de souches primaires du vih-1 et nouveaux anticorps de neutralisation du vih-1

Citations (5)

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US5086044A (en) * 1986-06-23 1992-02-04 Burroughs Wellcome Co. Treatment of human viral infections
WO1992007878A1 (fr) * 1990-10-26 1992-05-14 The Public Health Research Institute Of The City Of New York, Inc. Neutralisation d'anticorps monoclonaux humains specifiques contre la boucle v3 et le site de liaison cd-4 de hiv-1 gp120
US5234913A (en) * 1991-03-06 1993-08-10 Burroughs Wellcome Co. Antiviral nucleoside combination
US5245015A (en) * 1991-04-26 1993-09-14 Tanox Biosystems, Inc. Monoclonal antibodies which neutralize HIV-1 through reaction with a conformational epitope in vitro
US5266478A (en) * 1987-05-29 1993-11-30 Tanox Biosystems, Inc. Antibodies which target a neutralization site within the second variable region of human immunodeficiency virus type 1 gp120

Patent Citations (5)

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US5086044A (en) * 1986-06-23 1992-02-04 Burroughs Wellcome Co. Treatment of human viral infections
US5266478A (en) * 1987-05-29 1993-11-30 Tanox Biosystems, Inc. Antibodies which target a neutralization site within the second variable region of human immunodeficiency virus type 1 gp120
WO1992007878A1 (fr) * 1990-10-26 1992-05-14 The Public Health Research Institute Of The City Of New York, Inc. Neutralisation d'anticorps monoclonaux humains specifiques contre la boucle v3 et le site de liaison cd-4 de hiv-1 gp120
US5234913A (en) * 1991-03-06 1993-08-10 Burroughs Wellcome Co. Antiviral nucleoside combination
US5245015A (en) * 1991-04-26 1993-09-14 Tanox Biosystems, Inc. Monoclonal antibodies which neutralize HIV-1 through reaction with a conformational epitope in vitro

Non-Patent Citations (5)

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Title
AIDS RESEARCH AND HUMAN RETROVIRUSES, Vol. 9, Supplement 1, issued October 1993, SAFRIT et al., "Protection of Hu-PBL-SCID Mice From Infection With Human Immunodeficiency Virus Type 1 Through Passive Transfer of a Monoclonal Antibody Directed Against the Third Variable Region of the Envelope gp120", page s78. *
BIO/TECHNOLOGY, Vol. 12, issued February 1994, FOX J.L., "No Winners Against AIDS", page 128. *
CLINICAL AND EXPERIMENTAL IMMUNOLOGY, Vol. 88, issued 1992, FAHEY et al., "Status of Immune-Based Therapies in HIV Infection and AIDS", pages 1-5. *
CLINICAL MICROBIOLOGY REVIEWS, Vol. 5, No. 2, issued April 1992, BEAN B., "Antiviral Therapy: Current Concepts and Practices", pages 146-182. *
THE JOURNAL OF IMMUNOLOGY, Vol. 143, No. 12, issued 15 December 1989, LIOU et al., "A Chimeric Mouse-Human Antibody That Retains Specificity For HIV gp120 And Mediates The Lysis Of HIV-Infected Cells", pages 3967-3975. *

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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
WO1999004814A1 (fr) * 1997-07-24 1999-02-04 Roche Diagnostics Gmbh Preparations pharmaceutiques combinees contenant des anticorps monoclonaux humains destines a traiter l'hepatite b chronique
WO2001034177A2 (fr) * 1999-11-08 2001-05-17 The Government Of The United States Of America, A S Represented By The Secretary, Department Of Hea Lth & Human Services, The National Institutes Of Health Procede pour le traitement d'une infection virale a l'aide d'antagonistes du facteur stimulant la proliferation de macrophages
WO2001034177A3 (fr) * 1999-11-08 2002-01-31 Us Health Procede pour le traitement d'une infection virale a l'aide d'antagonistes du facteur stimulant la proliferation de macrophages
WO2002059154A2 (fr) * 2001-01-26 2002-08-01 Abgenix, Inc. Utilisation de souris transgenique pour isoler efficacement de nouveaux anticorps monoclonaux humains a activite de neutralisation de souches primaires du vih-1 et nouveaux anticorps de neutralisation du vih-1
WO2002059154A3 (fr) * 2001-01-26 2003-10-09 Abgenix Inc Utilisation de souris transgenique pour isoler efficacement de nouveaux anticorps monoclonaux humains a activite de neutralisation de souches primaires du vih-1 et nouveaux anticorps de neutralisation du vih-1

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