WO1999043328A1 - Treatment of hiv infections - Google Patents
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- WO1999043328A1 WO1999043328A1 PCT/US1999/002955 US9902955W WO9943328A1 WO 1999043328 A1 WO1999043328 A1 WO 1999043328A1 US 9902955 W US9902955 W US 9902955W WO 9943328 A1 WO9943328 A1 WO 9943328A1
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
- A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
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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
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
- A61K31/7056—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing five-membered rings with nitrogen as a ring hetero atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
- A61K38/13—Cyclosporins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6835—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
- A61K47/6849—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
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- 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
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
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- 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
- A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies
Definitions
- This invention relates to methods of treating HIV and AIDS.
- HAART Human Immunodeficiency Virus
- Current therapies for Human Immunodeficiency Virus (HIV) infections are typically built around highly active antiretroviral therapy (HAART).
- HAART therapies are often combinations or "cocktails" of two or more antiretroviral agents.
- R. M. Gulick "Current antiretroviral therapy: an overview", Qual. Life Res. 6(6):471-474 (1997); K. Henry et al., "Antiretroviral therapy for HIV infection. Heartening Successes mixed with continuing challenges", Postgrad. Med. 102(4):100-107 (1997); C. B. Hicks, “Update on antiretroviral therapy", Radiol. Clin. North Am. 35(5):995-1005 (1997); R. H. Goldschmidt, "Antiretroviral drug treatment for HIV/ AIDS", Am. Fam. Physician, 54(2):574- 580 (1996).
- Drugs used in HAART regimens include the nuceloside analogs
- HAART using these treatments may reduce plasma loads of active HIV virus in HIV- 1 -positive patients to undetectable amounts, apparently without the threat of developing resistant strains of HIV.
- M. Baiter "HIV Survives Drug Onslaught by Hiding Out in T Cells," Science 278:1227 (November 14, 1997). This document, and all documents cited to herein, are incorporated by reference as if fully reproduced below. The hope was that if active HIV replication was suppressed through
- Memory CD4+ T cells are CD4+CD8- T lymphocytes that are "resting" or quiescent.
- memory cells are generally non-proliferating, and are capable of being activated in case of a subsequent exposure to an antigen. In this way, they form part of the acquired immune response. Further information describing memory T cells can be found in a standard immunology textbook, such as E. Benjamin, et al., "Immunology: A Short Course,” (1996) (Wiley-Liss). Previous investigators had detected integrated viral DNA in memory T cells, but believed it to be defective. The investigators in the three studies found that once the memory T cells were activated, replication-competent HIN-1 was produced in most cases. In the first study, replication competent virus was routinely recovered from memory CD4+ T lymphocytes of 22 patients who had been treated successfully with HAART for up to 30 months.
- the drugs that make up HAART's are focused on actively replicating HIV in proliferating T cells and other proliferating immune system cells, such as macrophages.
- the drugs function by inhibiting virus replication and infection, and by inhibiting or killing infected proliferating cells. Accordingly, it does not seem likely that continued administration of HAART will reach the memory T cell HIV reservoir to eradicate the integrated and unintegrated virus contained within it.
- the invention relates to a method of treating an HIV- infected host comprising administering to the host a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, in a CD4+ T cell cytotoxic or cytostatic effective amount.
- the invention in another aspect, relates to a method of treating an HIV- infected host comprising administering highly active antiretroviral therapy; and coadrninistering to the host a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, in a CD4+ T cell cytotoxic or cytostatic effective amount.
- the invention relates to a kit comprising a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, wherein the therapeutic agent is present in a CD4+ T cell cytotoxic or cytostatic effective amount.
- the invention relates to a composition
- a composition comprising a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, wherein the therapeutic agent is present in a CD4+ T cell cytotoxic or cytostatic effective amount.
- the invention relates to a method of ex vivo or in vitro treatment of blood derived cells, bone marrow transplants, or other organ transplants comprising treating the blood derived cells, bone marrow transplants, or other organ transplants with a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, in a CD4+ T cell cytotoxic or cytostatic effective amount.
- the invention relates to a method of treating an HIV- infected host comprising: administering to the host a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, in a CD4+ T cell cytotoxic or cytostatic effective amount.
- the invention relates to the above method, where the therapeutic agent comprises a nucleoside analog, or a CD4+ T cell specific antibody alone or coupled or conjugated to a moiety that is cytotoxic or cytostatic with respect to CD4+ T cells.
- the invention relates to the above method, wherein the nucleoside analog comprises purine and pyrimidine and their analogs thereof.
- the invention relates to the method, where the nucleoside analog comprises pentostatin and analogs thereof, coformycin, cladribine, fludarabine, or a deoxyadenosine and analogs thereof.
- the invention relates to the method , where the therapeutic agent comprises pentostatin and analogs thereof.
- the invention relates to the method where the CD4+ T cell comprises a memory cell. In another aspect, the invention relates to the method, where the CD4+ T cells comprise both HIV-infected and non-HIV- infected CD4+ T cells. In a further aspect, the invention relates to the method where the antibody is specific for CD4+ memory T cells. In yet another aspect, the invention relates to the method further comprising reestablishing the host's immune system. In still another aspect, the invention relates to the method, wherein the step of reestablishing the host's immune system comprises providing bone marrow transplants, thymic stimulation, a ⁇ ninistration of various cytokine growth factors, vaccination, or administration of interleukins.
- Another aspect of the invention is a method of treating an HIV-infected host comprising administering highly active antiretroviral therapy; and coadrninistering to the host a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, in a CD4+ T cell cytotoxic or cytostatic effective amount.
- the invention relates to the method, where the therapeutic agent comprises a nucleoside analog, or a CD4+ T cell specific antibody alone or coupled or conjugated to a moiety that is cytotoxic or cytostatic with respect to CD4+ T cells.
- the invention relates to the method, wherein the nucleoside analog comprises purine and pyrimidine and their analogs thereof.
- the invention relates to the method, where the nucleoside analog comprises pentostatin and analogs thereof, coformycin, cladribine, fludarabine, or a deoxyadenosine and analogs thereof.
- the invention relates to the method, where the therapeutic agent comprises pentostatin and analogs thereof.
- the invention relates to the method where the CD4+
- T cell comprises a memory cell.
- the invention relates to the method, where the CD4+ T cells comprise both HIV-infected and non-HIV- infected CD4+ T cells.
- the invention relates to the method where the antibody is specific for CD4+ memory T cells.
- the invention relates to the method, wherein the therapeutic agent according to the invention is administered or coadministered parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, intrathecally, or in a slow release dosage form.
- the invention relates to the method, wherein the therapeutic agent is administered or coadministered singly or as a combination with another therapeutic agent.
- the invention relates to the method, wherein the combination comprises a deoxyadenosine and pentostatin.
- the invention relates to the method, wherein the combination comprises 2', 3' - dideoxyadenosine and pentostatin.
- the invention relates to the method, wherein the therapeutic agent is pentostatin, and the pentostatin is administered or coadministered intravenously in doses of about four to ten mg/sq m once per day for about three consecutive days once per month, about four to five mg/sq m/day weekly for about four weeks and about fortnightly thereafter, to the generally frequented dose of about four mg/sq m about every two weeks for a maximum dosage period of about one year.
- the therapeutic agent is pentostatin
- the pentostatin is administered or coadministered intravenously in doses of about four to ten mg/sq m once per day for about three consecutive days once per month, about four to five mg/sq m/day weekly for about four weeks and about fortnightly thereafter, to the generally frequented dose of about four mg/sq m about every two weeks for a maximum dosage period of about one year.
- the invention relates to a kit comprising a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, wherein the therapeutic agent is present in a CD4+ T cell cytotoxic or cytostatic effective amount.
- the invention relates to the kit, where the therapeutic agent comprises a nucleoside analog, or a CD4+ T cell specific antibody alone or coupled or conjugated to a moiety that is cytotoxic or cytostatic with respect to
- the invention relates to the kit, wherein the nucleoside analog comprises purine and pyrimidine and their analogs thereof. In a further aspect, the invention relates to the kit, where the nucleoside analog comprises pentostatin and analogs thereof, coformycin, cladribine, fludarabine, or a deoxyadenosine and analogs thereof. In still another aspect, the invention relates to the kit, where the therapeutic agent comprises pentostatin and analogs thereof.
- the invention relates to a composition
- a composition comprising a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, wherein the therapeutic agent is present in a CD4+ T cell cytotoxic or cytostatic effective amount.
- the invention relates to the composition , where the therapeutic agent comprises a nucleoside analog, or a CD4+ T cell specific antibody alone or coupled or conjugated to a moiety that is cytotoxic or cytostatic with respect to CD4+ T cells.
- the invention relates to the composition, wherein the nucleoside analog comprises purine and pyrimidine and their analogs thereof.
- the invention relates to the composition, where the nucleoside analog comprises pentostatin and analogs thereof, coformycin, cladribine, fludarabine, or a deoxyadenosine and analogs thereof.
- the invention relates to the composition, where the therapeutic agent comprises pentostatin and analogs thereof.
- the invention relates to a method of ex vivo or in vitro treatment of blood derived cells, bone marrow transplants, or other organ transplants comprising treating the blood derived cells, bone marrow transplants, or other organ transplants with a therapeutic agent that is cytotoxic or cytostatic with respect to CD4+ T cells, but has reduced cytotoxic or cytostatic activity with respect to T lymphocyte stem cells, in a CD4+ T cell cytotoxic or cytostatic effective amount.
- the invention relates to the method, where the therapeutic agent comprises a nucleoside analog, or a CD4+ T cell specific antibody alone or coupled or conjugated to a moiety that is cytotoxic or cytostatic with respect to CD4+ T cells.
- the invention relates to the method, wherein the nucleoside analog comprises purine and pyrimidine and their analogs thereof.
- the invention relates to the method, where the nucleoside analog comprises pentostatin and analogs thereof, coformycin, cladribine, fludarabine, or a deoxyadenosine and analogs thereof.
- the invention relates to the method, where the therapeutic agent comprises pentostatin and analogs thereof.
- T cells but is not cytotoxic or cytostatic, or has reduced such activity, with respect to T lymphocyte stem cells, in a cytotoxic or cytostatic effective amount, may eliminate or reduce the reservoir of HIV-infected memory T cells. This is particularly true if the host is in need of this treatment or (co)administration, etc. At this point, an overview of how the invention might be practiced in one preferred embodiment may be helpful.
- an HIV positive patient receives HAART, together with appropriate pharmaceuticals, such as antivirals; antifungals; and antibiotics, to protect against opportunistic infections. Additionally, the patient is coadministered one or more therapeutic agents, according to the invention.
- This regimen is continued for a period past the point when the levels of integrated and unintegrated HIV in active and memory T cells are undetectably low.
- the patient is weaned from HAART and from the therapeutic agents according to the invention.
- the patient is monitored for reestablishment of normal immune function and for signs of reemergence of HIV infection.
- any needed conjunctive immunotherapy such as bone marrow transplants, various cytokines or vaccination, is administered. If there are no signs of HIV infection for a suitable period, then the patient is weaned from the pharmaceuticals that protect against opportunistic infections. After this, the patient is monitored on a routine basis for life to detect reemergence of HTV infection, in which case repeat therapy according to the above preferred embodiment must be undertaken
- the present invention may serve as an adjunct to this conventional therapy through coadministration.
- the present invention may be practiced apart from conventional therapy, if appropriate.
- the nature of the inventive therapeutic agents is such that their administration or coadministration may have an antiviral effect.
- Such an antiviral effect may be additive, in the case of coadministration with HAART, or it may be the primary antiviral effect afforded the patient. In either situation, performing treatment on
- HIV-infected patients according to the invention is an important advance because the inventive treatment reaches memory cells.
- Memory cells are a particularly difficult target to reach with most conventional anti-HIV therapies. As noted above, such therapies are most effective against HIV in proliferating cells. Such cells are much more interactive with their environment, and thus offer more opportunity for exogenous intervention. In fact, prior to this invention, approaches to HIV therapy were focused on such proliferating cells almost exclusively, because of the relative ease of intervention. However, to reach memory cells, which are by definition non-proliferating until activated, non-conventional approaches are needed. Accordingly, the invention provides for therapeutic agents that have cytotoxic or cytostatic effects with respect to memory cells. These inventive therapeutic agents are characterized by their differential ability to affect non-proliferating T lymphocytes, as compared to conventional HIV therapies.
- inventive therapeutic agents may intervene in essential cellular structure that is not involved in cell replication.
- therapeutic agents according to the invention may accelerate non ⁇ replicating DNA strand breaks, consequently inducing apoptosis.
- inventive 1 1
- therapeutic agents might induce lysis of resting/memory cells by selectively binding to and disrupting the membrane of memory cells.
- cytotoxic or cytostatic effects of the therapeutic agents according to the invention include both apoptosis and classic cell death (eg. lysis, etc.) mechanisms.
- the therapeutic agents may selectively activate apoptotic genes in memory cells, resulting in programmed cell death. This may be accomplished, for example, by providing therapeutic agents that are taken up selectively by memory cells and intervene in the regulatory pathways of the memory T cell's apoptotic genes.
- inventive therapeutic agents may selectively modify a memory cell's ability to adapt to environmental stresses, such as endogenous toxins (e.g. free radicals). This renders the memory cells particularly vulnerable to the introduction of such environmental stresses, and leads to the differential cell death of such cells.
- environmental stresses such as endogenous toxins (e.g. free radicals).
- Another class of inventive therapeutic agents may act by selectively activating the host's reservoir of memory cells. Such activated T cells may begin proliferating, thus exposing any integrated or unintegrated HIV to conventional
- HAART This allows use of HAART to eliminate or reduce the reservoir of HTV contained in the memory cell pool.
- nucleoside analogs Take, for example, nucleoside analogs. Such analogs have been used in a variety of applications, including antiviral and oncological applications. In these applications, any potential side effects that differentially targeted memory cells, such as loss of acquired immunity, were seen as undesirable. However, in the context of this invention, loss of acquired immunity through the elimination of memory T cells, is a potentially desirable condition.
- Nucleoside analogs useful in this invention include analogs containing purine and pyrimidine, and their analogs thereof. Included within the definition of analogs are various prodrugs of the active species. Development of such prodrugs may be according to methods known in the art. Additional information may be found in U.S. Patent 5,177,064 to Bodor, and in U.S. Patent 5,459,256 to Marquez et al.
- Preferred nucleoside analogs include analogs containing adenine, guanine, cytosine, uracil, and thymine, and their analogs thereof.
- 2'- deoxycoformycin also referred to as DCF, pentostatin, or NIPENT®
- an inhibitor of adenosine deaminase an inhibitor of adenosine deaminase
- fludarabine monophosphate (FLU) a fluorinated analogue of adenine that is relatively resistant to adenosine-deaminase and 2-chloro-2'-deoxyadenosine (also known as cladribine or 2CDA) a drug also resistant to adenosine deaminase through introduction of a chloride at the carbon 2
- deoxyadenosines generally, including 2'-deoxyadenosine, 3 '-deoxyadenosine, and dideoxyadenosine.
- the analogs according to the invention have demonstrated activity against quiescent, resting, lymphocytes (i.e. memory cells). For example, upon a ⁇ ininistering DCF, FLU or 2CDA, prolonged lymphopenia predominating in T cells, especially in the CD4+ subset, and an increased frequency of opportunistic infections has been observed.
- ADA adenosine deaminase
- T cells might be more sensitive than B cells to intervention in the ADA pathway.
- ADA levels have been found to be tenfold greater in T cells than in B cells.
- ADA inhibition since T cells display greater dATP accumulation, affects more T than B cells.
- ADA pathway intervention seems unclear, it may be that analogs of adenosine resistant to cellular deamination might mimic the ADA-deficient state. They would thus have a potential therapeutic activity on resting lymphocytes without damaging other cell types. Lack of ADA seems to lead to a build up of deoxyadenosine and adenosine triphosphate in the cell, thus fatally accelerating DNA strand breaks in the cell.
- NAD nicotinamide adenosine dinucleotides
- nucleoside analogs according to the invention can act on quiescent lymphocytes via an apoptotic process.
- NAD precursor of nicotinamide or 3-aminobenzamide an inhibitor of poly (ADP-ribose) synthetase, prevented NAD depletion and reduces 2CDA toxicity, tends to support this hypothesis.
- DCF deoxycytidine kinase
- dATP deoxyadenosine-5'-triphosphate
- FLU and 2CDA are rather resistant to the enzyme. Both drugs are initially phosphorylated by DCK and contribute to the accumulation of cellular adenosine triphosphate. As noted above, the accumulation of adenosine triphosphate, whether by the presumed DCF mechanism, or the FLU or 2CDA mechanism, promotes the apoptotic death of the cell.
- Other therapeutic agents useful in the practice of this invention include cyclosporine, tacrolimulus (FK506), and antibodies directed against specific T- cell epitopes (either alone or conjugated with other agents, such as cytotoxins, radiation/photochemical sensitizers), cytostasis inducing compounds (e.g. radiation/photochemical sensitizers), peptide mimetics that target specific receptors or other proteins on T-cells, analogs of these agents, and other unique pathways that may be amenable to intervention, preferably T-cells, and more preferably CD4+ cells.
- cytotoxins e.g. radiation/photochemical sensitizers
- cytostasis inducing compounds e.g. radiation/photochemical sensitizers
- peptide mimetics that target specific receptors or other proteins on T-cells, analogs of these agents, and other unique pathways that may be amenable to intervention, preferably T-cells, and more preferably CD4+ cells.
- the therapeutic agents according to the invention may be administered or coadministered in any conventional dosage form.
- they may be administered or coadministered parenterally, intraperitoneally, intravenously, intraarterially, transdermally, sublingually, intramuscularly, rectally, transbuccally, intranasally, liposomally, via inhalation, vaginally, intraoccularly, via local delivery by catheter or stent, subcutaneously, intraadiposally, intraarticularly, or intrathecally.
- the therapeutic agents according to the invention may also be administered or coadministered in slow release dosage 17
- therapeutic agents may be administered or coadministered with conventional pharmaceutical excipients and additives.
- the therapeutic agents may be administered or coadministered singly or in combinations of therapeutic agents.
- One preferred example of such a combination is the combination of deoxyadenosines with pentostatin. It has been reported that pentostatin enhances the clinical anti-HIV activity of related adenosine analogs presumably due to prevention of degradation of the adenosine analogs by adenosine deaminase. G.S.
- Dosage amounts and frequency will vary according to the particular therapeutic agent, dosage form, and individual patient characteristics. Generally speaking, determining the dosage amount and frequency for a particular therapeutic agent, dosage form, or individual patient characteristic can be accomplished using conventional dosing studies, coupled with appropriate diagnostics.
- pentostatin is used as the therapeutic agent.
- pentostatin may be administered or coadministered intravenously in doses of about four to ten mg/sq m once per day for about three consecutive days once per month, about four to five mg/sq m/day weekly for about four weeks and about fortnightly thereafter, to the generally frequented dose of about four mg/sq m about every two weeks for a maximum dosage period of about one year.
- this dosing regimen may be adjusted depending upon the individual patient's needs.
- administering or coadrninistering the therapeutic agent according to the invention It may be desirable, in certain circumstances, to continue HAART.
- the endpoint might preferably occur when the level of active virus is undetectable and the number of CD4+ T lymphocyte memory cells, especially those containing HIV, is undetectably low.
- the level of active virus may be considered undetectable low using conventional assays of viral activity, including measuring copies of HIV RNA/ml.
- the number of CD4+ T lymphocyte memory cells can likewise be determined using conventional assays and screens.
- This intervention may take the form of reestablishing the patient's immune system through procedures such as bone marrow transplants, thymic stimulation, administration of various cytokine growth factors and/or interleukins, vaccination, and other similar, conventional, procedures.
- the patient's immune system may be considered reestablished when conventional measures of immune system function have returned to reasonably normal levels.
- T cells T cells. During ontogeny and in T cell development, precursors of T cells migrate from the bone marrow to the thymus, where most T cell development occurs. In the thymus, T cells mature, express antigen specificity and are selected for appropriate antigen binding. More complete discussion of T cell development may be found in "Cancer: Principles and Practice of Oncology” (1997) (Vincent
- Practicing the invention as disclosed permits these stem cells to undergo the thymic maturation process and develop into mature CD4+ cells at a significantly reduced risk of HIV infection. Furthermore, it is within the scope of the invention to stimulate the production of stem cells (through, eg., bone marrow transplants), and of mature CD4+ and other immune system components (through various forms of immunostimulation).
- the patient may be weaned from the drugs that are administered or coadministered to ward off opportunistic infections.
- the patient should be closely monitored for signs of relapse. Such signs include increasing active HIV load, abnormal T cell counts, symptoms of opportunistic infections, etc. If signs of relapse are seen, then the patient should not be weaned from their medications for a further evaluation period. It may be necessary to 20
- the patient is successfully weaned from the last of the HAART, inventive therapeutics, and drugs to ward off opportunistic infections, and the patient's immune system is stable, then it may be possible for the patient to be in remission for long periods of time. Of course, during that time, the patient should be routinely monitored for reemergent signs of infection. If such signs reemerge, then the patient may require repeat treatments according to the invention.
- the invention may be practiced in an in vitro or ex vivo environment. All of the discussion above that is relevant to an in vitro or ex vivo environment applies to such embodiments.
- practice of an in vitro or ex vivo embodiment of the invention might be useful in the practice of immune system transplants, such as bone marrow transplants or peripheral stem cell procurement.
- the inventive therapeutic agents might be used, as generally described above, to purge the transplant material to reduce the risk of HIV infection due to HIV-infected memory T cells.
- practice of the invention might be used to purge whole blood supplies to reduce the risk of HIV infection due to HIV-infected memory T cells.
- Other such in vitro or ex vivo applications will occur to one of skill in the art and are therefore contemplated as being within the scope of the invention.
- CD4+RO+ cells are enriched by magnetic separation and FACS sorting, and assayed to determine infectivity with respect to naive and uninfected cell co- culture experiments. This analysis of CD4+RO+ memory cells shows the presence of infective HIV.
- Pentostatin is therefore administered at a dose of 4 mg/m 2 by intravenous infusion once every two weeks for a period of 3 months until CD4+ cells, including memory cells, are at low levels.
- the patient is maintained on a maintenance dose of HAART, along with antibiotics and antifungal therapy.
- Stem cell or precursor cell replacement is provided through a bone marrow transplant and cytokine therapy, both of which are performed according to conventional techniques.
- the patient is followed at frequent intervals and monitored for CD34 cell level, reestablishment of CD4+ cells and quantitation of CD4+RO+ cells. Additionally, the patient's plasma is assayed for viral load by cell co-culture experiments. On reducing virus load in active and memory CD4+ T cells to low or non-detectable concentrations, the patient is weaned from pentostatin and HAART. After 3 months, the patient is weaned from antibiotic and antifungal therapy. Following this, the patient is followed at
- CD4+RO+ cells are enriched by magnetic separation and FACS sorting, and assayed to determine infectivity with respect to naive and uninfected cell co- culture experiments. This analysis of CD4+RO+ memory cells shows the presence of infective HIV.
- Fludarabine is injected intravenously at a dose of 10 mg/m 2 for a period of 5 days every 28 days to the patient until CD4+ cells, including memory cells, are at low levels.
- CD4+ cells including memory cells
- the patient is maintained on a maintenance dose of HAART, along with antibiotics and antifungal therapy.
- Stem cell or precursor cell replacement is provided through a bone marrow transplant and cytokine therapy, both of which are performed according to conventional techniques.
- the patient is followed at frequent intervals and monitored for CD34 cell level, reestablishment of CD4+ cells and quantitation of CD4+RO+ cells. Additionally, the patient's plasma is assayed for viral load by cell co-culture experiments. On reducing virus load in active and memory CD4+ T cells to low or non-detectable concentrations, the patient is weaned from fludarabine and HAART. After 3 months, the patient is weaned from antibiotic and antifungal therapy. Following this, the patient is followed at 6 month intervals and assayed for viral content.
- RNA PCR non-detectable HIV viral loads
- CD4+ memory cells RO+/HLA DR-
- the antibody is obtained using similar techniques to those set forth in the discussion of the CD4+ specific antibody cM-T412 in N. Llewellyn-Smith, et al., "Effects of anti-CD4 antibody treatment on lymphocyte subsets and stimulated tumor necrosis factor alpha production: a study of 29 multiple sclerosis patients entered into a clinical trial of Cm- T412". Neurology, 48:810-816 (1997).
- CD4+ cells including memory cells
- HAART a maintenance dose of HAART
- Stem cell or precursor cell replacement is provided through a bone marrow transplant and cytokine therapy, both of which are performed according to conventional techniques.
- the patient is followed at frequent intervals and monitored for CD34 cell level, reestablishment of CD4+ cells and quantitation of CD4+RO+ cells. Additionally, the patient's plasma is assayed for viral load by cell co-culture experiments. On reducing virus load in active and memory CD4+ T cells to low or non-detectable concentrations, the patient is weaned from antibody therapy and HAART. After 3 months, the patient is weaned from antibiotic and antifungal therapy. Following this, the patient is followed at 6 month intervals and assayed for viral content.
- CD4+RO+ cells are enriched by magnetic separation and FACS sorting, and assayed to determine infectivity with respect to naive and uninfected cell co-culture experiments. This analysis of CD4+RO+ memory cells shows the presence of infective HIV.
- the monoclonal antibody conjugate is a conjugate of an antibody specific for CD4+-memory cell antigens together with ricin.
- the antibody is obtained using similar techniques to those set forth in the discussion of the
- the ricin Mab conjugate is constructed using conventional techniques.
- CD4+ cells including memory cells
- HAART a maintenance dose of HAART
- Stem cell or precursor cell replacement is provided through a bone marrow transplant and cytokine therapy, both of which are performed according to conventional techniques.
- the patient is followed at frequent intervals and monitored for CD34 cell level, reestablishment of CD4+ cells and quantitation of CD4+RO+ cells. Additionally, the patient's plasma is 25
- the patient is weaned from antibody conjugate therapy and HAART. After 3 months, the patient is weaned from antibiotic and antifungal therapy. Following this, the patient is followed at 6 month intervals and assayed for viral content.
- CD4+RO+ cells are enriched by magnetic separation and FACS sorting, and assayed to determine infectivity with respect to naive and uninfected cell co-culture experiments. This analysis of CD4+RO+ memory cells shows the presence of infective HIV.
- Cyclosporine is administered orally at a dose of 12 mg/kg/day and continued at this dose level on a daily basis for 2 weeks. This dose is tapered by 5% per week to a maintenance dose of 8 mg/kg/day. for a period of 3 months until CD4+ cells, including memory cells, are at low levels. During administration of cyclosporine and for a period of approximately 1-2 months thereafter, or until CD4+ cells recover, the patient is maintained on a maintenance dose of HAART, along with antibiotics and antifungal therapy. Stem cell or precursor cell replacement is provided through a bone marrow transplant and cytokine therapy, both of which are performed according to conventional techniques.
- the patient is followed at frequent intervals and monitored for CD34 cell level, reestablisbment of CD4+ cells and quantitation of CD4+RO+ cells. Additionally, the patient's plasma is assayed for viral load by cell co-culture experiments. On reducing virus load 26
- the patient in active and memory CD4+ T cells to low or non-detectable concentrations, the patient is weaned from cyclosporine and HAART. After 3 months, the patient is weaned from antibiotic and antifungal therapy. Following this, the patient is followed at 6 month intervals and assayed for viral content.
- RNA PCR non-detectable HIV viral loads
- CD4+RO+ cells are enriched by magnetic separation and FACS sorting, and assayed to determine infectivity with respect to naive and uninfected cell co-culture experiments. This analysis of CD4-r-RO+ memory cells shows the presence of infective HIV. Pentostatin is therefore coadministered in combination with 2', 3'- dideoxyadenosine (ddAdo).
- Pentostatin is administered intravenously at 4-5 mg/m 2 and ddAdo is administered intravenously at 5-7 mg/m 2 every two weeks for a period of 3 months until CD4+ cells, including memory cells, are at low levels.
- ddAdo is administered intravenously at 5-7 mg/m 2 every two weeks for a period of 3 months until CD4+ cells, including memory cells, are at low levels.
- the patient is maintained on a maintenance dose of HAART, along with antibiotics and antifungal therapy.
- Stem cell or precursor cell replacement is provided through a bone marrow transplant and cytokine therapy, both of which are performed according to conventional techniques.
- the patient is followed at frequent intervals and monitored for CD34 cell level, reestablishment of CD4+ cells and quantitation of CD4+RO+ cells. Additionally, the patient's plasma is assayed for viral load by cell co-culture experiments. On reducing virus load in active and memory CD4+ T cells to low or non-detectable concentrations, 27
- the patient is weaned from pentostatin, ddAdo and HAART. After 3 months, the patient is weaned from antibiotic and antifungal therapy. Following this, the patient is followed at 6 month intervals and assayed for viral content.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP99906918A EP1056459B1 (en) | 1998-02-26 | 1999-02-11 | Treatment of hiv infections |
CA002320764A CA2320764A1 (en) | 1998-02-26 | 1999-02-11 | Treatment of hiv infections |
DE69931148T DE69931148D1 (en) | 1998-02-26 | 1999-02-11 | TREATMENT OF HIV INFECTIONS |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US09/032,881 | 1998-02-26 | ||
US09/032,881 US6800616B2 (en) | 1998-02-26 | 1998-02-26 | Treatment of HIV infections |
Publications (1)
Publication Number | Publication Date |
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WO1999043328A1 true WO1999043328A1 (en) | 1999-09-02 |
Family
ID=21867353
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Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1999/002955 WO1999043328A1 (en) | 1998-02-26 | 1999-02-11 | Treatment of hiv infections |
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US (1) | US6800616B2 (en) |
EP (1) | EP1056459B1 (en) |
AT (1) | ATE324898T1 (en) |
CA (1) | CA2320764A1 (en) |
DE (1) | DE69931148D1 (en) |
WO (1) | WO1999043328A1 (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1127582A2 (en) * | 2000-02-25 | 2001-08-29 | Cordis Corporation | Use of cladribine on a stent to prevent restenosis |
Families Citing this family (2)
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US20030065382A1 (en) * | 2001-10-02 | 2003-04-03 | Fischell Robert E. | Means and method for the treatment of coronary artery obstructions |
US20050260136A1 (en) * | 2004-05-20 | 2005-11-24 | Kaplan Leonard L | Topical immune competency diagnostic compositions and methods of use |
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Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1127582A2 (en) * | 2000-02-25 | 2001-08-29 | Cordis Corporation | Use of cladribine on a stent to prevent restenosis |
EP1127582A3 (en) * | 2000-02-25 | 2001-09-19 | Cordis Corporation | Use of cladribine on a stent to prevent restenosis |
AU780539B2 (en) * | 2000-02-25 | 2005-03-24 | Cordis Corporation | Use of cladribine on a stent to prevent restenosis |
Also Published As
Publication number | Publication date |
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US6800616B2 (en) | 2004-10-05 |
EP1056459B1 (en) | 2006-05-03 |
CA2320764A1 (en) | 1999-09-02 |
US20010049359A1 (en) | 2001-12-06 |
ATE324898T1 (en) | 2006-06-15 |
EP1056459A1 (en) | 2000-12-06 |
DE69931148D1 (en) | 2006-06-08 |
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