WO1992001451A1 - Procede permettant de tuer des cellules infectees par le vih - Google Patents

Procede permettant de tuer des cellules infectees par le vih Download PDF

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Publication number
WO1992001451A1
WO1992001451A1 PCT/US1991/003383 US9103383W WO9201451A1 WO 1992001451 A1 WO1992001451 A1 WO 1992001451A1 US 9103383 W US9103383 W US 9103383W WO 9201451 A1 WO9201451 A1 WO 9201451A1
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chloroquine
hiv
cells
infected cells
infected
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PCT/US1991/003383
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English (en)
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Ellen S. Vitetta
Jonathan Uhr
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Board Of Regents, The University Of Texas System
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Priority to AU79565/91A priority Critical patent/AU7956591A/en
Publication of WO1992001451A1 publication Critical patent/WO1992001451A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines

Definitions

  • the present invention relates to a method of treating Human Immunodeficiency Virus (HIV) infections, wherein chloroquine is employed to selectively kill HIV-infected cells.
  • HIV Human Immunodeficiency Virus
  • HIV is a retrovirus that causes a variety of immuno- logical deficiencies in humans. Particularly, it causes acquired immune deficiency syndrome (AIDS) and AIDS related complex (ARC). 1
  • AIDS acquired immune deficiency syndrome
  • ARC AIDS related complex
  • T4 lymphocytes defend against invading foreign matter; thus, their destruction renders the body susceptible to a spectrum of diseases.
  • HIV also infects other immune system tissue such as monocytes, nervous system tissue, intestinal tissue and probably some bone marrow cells. Monocytes and macrophages (matured monocytes) are not killed outright by HIV. Rather, it is believed that, once infected, these cells serve to continuously incubate the virus.
  • T4 T4
  • a specific HIV protein known as gpl20 whose precursor is gpl60, recognizes and binds to CD4.
  • core proteins and viral RNA of the virus are delivered into the cell.
  • the viral RNA is then transcribed into DNA by a reverse transcriptase. This DNA can then integrate into the host cell's DNA (in which case the infection is latent) or it can commandeer the cell's bio ⁇ chemical machinery for viral replication. If replication is rapid enough, the host cell lyses.
  • HIV infection poses particularly formid ⁇ able challenges because HIV infects the very cells that defend against infections. Furthermore, the simplicity of retroviruses, their propensity to alter their antigenic properties, and their ability to integrate into the host cell's genome have troubled researchers trying to design specific treatments. Additionally, treatment of HIV related central nervous system (CNS) disorders, is complicated by the blood-brain barrier's general impenetrability to drugs.
  • CNS central nervous system
  • AZT azidothymidine
  • AZT treatment has many drawbacks.
  • the drug is highly toxic to many individuals.
  • AZT does appear to improve the quality of life, there is no indication that AZT actually is effective in all circumstances. It certainly does not cure the disease. Some individuals are particularly sensitive to AZT and cannot tolerate it.
  • drugs on the horizon however, these are merely in the clinical trial stage.
  • substances such as phosphonoformate, rifabutin, ddC, ddA and dd, may inhibit HIV's reverse- transcriptase. Some of these may also act as chain terminators of RNA and DNA chain extensions.
  • Other substances such as dextran sulfate, rCD4 and certain monoclonal antibody products, may serve to inhibit viral binding at CD4 sites.
  • chloroquine has been studied as a method for treating HIV infections, its use has been discounted because it is thought only to inhibit viral entry into cells or inhibit replications of virus and infected cells. Accordingly, there is still a great need for methods which also treat infected cells. Particularly, there is a need for methods that will kill HIV-infected cells as opposed to methods that are simply directed to either alleviating the symptoms or inhibiting replications.
  • An object of this invention is to selectively kill cells infected by the Human Immunodeficiency Virus. Another object is to provide a drug that is useful in the treatment of HIV infections whose general pharmacology is known and predictable. Yet another object is to provide a treatment that is relatively low in cost when compared with currently available treatments such as AZT.
  • Chloroquine's pharmacology as to humans is well known to persons skilled in the medical sciences.
  • chloroquine concentrates in the same tissues that HIV is believed to infect.
  • the inventor's studies reveal that chloroquine is toxic to HIV-infected human cultured cell lines. Accordingly, it is expected that chloroquine will safely and effectively treat human HIV infections such as AIDS, ARC, and HIV-related central nervous system disorders.
  • Methods of administering chloroquine to HIV-infected individuals are expected to be similar to how it is admin ⁇ istered in treating human malarial infections. These include oral or parenteral administration.
  • the invention is carried out by subjecting cells infected by the HIV virus to a sufficient amount of chloroquine to kill HIV- infected cells.
  • the HIV infected cells can be killed by subjecting them to a concentration of 10 to 20 ⁇ g/ml/day of chloroquine. However, a preferred concentration range is 2 to 5 ⁇ g/ml/per day of chloroquine. It is contemplated that this method can be adapted for killing HIV infected cells in humans.
  • a dose of 300 to 500 mg per day of chloroquine per day is administered to individuals infected with the HIV virus. Administration is continued until HIV infected cells are killed.
  • chloroquine can be administered orally at a dose of 300 to 500 mg per day, or, alternatively, parenterally at a dose of 200 to 300 mg per day.
  • Chloroquine can also be used to treat the symptoms of debilitation, chronic opportunistic infection, and autoimmune reactions, which are associated with HIV infections.
  • chloroquine is administered at a dosage sufficient to reduce one or more of the symptoms.
  • administration of chloroquine can, again, be orally at a dose of 300 to 500 mg per day or parenterally at a dose of 200 to 300 mg per day. In either case, this administration is continued for the duration of the infection.
  • the administration of the above dosages can be adapted to include an initial dose which is double the dosage of the subsequent doses.
  • Chloroquine may also be combined with an immunotoxin having anti-HIV activity such as a CD4-, anti-gpl20- or anti-gp41-based immunotoxin, preferably linked with ricin A chain or deglycosylated ricin A chain (dgA) , for enhanced toxicity to the infected cells.
  • an immunotoxin having anti-HIV activity such as a CD4-, anti-gpl20- or anti-gp41-based immunotoxin, preferably linked with ricin A chain or deglycosylated ricin A chain (dgA) , for enhanced toxicity to the infected cells.
  • the dose will typically be between about 200 and 300 mg of chloroquine, and between about 30 and 50 mg of the immunotoxin, administered over a one week course.
  • Figure l shows the effect of varying concentrations of chloroquine on cultured U937 human cells infected with either a SAN (•) or BAG (0) HIV isolate, or on uninfected control cells of the same kind (A) .
  • Figure 2 shows the effect of various concentrations of immunotoxins in combination with a constant concentration of chloroquine and without chloroquine on HIV-infected cultured human cells and uninfected cells of the same kind.
  • Figure 2A is shown the effects of treatment with either control immunotoxin (Ig-dgA, ⁇ ) or with anti-gp41 immunotoxins (antibody 98-6-dgA, 0 . antibody 50-69-dgA, A) on viability of HIV infecte H9 cells.
  • Figure 2B are the effects of these agents on control, uninfected H9 cells.
  • Chloroquine widely known as an anti-malarial compound, is also known to have certain antiviral effects. 2 It has previously been proposed that chloroquine can inhibit viral entry into cells. In vitro studies indicate that chloroquine prevents the processing of envelope glycoproteins involved in recognizing CD4. 3 ' 4 Some in vitro studies also indicate that chloroquine inhibits pH- dependent entry of HIV into uninfected cells. 5
  • the present invention is a breakthrough, beyond these known effects of chloroquine, in that chloroquine is employed to selectively kill cells already infiltrated by HIV.
  • chloroquine is employed to selectively kill cells already infiltrated by HIV.
  • HIV-infected human H9 T-cells have been found by the inventors to be up to fifty-fold more sensitive to chloroquine than uninfected cells.
  • concentrations necessary to kill infected cells in vitro are within the dosage range used for in vivo treatments of other diseases such as malaria. 6 ' 7 (See, infra, example 1). It is proposed that chloroquine functions in part by reducing the reservoir of HIV infected cells and thereby reduces or delays the progression of the disease.
  • chloroquine collects in higher concen ⁇ trations in some tissues than in others.
  • the tissues where the higher concentrations of chloroquine are found include the tissues that HIV is most likely to infect.
  • chloroquine concentrates in the lymphoid system, wherein HIV-infected T cells, monocytes, dendritic cells and B cells are believed to reside. These cells are major reservoirs of HIV in infected humans. Leukocytes also concentrate chloroquine. Additionally, chloroquine concentrates in the cerebrospinal fluid. Hence, the blood-brain barrier would not impede using chloroquine to treat HIV infected CNS tissues. Chloroquine concentration in the liver, spleen, kidney and lungs can be 200 to 700 times greater than in the plasma.
  • Chloroquine's quality of specifically concentrating in the very tissues likely to be infected by HIV means that chloroquine can be delivered to these tissues in an appro ⁇ priate dosage while exposing the tissues unsusceptible to infection to a relatively low dosage. This quality of chloroquine should minimize the potential for adverse reactions in the unsusceptible tissues.
  • chloroquine can be compatibly used in combination with other pharmacologicals.
  • in vitro studies show that chloroquine, in conjunction with immunotoxins, enhances the immunotoxin's effect. (See example 2) This is particularly true of immunotoxins directed against the gp41 component of HIV, but is also true of immunotoxins directed against gpl20.
  • chloroquine will also synergize with other drugs such as AZT.
  • chloroquine is a type of 4-aminoquinoline.
  • Exemplary congeners generally of the 4-aminoquinoline family, include amodiaquine, hydroxychloroquine, quinacrine, pamaquine, pentaquine, and the like (see, e.g.,
  • Wiselogle 9 Wiselogle 9
  • Chloroquine's general pharmacology is well studied from its use in treating malaria 6 ' 7 .
  • chloroquine has proved effective against a variety of other disorders, including inflammatory diseases, certain lupus diseases, certain photoallergic reactions, and cardiac arrhythmias.
  • Chloroquine is believed to have several biological mechanisms: it completely inhibits certain enzymes, it has been shown to inhibit incorporation of 32 p-labeled phosphate into RNA and DNA, and it tightly binds to double stranded DNA. Chloroquine also inhibits DNA and RNA polymerase by combining with DNA primer. 7
  • chloroquine The metabolism of chloroquine is well understood. When ingested, chloroquine quickly and nearly completely assimilates into the bloodstream, binding mostly to nondiffusible plasma constituents. The body does not rapidly excrete chloroquine, but it does degrade chloroquine into several metabolites. Particularly, chloroquine is degraded into a metabolite called desethylchloroquine and bisdesethylchloroquine. Degradation metabolites account for about 30% of the chloroquine absorbed by the digestive system. The remaining 70% is unchanged chloroquine.
  • Chloroquine can be taken orally, in tablet form, or parenterally by injection. Orally, chloroquine is given either before or after meals. It is expected that chloroquine can be administered to treat HIV infections by selectively killing HIV infected human cells in an individual diagnosed with HIV.
  • An initial dose of about 600 mg is administered, orally or parenterally on each of two consecutive days.
  • Suppressive doses of about 300 mg daily should then be given weekly for 2 to 3 weeks.
  • Infants or children should not be administered more than about 10 mg of chloroquine per kilogram of body weight per day.
  • Chloroquine is known to have some side effects; these are discussed in detail in medical references such as Goodman and Gilman's, The Pharmacological Basis of Therapeutics and the Physician's Desk Reference. A brief description of some of chloroquine's known side effects follows.
  • chloroquine should not be used during pregnancy.
  • This example demonstrates the successful use of chloroquine to selectively kill HIV-infected U937 cells, an accepted test system for demonstrating anti-HIV activity. (See Figure 1) . It also shows doses of chloroquine which have been successfully employed to kill HIV-infected cells.
  • U937 is a monocyte cell line that was selected because it can be chronically infected with HIV and is resistent to the lytic effects of the virus.
  • the tested U937 cells comprised a set of cells infected with the BAG isolate of HIV, a set of cells infected with the SAN isolate of HIV, and uninfected cells.
  • the BAG and SAN isolates are separate HIV isolates from different patients.
  • the control cells were infected cells but were not subjected to any chloroquine. Serial dilutions of chloroquine were plated in 96-well microliter plates. Cells were then added to make a final concentration of 4 x 10 5 /ml. After the plates were incubated for 36 hours they were pulsed with tritiated thymidine. Cells were then harvested and thymidine incorporation determined using a Beta counter. The uptake of tritiated thymidine in the cell's DNA gives a measure of cell division at a specific time.
  • Figure 1 shows the effect of increasing concentrations of chloroquine on the viability of identical cells handled identically except with and without exposure to chloroquine. The effects were measured by measuring the uptake of labeled thymidine, which is a measure of DNA replication and, hence, cell viability.
  • the symbols represent: (0) U937 infected with the BAG isolate of HIV; (•) U937 infected with the SAN isolate of HIV; (A) uninfected U937 cells. Results are expressed as a percentage of control cells.
  • Figure 1 shows that as the concentration of chloroquine was increased, so did the toxic effects that were observed against the HIV-infected cells. These studies show that HIV infected cells were fifty times more sensitive to chloroquine than uninfected cells. In other words, at a concentration of about 2 x 10 ⁇ 9 M, 50% of the U937 cells infected with either of the HIV isolates were killed, while the uninfected control U937 cells were unaffected. From Figure 1 it can also be observed that the effective concentrations at which infected cells are killed in vitro are within the range of doses used to treat other diseases in vivo (e.g. malaria) . 6 ' 7 The doses used in this study were about 1 to 20 ⁇ g/ l, and thus similar to dosage ranges that have been obtained for chloroquine in patients in the treatment of malaria.
  • the doses used in this study were about 1 to 20 ⁇ g/ l, and thus similar to dosage ranges that have been obtained for chloroquine in patients in the treatment of malaria.
  • Immunotoxins are conjugates formed between a cell surface binding ligand, such as a cell surface-directed antibody, and a toxin moiety, such as deglycosylated ricin A chain (dgA) .
  • dgA deglycosylated ricin A chain
  • IT-dga immunotoxin- dgA conjugate
  • concentration of the immunotoxin- dgA conjugate (IT-dga) employed was varied while keeping the concentration of chloroquine constant at 2 x 10 ⁇ 5 M.
  • Each IT-dgA was plated in serial dilution. Dilutions were made in complete media (RPMI 1640 with 15% (v/v) heat inactivated fetal calf serum and antibiotics) , with or without chloroquine. Cells were then added and cell viability measured by thymidine uptake as described in Example 1. The results are expressed in Figure 2 as viability in terms of percentage of control cells which remain alive (untreated cells ⁇ chloroquine) .
  • the controls employed for these studies included the use of a polyclonal human immunoglobulin immunotoxin prepared by Sandoz, Inc. and having specificity unknown to the inventors (Ig-dgA) , as well as the use of uninfected cells.
  • Figure 2A shows the effects of treatment with either control immunotoxin (Ig-dgA, ⁇ ) or with an i-gp41 immunotoxins (antibody 98-6-dgA, 0 antibody 50-69-dgA, A) on viability of HIV infected H9 cells.
  • control immunotoxin Ig-dgA, ⁇
  • i-gp41 immunotoxins antibody 98-6-dgA, 0 antibody 50-69-dgA, A
  • FIG. 2C is shown a similar study, except for the inclusion of chloroquine together with the respective control or anti-gp41 immunotoxins (open symbols) , and the use of HTLV III b infected U937 cells.
  • the anti-gp41 immuntoxins were administered alone, a 50% killing of HTLV III b infected U937 cells was observed at between about 10 ⁇ 8 and 10 ⁇ 9 M.
  • chloroquine was included, a dramatic shift in the curve of about 2 to 3 orders of magnitude to the left was observed, with a 50% killing at a concentration of between about 10 ⁇ 10 and about 10 "11 M.
  • Figure 2B shows that no effect was observed for the combination of anti-gp41 immunotoxins with chloroquine on uninfected U937 cells.

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Abstract

L'invention concerne l'utilisation de chloroquine pour tuer de manière sélective des cellules infectées par le VIH. L'invention implique, en partie, l'utilisation de chloroquine dans des régimes de traitement administrés à des individus infectés par le VIH, la chloroquine étant administrée à des doses efficaces au niveau pharmacologique. Bien qu'on se propose de n'administrer que de la chloroquine aux individus infectés par le VIH, d'autres améliorations semblent être possibles en administrant de la chloroquine en association avec d'autres agents tels que des immunotoxines anti-VIH (par exemple, des immunotoxines à base de CD4, ou des immunotoxines anti-gp41 ou à base d'anti-gp120). Dans ces versions, on pense que la chloroquine va agir en synergie avec les immunotoxines anti-VIH pour tuer sélectivement les cellules infectées par le VIH. Bien qu'on préfère utiliser de la chloroquine, on se propose d'utiliser d'autres composés apparentés tels des agents anti-malaria de 4-aminoquinoline ou des agents ou des congénères de la famille de la chloroquine, pour obtenir des améliorations en rapport avec l'invention.
PCT/US1991/003383 1990-06-12 1991-05-15 Procede permettant de tuer des cellules infectees par le vih WO1992001451A1 (fr)

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US536,887 1990-07-20

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1374867A1 (fr) * 2002-06-28 2004-01-02 Valpharma S.A. Utilisation de la chloroquine, de l'hydroxychloroquine et de dérivés de la 4-aminoquinoline comme médicament dans des thérapies anti-rétrovirales, actives contre des souches VIH et contre des souches VIH résistantes, qui sont résistantes aux inhibiteurs nucléosidiques et non-nucléosidiques de la transcriptase inverse et aux inhibiteurs de protéases
US6692745B2 (en) * 2000-01-28 2004-02-17 Arogenics Pharmaceuticals, Inc. Compositions and methods for inhibition of HIV-1 infection
US6734192B1 (en) * 1999-08-23 2004-05-11 Mp-1 Inc. Treatment of viral infections
WO2005027855A3 (fr) * 2003-02-21 2006-01-26 Jarrow Formulas Inc Procedes pour le traitement de vih ou de paludisme mettant en oeuvre des combinaisons de chloroquine et des inhibiteurs de protease
US7138119B2 (en) 2000-09-15 2006-11-21 Progenics Pharmaceuticals, Inc. Compositions and methods for inhibition of HIV-1 infection
US7345153B2 (en) 1996-01-17 2008-03-18 Progenics Pharmaceuticals, Inc. Compounds capable of inhibiting HIV-1 infection
US7666419B2 (en) 2002-02-22 2010-02-23 Progenics Pharmaceuticals Inc. Anti-CCR5 antibody
AU2008201715B2 (en) * 2003-02-21 2011-04-14 Jarrow Formulas, Inc. Methods for treatment of HIV or malaria using combinations of chloroquine and protease inhibitors
CN1901914B (zh) * 2003-02-21 2011-06-08 加罗配方公司 包含喹啉抗疟化合物和蛋白酶抑制剂的组合的药物组合物及其应用
US8232240B2 (en) * 2005-02-23 2012-07-31 The Brigham And Women's Hospital, Inc. Inhibitors of enveloped virus infectivity

Citations (1)

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US470692A (en) * 1892-03-15 Mince-meat machine

Patent Citations (1)

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US470692A (en) * 1892-03-15 Mince-meat machine

Non-Patent Citations (5)

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Title
AIDS Research and Human Retroviruses, vol. 6, no. 4, April 1990, Mary Ann Liebert, Inc., Publishers, W.-P. Tsai et al.: "Inhibition of human immunodeficiency virus infectivity by chloroquine", pages 481-489 *
Chemical Abstracts, vol. 114, no. 3, 21 January 1991, (Columbus, Ohio, US), & US-A-470 692 (NATIONAL INSTITUTES OF HEALTH) 1 August 1990 *
Int. Conf. AIDS, vol. 5, 4-9 June 1989, abstract no. M.C.P. 119, I. Desportes et al.: "Effect of chloroquine on HIV1 infection of monocytes" *
Int. Conf. AIDS, vol. 5, 4-9 June 1989, abstract no. M.C.P. 66, W.P. Tsai et al.: "Inhibition of human immunodeficiency virus infectivity by chloroquine" *
The Western Journal of Medicine, vol. 146, no. 2, February 1987, B.L. Kagan: "Lysosomotropic agents in AIDS treatment", page 234 *

Cited By (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7345153B2 (en) 1996-01-17 2008-03-18 Progenics Pharmaceuticals, Inc. Compounds capable of inhibiting HIV-1 infection
US6734192B1 (en) * 1999-08-23 2004-05-11 Mp-1 Inc. Treatment of viral infections
US6692745B2 (en) * 2000-01-28 2004-02-17 Arogenics Pharmaceuticals, Inc. Compositions and methods for inhibition of HIV-1 infection
US7138119B2 (en) 2000-09-15 2006-11-21 Progenics Pharmaceuticals, Inc. Compositions and methods for inhibition of HIV-1 infection
US7666419B2 (en) 2002-02-22 2010-02-23 Progenics Pharmaceuticals Inc. Anti-CCR5 antibody
EP1374867A1 (fr) * 2002-06-28 2004-01-02 Valpharma S.A. Utilisation de la chloroquine, de l'hydroxychloroquine et de dérivés de la 4-aminoquinoline comme médicament dans des thérapies anti-rétrovirales, actives contre des souches VIH et contre des souches VIH résistantes, qui sont résistantes aux inhibiteurs nucléosidiques et non-nucléosidiques de la transcriptase inverse et aux inhibiteurs de protéases
WO2005027855A3 (fr) * 2003-02-21 2006-01-26 Jarrow Formulas Inc Procedes pour le traitement de vih ou de paludisme mettant en oeuvre des combinaisons de chloroquine et des inhibiteurs de protease
AU2004273773B2 (en) * 2003-02-21 2008-01-24 Jarrow Formulas, Inc. Methods for treatment of HIV or malaria using combinations of chloroquine and protease inhibitors
AU2008201715B2 (en) * 2003-02-21 2011-04-14 Jarrow Formulas, Inc. Methods for treatment of HIV or malaria using combinations of chloroquine and protease inhibitors
AU2008201715B8 (en) * 2003-02-21 2011-04-21 Jarrow Formulas, Inc. Methods for treatment of HIV or malaria using combinations of chloroquine and protease inhibitors
CN1901914B (zh) * 2003-02-21 2011-06-08 加罗配方公司 包含喹啉抗疟化合物和蛋白酶抑制剂的组合的药物组合物及其应用
US8232240B2 (en) * 2005-02-23 2012-07-31 The Brigham And Women's Hospital, Inc. Inhibitors of enveloped virus infectivity

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