WO1993023080A1 - Cytotoxicite d'especes activees ciblees - Google Patents

Cytotoxicite d'especes activees ciblees Download PDF

Info

Publication number
WO1993023080A1
WO1993023080A1 PCT/US1993/004582 US9304582W WO9323080A1 WO 1993023080 A1 WO1993023080 A1 WO 1993023080A1 US 9304582 W US9304582 W US 9304582W WO 9323080 A1 WO9323080 A1 WO 9323080A1
Authority
WO
WIPO (PCT)
Prior art keywords
complex
prooxygenator
affixation element
binding
site
Prior art date
Application number
PCT/US1993/004582
Other languages
English (en)
Inventor
Eric T. Fossel
Original Assignee
The Beth Israel Hospital Association
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 The Beth Israel Hospital Association filed Critical The Beth Israel Hospital Association
Publication of WO1993023080A1 publication Critical patent/WO1993023080A1/fr

Links

Classifications

    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B82—NANOTECHNOLOGY
    • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
    • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
    • 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
    • A61K47/62—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 a protein, peptide or polyamino acid
    • A61K47/66—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 a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells
    • A61K47/665—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 a protein, peptide or polyamino acid the modifying agent being a pre-targeting system involving a peptide or protein for targeting specific cells the pre-targeting system, clearing therapy or rescue therapy involving biotin-(strept) avidin systems

Definitions

  • This invention comprises a method of treating animals, including humans, for conditions such as cancer by producing a discrete site cytotoxic environment in an animal, including a human, by the steps of administering to an animal a therapeutically effective dosage of a prooxygenator-affixation element complex; in conjunction with, administering to the animal a therapeutically effective amount of an oxygen source substrate thus producing oxygen free radical species including superoxides at a cytotoxic level at the site of complex binding.
  • the present invention further comprises a prooxygenator-affixation element complex.
  • the pro ⁇ xygenator moiety is xanthine oxidase
  • the affixation element is a tumor specific antibody
  • the oxygen source substrate is xanthine.
  • the fibrin barrier may be eliminated by thrombolytic agents.
  • treatment of cancers, and particularly solid tumors is hampered by inadequate circulatory investment of such tumors.
  • the most rapidly growing tumors may be the most difficult ones in which to obtain therapeutic concentrations of anti-tumor agents.
  • the present invention is, in its preferred embodiment, directed to providing the delivery of one or more therapeutic agents quite specifically to a given site, but not so specifically that only a given individual cell is treated.
  • the therapeutic agents are activated 'oxygen species (collectively,
  • AOS of the present invention include peroxides such as hydrogen peroxide (H 2 0 2 ) and superoxide (0 2 * ) , and singlet oxygen ⁇ 2 ) . It is just such AOS that have been conjectured as active agents in polymorphoneuclear neutrophils after activation by pathogens, cytokines or other cell activators.
  • This invention utilizes the known technology of binding compounds to antibodies so that neither the ability of the antibody to bind to antigen nor the activity of the bound compound is impaired.
  • An examples of this technology are U.S. Pat. No. 4,671,958 issued to Rodwell et al. , and U.S. Pat. No.
  • U.S. Pat. No. 4,671,958 describes a method for site specific covalent attachment of a compound to an antibody molecule by selectively oxidizing a carbohydrate moiety of the antibody, located outside the antigen binding region of the antibody, to form an aldehyde group with an amine group (such as a primary amine, secondary amine, hydrazine, hydrazide, hydroxylamine, phenylhydrazine or semicarbazide) to form a Shiff base (e.g., oxime, hydrazone, phenylhydrazone, or semicarbazone, respectively) .
  • substrate linkers are modified by attaching hydrazine or hydrazide derivatives to one end of the linker.
  • the unmodified sites on the linker may or may not be covalently attached to a compound.
  • Linkers are synthetic or naturally
  • SUBSTITUTE SHEET occurring substrates which are susceptible to cleavage by any of the components of complement are described and disclosed in U.S. Pat. No. 4,671,958, including N-Boc-tyrosine o-nitrophenyl ester, N-acetyl-gly-lys-methyl ester and others well known in the art.
  • substrate linkers which are attached to a compound via an ester or amide link are modified by attaching a hydrazide such as phenylhydrazine to the opposite amino terminus of the peptide chain.
  • the hydrazide derivative of the peptide linker is attached to a compound via an ester or amide link is then reacted with an oxidized immunogloublin fragment containing an oxidized carbohydrate. This results in hydrazone formation and the covalent attachment of the compound to the carbohydrate side chain of the immunoglobulin via a linker group which is susceptible to cleavage by complement.
  • the described covalent attachment of linker to the carrier antibody does not interfere with the antigen binding site of the molecule nor with complement fixation. Schematically this may be represented:
  • antibody- ⁇ "jjSSSS" ⁇ -CH N-NH- -NH-imker- [ ⁇ ] -compound where ⁇ represents an amide or ester bond.
  • This invention includes a prooxygenator-affixation element complex.
  • the prooxygenator-affixation element complex comprises a pro ⁇ xygenator moiety of at least one
  • the prooxygenator-affixation element complex comprises an affixation element being an antibody.
  • Particular antibodies are those that bind to melanoma, carcinoma, adenocarcinoma, sarcoma, neuroblastoma, myeloma, lymphoma, or leukemia cells.
  • Examples within the invention are antibodies such as ⁇ -MSH, carcino-embryonic antigen, ⁇ -fetoprotein, or SSEA-1.
  • prooxygenator-affixation element complex comprises an affixation element being an peptide such as the diphtheria fragment B, or IL-2 binding site.
  • This invention also includes a method of producing discrete site cytotoxic environment in an animal, including a human, comprising the steps of:
  • the affixation element of the prooxygenator-affixation element complex performs the step of binding the complex to a cell.
  • Some pro ⁇ xygenator elements of the method are xanthine oxidase, superoxide dismutase, or
  • Certain oxygen source substrates of the method are methylxant ines such as xanthine, caffeine or theophylline.
  • the method of this invention also encompasses the step of maintaining the AOS concentration in a discrete area to at least about 10 "8 M/minute for a particular intervals of at least about 15 minutes, and preferably at least about 10 *6 M/minute for a particular interval or intervals of at least about 15 minutes, and more preferably at least about 10 "5 M/minute for a particular intervals of at least about 15 minutes.
  • the method includes administering to an animal a therapeutically effective dosage of a prooxygenator-affixation element complex which comprises binding said complex to at least about 50% and preferably at least about 80% of the binding sites at the general site of cytotoxic environment production.
  • this invention includes adding to a tissue culture of a tumor to be tested two or more graduated dosages of a pro ⁇ xygenator-affixation element complex wherein said complex has a binding affinity for the tumor being tested; and thereafter, administering to said culture a therapeutically effective amount of an oxygen source substrate; determining tumor growth inhibition in said tissue culture.
  • Pro ⁇ xygenator shall mean at least one moiety which produces an AOS upon exposure to at least one oxygen bearing substrate.
  • multiple pro ⁇ xygenator moieties may be attached to a single affixation moiety. These may be the same pro ⁇ xygenator moieties or different pro ⁇ xygenator moieties.
  • xanthine oxidase and a peroxidase such as superoxide dismutase may be cojoined to a single affixation moiety.
  • marker moieties such as radio labels, fluorescent materials or NMR labels may be affixed.
  • AOS of the present invention shall mean activated oxygen species including peroxides such as hydrogen peroxide (H 2 0_) and oxygen free radicals, (0 ⁇ ), HO-, and HOO- .
  • peroxides such as hydrogen peroxide (H 2 0_) and oxygen free radicals, (0 ⁇ ), HO-, and HOO- .
  • the particular AOS, Oj; is termed "superoxide.”
  • AOS of this invention further include singlet oxygen ( 1 0 2 ) .
  • Paradigm reactions of this invention are (1) the conversion of xanthine to superoxide, the oxygen free radical (O ⁇ ) by the enzyme xanthine oxidase, and (2) the conversion of xanthine to uric acid and superoxide, an oxygen free radical (Oj; ) .
  • Affixation element shall mean a cell receptor site moiety such as an antibody or peptide capable of affixing the complex to a- site on a cell.
  • the affixation element of the complex is understood to have a binding affinity for the site of cytotoxic environment production. This can be at a site
  • SUBSTITUTE SHEET particular to a tumor, but also particular to certain classes of cells such as interleukin binding cites.
  • An affixation element will also be required to cojoin at least one pro ⁇ xygenator moiety and preferably more than one such moiety.
  • affixation elements are the cell binding fragment of diphtheria toxin (fragment B) , the IL-2 binding site, and antitumor antibodies such as ⁇ -MSH. It is understood that in the practice of this invention, some sites undergo phagocytosis. That is the site of cellular affixation which is initially external becomes drawn into the cell. While it is preferred that the cell bound prooxygenator-affixation element complex remain external to the cell, this is not an absolute requirement.
  • Antibodies are a particular category of affixation element, generally comprising proteins circulating in plasma.
  • D. Complex shall mean a pro ⁇ xygenator moiety bound to an affixation element such that (1) the pro ⁇ xygenator moiety remains capable of enzymatically converting an oxygen source substrate into AOS, and (2) the affixation element as complexed to the pro ⁇ xygenator moiety maintains specificity for the target site of affixation.
  • E. Xanthine oxidase shall mean the the enzyme xanthine:oxygen oxidoreductase, an iron-molybdenum flavoprotein.
  • Discrete site cytotoxic environment shall mean the provision of a cytotoxic environment at a defined location proximate to a prooxygenator-affixation element complex bound to a cell, but not limited to the single bound cell.
  • Cytotoxic environment shall mean an environment that results in reduction or cessation of proliferation of a cell type and further may include death of some or all cells of a given cell type.
  • Cell is used as an inclusive term encompassing differentiated tissue, single cells, bacteria, multicellular pathogenic organisms, viri, retroviri, and neoplastic cells. Cytotoxic environment shall further be expansively understood to include AOS as a "neo-adjuvant," that is as a potentiator of other therapies.
  • Tumor specific antibody shall mean an antibody that preferentially binds to neoplastic cells.
  • antibodies to malignant melanoma, carcinoma, adenocarcinoma, sarcoma (including, Kaposis sarcoma) , neuroblastoma, myeloma, lymphoma, and leukasmias are particularly preferred.
  • Xanthine shall refer to methylxanthines and analogues and derivatives thereof. This shall be understood to include, without limitation, hypoxanthine, caffeine, theophylline, theobromine, dysphylline, enprofyline, and pentoxifylline.
  • Therapeutically effective shall mean a dosage that produces the desired physiological effect.
  • a prooxygenator-affixation element complex therapeutically effective means that sufficient complex is bound such that when presented with oxygen bearing substrate a cytotoxic environment arises. In the practice of the method of this invention two steps are required. First the complex must be bound to the target cells in therapeutically effective concentration -- which is necessarily a potential for physiological activity realized as permanent effect only upon the presentation of oxygen bearing substrate.
  • Therapeutically effective as to a dosage of oxygen bearing substrate shall be one sufficient to establish a cytotoxic environment at the site of complex binding in the presence of bound complex.
  • Such dosage provides an environment that results in reduction or cessation of proliferation of a cell type and further may include death of some or all cells of a given cell type or at a given location.
  • Tumor Specific Antigens Tumor cells can frequently be targeted by antigenic determinants. Cells infected with oncogenic viri frequently have two recognition antigens displayed on the cell surface, either of which may provide suitable sites for antibody binding.
  • Oncofetal antigens may be expressed on the surface tumor cells which differentiate adult tissues from tumor tissues. Examples of these are carcino-embryonic antigen (CEA) in cancer of the intestine and ⁇ -fetoprotein in hepatic carcinoma.
  • CAA carcino-embryonic antigen
  • monoclonal antibodies raised against human melanoma cells that also react with tumors of neural origin.
  • Another monoclonal antibody defines the SSEA-1 antigen found on a variety of human tumors. Tumors induced by chemical agents such as benzopyrene have tumor specific antigens.
  • researchers have particularly noted the tumor specificity of the
  • SUBSTITUTESHEET Ig idiotype on the surface of chronic leukaemic cells can be prepared by methods well known in the art and do not comprise a part of this invention.
  • Tumors sensitive to the AOS therapy of this invention, and therapeutically effective dosage levels may be determined by in vitro techniques which are known in the art.
  • a tumor may be conveniently grown in tissue cultures.
  • tissue cultures To the tissue cultures a variety of prooxygenator-affixation element complexes at a variety of concentrations may be presented with various oxygen source substrates in a checker board assay or the like. The most inhibited tissue cultures will define the therapeutically effective complexes, oxygen source substrates, and may be extrapolated to define a range of therapeutically effective dosages.
  • Additional agents may be cross tested in, for example, traditional in vitro Combination Effect Test or the Therapeutic Index Test, to determine if neo-adjuvant activity may be advantageously used as well.
  • the Combination Effect Test employs a series of tests to determined combined drug efficacy.
  • One such test is the "Checker Board Assay” to test different serial dilutions of the drugs to be combined with AOS administration as challenged by a test cell culture of cancer cells in agar or broth.
  • Another test is the Virus Titer Reduction Assay, measuring the reduction in multiplication of virus as grown in host cells.
  • Another test is
  • SUBSTITUTESHEET an increase in the therapeutic index which is the dose lethal to 50% of the subjects as compared to the dose therapeutically effective in 50% of the cases.
  • the use of the Combination Effect Test allows for the coadministration of AOS with other drugs in a useful and efficacious manner. Particular reference is made to the increased efficacy of Tumor Necrosis Factor by the practice of this invention.
  • the compositions and methods of this invention possess valuable pharmacological properties.
  • the prooxygenator-affixation element complex can localize on or near such targets as tumors cells, cysts, areas of inflammation, and individual viri or retroviri.
  • the prooxygenator-affixation element complex will provide discrete site cytotoxic environment.
  • Such discrete site cytotoxic environment will retard or reverse growth of the target cells or organisms.
  • the desired effect will further include cytotoxic treatment of other nearby cells or organisms at the same discrete site.
  • the discrete site cytotoxic effect is of great benefit in the field of medicine, particularly in the field of cancer therapy. This benefit is demonstrated, for example,
  • SUBSTITUTE SHEET using the method of administering a complex of tumor specific antibody-xanthine oxidase in conjunction with administration of xanthine.
  • a cytotoxic environment at the tumor site is established to preferentially kill tumor cells, with minimal off site toxicity.
  • these compositions can be used with indications providing a binding site for the complex. Included indications are solid tumor neoplasms as well as systemic neoplasms including cancers, leukasmias, viral diseases wherein the virus is "recognized” and attached by the antibody, brucellosis, shistomiasis, malaria, and bacterial infections.
  • compositions and method are particularly useful as antitumor agents wherein the tumor is strongly antigenically identifiable by the antibody of the complex and wherein the tumor is susceptible to AOS.
  • the composition can be used in conjunction with other therapeutic agents as a neo-adjuvant.
  • the compositions can be used in in vitro diagnostics for determining which target cells are sensitive or susceptible to treatment via AOS (alone or in combination with other drugs) at concentrations obtainable in vivo.
  • the compositions of this invention are generally administered to animals, including but not limited to mammals, and avians, and particularly, livestock, household pets, humans, cattle, cats, dogs, poultry, etc.
  • compositions of this invention can be processed in accordance with conventional methods of Galenic pharmacy to produce medicinal agents for administration to patients, e.g., mammals including humans.
  • the compositions of this invention can be employed in admixture with conventional excipients, i.e., pharmaceutically acceptable organic or inorganic carrier substances suitable for parenteral, enteral (e.g., oral or inhalation) or topical application which do not deleteriously react with the active compositions.
  • Suitable pharmaceutically acceptable carriers include but are not limited to water, and salt solutions (e.g., isotonic saline, buffered saline) and injectable formulations (including i.v., and peritoneal) .
  • compositions can be sterilized but must not be denatured.
  • pharmaceutical preparations may be mixed with auxiliary agents, e.g., lubricants, preservatives, stabilizers, wetting agents, emulsifiers, salts for influencing osmotic pressure, buffers, and the like which do not deleteriously react with the active compositions. They can also be combined where desired with other active agents, e.g., prooxygenator-affixation element complex administered with an oxygen source substrate.
  • SUBSTITUTE SHEET For parenteral application, particularly suitable are injectable, sterile solutions, preferably aqueous solutions, as well as suspensions, or emulsions. Ampoules are convenient unit dosages.
  • the prooxygenator-affixation element complex and/or oxygen source substrate may be administered via intravenous shunt permitting "up stream” introduction of therapeutic agents and "down stream” removal of therapeutic agents.
  • Sustained or directed release compositions can be formulated, e.g., liposomes, or those wherein the active component is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc.
  • SUBSTITUTE SHEET Intravenous administration is preferred.
  • the specific mode of administration will vary with the site of treatment and the particular active agents.
  • the method of administration will preferably be selected to develop the highest AOS concentration at the site of treatment.
  • Dosages of both the prooxygenator-affixation element complex administered and the oxygen source substrate (s) may be determined empirically by methods known to those skilled in the art. However the method and agents of the instant invention are uniquely determinable by calculation. An antibody's affinity for target binding sites is determinable by standard methods. Similarly, the general number of binding sites in a given antibody-receptor application of the invention is determinable. In the case of superoxide (Oj; ) as produced by xanthine oxidase, the following calculations are instructive.
  • Each xanthine throws off one superoxide, Oj .
  • the specific activity of xanthine oxidase is — 14,000, thus the enzyme can produce 14,000 ⁇ M of Oj- per minute.
  • a given cell has about 40,000 binding sites for a given antibody. 4. Based on a single cell (and presuming only one enzyme per antibody), the area local to that cell may have 5.6 x 10 8 ⁇ M Oj;/min, or roughly 560M/sec. 5.
  • the lifetime of superoxide is about 10 "6 to 10 "9 .
  • SUBSTITUTE SHEET 6 Thus maintained site concentration at an instantaneous sampling is between about 10 "5 to about 10 "8 M of superoxide/minute. Concentration levels can be altered by binding more than one enzyme to an antibody, or utilizing enzymes of increased activity. Further, attachment of antibody and associated enzymatic activity as generally distributed in an area will result in nodes of increased AOS concentration. While these will vary widely with each antibody, binding site, volume over which antibody complex is distributed and the half-life of the complex, such determinations are within the recognized skill of practitioners in the art. Dosages based on these factors -- bearing in mind tolerable toxicity levels -- will then be determined.
  • the dosage and time of administration of oxygen source substrate(s) to form AOS from a complex containing xanthine oxidase may be either determined empirically or calculated.
  • the dosage of caffeine will not exceed the capacity of the xanthine oxidase to form AOS. Calculation will include volume throughout which the xanthine is distributed and the half-life of caffeine in vivo.
  • caffeine and theophylline in humans it is known to be distributed into all body compartments, and its apparent
  • SUBSTITUTESHEET distribution is about 0.4 to about 0.6 liter/kg of body weight, and higher in premature infants.
  • the half-life of caffeine in plasma is about 3 to 7 hours. Variance in the half-life, however, in specific circumstances is well known to those skilled in the art. For example, the half-life may double in women in the later stages of pregnancy, or be up to 50 hours in premature infants. There is also well document substantial inter-individual variation in clearance of methylxanthines, and such clearance should be tested to determine the individual dosage requirements.
  • Caffeine dosages typically should not exceed 15 g/kg and plasma concentrations of 30 ⁇ g/ml.
  • methylxanthine dosage levels are well known in the art, such as are found in Goodman and Gilman's The Pharmacological Basis of Therapeutics Eighth Edition, Eds., Gilman, Rail, Nies, Taylor (Pergamon Press, New York, New York, 1990) , the teachings of which are incorporated herein by reference.
  • the dosage of the compositions according to this invention generally are designed to afford maximal tolerated delivery of AOS to the target site. It will be appreciated that the actual preferred amounts of active compositions in a specific case will vary according to the specific compositions being utilized, the particular compositions formulated, the mode of application, and the particular situs and organism being treated. Dosages for a given host can be determined using conventional considerations,
  • SUBSTITUTE SHEET e.g., by customary comparison of the differential activities of the subject compositions and of a known agent, e.g., by means of an appropriate, conventional pharmacological protocol.
  • a subject in need of AOS therapeutic treatment and having an antibody specific treatment site is administered xanthine to a concentration of about 10 "9 to about 10 "5 M.
  • Particular effective concentrations are from about concentration of about 10" 8 to about 10 "6 M, as well as from about concentration of about 10" 6 to about 10' 5 M.
  • maximum concentration is established over time, with xanthine administration curtailed when unsuitable toxicity begins to be manifested. Maximum concentration is reached about 1 hour after oral administration.
  • administration of xanthine in doses of from about 300 mg to 500mg is useful.
  • the pro ⁇ xygenator-affixation element complex xanthine oxidase bound to an antibody specific to the treatment site, administered intravenously to establish a concentration which will bind to binding sites in from about 20% to 100% of such sites.
  • Xanthine oxidase bound to said antibody is periodically readministered in proportion to the rate at which enzyme-antibody is deactivated, here about every three hours. Due to the long half-life of xanthine, it is not usually necessary to
  • SUBST1TUTE SHEET readminister xanthine during the course of this treatment.
  • it is useful to administer the prooxygenator-affixation element complex prior to administration of the substrate.
  • Example 1 Xanthine Oxidase/ ⁇ _-MSH Complex
  • xanthine is administered intravenously to obtain a plasma level of 10-30 ⁇ g/ml which is maintained over 4 hours by additional xanthine administration as required.
  • a prooxygenator-affixation element complex consisting of a pro ⁇ xygenator moiety of xanthine oxidase and an affixation element of ⁇ -melanocyte stimulating hormone ( ⁇ -MSH) is administered, i.v.
  • the xanthine oxidase/ ( ⁇ -MSH complex is suspended in isotonic saline.
  • Administration is intravenous at a dosage of 100 mg every ten minutes until 80% of the binding sites on target cells are occupied.
  • binding cites on target cells refers to the binding of the prooxygenator-affixation element complex the at the site of cytotoxic environment production. Such binding results from the affinity between complex and binding cite. This treatment is repeated daily for 5 days.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Nanotechnology (AREA)
  • Molecular Biology (AREA)
  • General Health & Medical Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biophysics (AREA)
  • Biotechnology (AREA)
  • General Engineering & Computer Science (AREA)
  • Medical Informatics (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Cell Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

L'invention concerne un procédé de traitement d'affections telles que le cancer chez les animaux et chez l'homme. Ledit procédé consiste à produire un environnement cytotoxique local discret chez un animal, y compris l'homme, par administration d'un dosage thérapeutiquement efficace d'un complexe d'éléments de fixation/pro-oxygénation ainsi que d'un volume thérapeutiquement efficace d'un substrat source d'oxygène afin de produire des espèces de radicaux libres d'oxygène tels que le superoxyde sur le site de liaison. L'invention se rapporte également au complexe d'éléments de fixation/pro-oxygénation. Dans un mode de réalisation, l'élément de pro-oxygénation est la xanthine-oxydase, l'élément de fixation est un anticorps spécifique aux tumeurs, et le substrat source d'oxygène est de la xanthine.
PCT/US1993/004582 1992-05-13 1993-05-13 Cytotoxicite d'especes activees ciblees WO1993023080A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US88247892A 1992-05-13 1992-05-13
US07/882,478 1992-05-13

Publications (1)

Publication Number Publication Date
WO1993023080A1 true WO1993023080A1 (fr) 1993-11-25

Family

ID=25380664

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1993/004582 WO1993023080A1 (fr) 1992-05-13 1993-05-13 Cytotoxicite d'especes activees ciblees

Country Status (2)

Country Link
AU (1) AU4375293A (fr)
WO (1) WO1993023080A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000011965A2 (fr) * 1998-08-28 2000-03-09 The University Of Bath Compositions pouvant etre ingerees, comprenant des agents antibacteriens
WO2000012112A2 (fr) * 1998-08-28 2000-03-09 The University Of Bath Ameliorations du traitement des lesions
EP1226235A2 (fr) * 1999-10-22 2002-07-31 LESKOVAR, Peter Constructions cellulaires adaptees a l'immunotherapie, leur production et leur utilisation
WO2019099687A1 (fr) * 2017-11-16 2019-05-23 Antigenesis Llc Systèmes et procédés de mort cellulaire immunogène induite par lysosome

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4671958A (en) * 1982-03-09 1987-06-09 Cytogen Corporation Antibody conjugates for the delivery of compounds to target sites
US4762707A (en) * 1982-03-17 1988-08-09 Sanofi (Societe Anonyme) New conjugates associating, by covalent bond, an enzyme with an antibody, and medicinal associations using the said conjugates
US4867973A (en) * 1984-08-31 1989-09-19 Cytogen Corporation Antibody-therapeutic agent conjugates
US4906469A (en) * 1983-08-23 1990-03-06 Sanofi Appropriate cytotoxic pharmaceutical combination especially for the treatment of cancers
US4937183A (en) * 1988-02-03 1990-06-26 Cytogen Corporation Method for the preparation of antibody-fragment conjugates
US4971991A (en) * 1987-12-01 1990-11-20 Kohshiro Umemura Physiological function enhancing agents activated by ultrasonic waves for the treatment of tumors
US4975278A (en) * 1988-02-26 1990-12-04 Bristol-Myers Company Antibody-enzyme conjugates in combination with prodrugs for the delivery of cytotoxic agents to tumor cells

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4671958A (en) * 1982-03-09 1987-06-09 Cytogen Corporation Antibody conjugates for the delivery of compounds to target sites
US4762707A (en) * 1982-03-17 1988-08-09 Sanofi (Societe Anonyme) New conjugates associating, by covalent bond, an enzyme with an antibody, and medicinal associations using the said conjugates
US4906469A (en) * 1983-08-23 1990-03-06 Sanofi Appropriate cytotoxic pharmaceutical combination especially for the treatment of cancers
US4867973A (en) * 1984-08-31 1989-09-19 Cytogen Corporation Antibody-therapeutic agent conjugates
US4971991A (en) * 1987-12-01 1990-11-20 Kohshiro Umemura Physiological function enhancing agents activated by ultrasonic waves for the treatment of tumors
US4937183A (en) * 1988-02-03 1990-06-26 Cytogen Corporation Method for the preparation of antibody-fragment conjugates
US4975278A (en) * 1988-02-26 1990-12-04 Bristol-Myers Company Antibody-enzyme conjugates in combination with prodrugs for the delivery of cytotoxic agents to tumor cells

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
ACCOUNTS OF CHEMICAL RESEARCH, Vol. 5(10), issued October 1972, I. FRIDOVICH, "Superoxide Radical and Superoxide Dismutase", pages 321-326. *
MOLECULAR AND CELLULAR BIOCHEMISTRY, Vol. 10(1), issued 31 January 1976, A. BOZZI et al., "Enzyme Defence Against Reactive Oxygen Derivatives. II. Erythrocytes and Tumor Cells", pages 11-16. *

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6682732B1 (en) 1998-08-28 2004-01-27 The University Of Bath Treatment of lesions
WO2000012112A2 (fr) * 1998-08-28 2000-03-09 The University Of Bath Ameliorations du traitement des lesions
WO2000012112A3 (fr) * 1998-08-28 2001-02-15 Univ Bath Ameliorations du traitement des lesions
GB2357969A (en) * 1998-08-28 2001-07-11 Univ Bath Improvements in or relating to the treatment of lesions
WO2000011965A3 (fr) * 1998-08-28 2001-08-23 Univ Bath Compositions pouvant etre ingerees, comprenant des agents antibacteriens
GB2370486A (en) * 1998-08-28 2002-07-03 Univ Bath Ingestible compositions comprising antibacterial agents
WO2000011965A2 (fr) * 1998-08-28 2000-03-09 The University Of Bath Compositions pouvant etre ingerees, comprenant des agents antibacteriens
EP1226235A2 (fr) * 1999-10-22 2002-07-31 LESKOVAR, Peter Constructions cellulaires adaptees a l'immunotherapie, leur production et leur utilisation
WO2019099687A1 (fr) * 2017-11-16 2019-05-23 Antigenesis Llc Systèmes et procédés de mort cellulaire immunogène induite par lysosome
CN111788226A (zh) * 2017-11-16 2020-10-16 抗原生成有限责任公司 溶酶体诱导的免疫原性细胞死亡的系统和方法
JP2021503503A (ja) * 2017-11-16 2021-02-12 アンティジェネシス・リミテッド・ライアビリティ・カンパニーＡｎｔｉｇｅｎｅｓｉｓ ＬＬＣ リソソーム誘発性免疫原性細胞死のシステムおよび方法
EP3710481A4 (fr) * 2017-11-16 2021-08-18 Antigenesis LLC Systèmes et procédés de mort cellulaire immunogène induite par lysosome
JP7500005B2 (ja) 2017-11-16 2024-06-17 ヴィスカ・バイオ・インコーポレイテッド リソソーム誘発性免疫原性細胞死のシステムおよび方法

Also Published As

Publication number Publication date
AU4375293A (en) 1993-12-13

Similar Documents

Publication Publication Date Title
EP0354729B1 (fr) Conjugués de médicaments cytotoxiques
JP2738414B2 (ja) 腫瘍細胞に細胞障害性物質を供給するためのプロドラッグと組合せた抗体−酵素結合体
US5911995A (en) EGF-genistein conjugates for the treatment of cancer
Morahan et al. Antitumor action of pyran copolymer and tilorone against Lewis lung carcinoma and B-16 melanoma
JPH10505056A (ja) チロシンキナーゼ阻害剤を含有する免疫接合体
JPH05502787A (ja) 外因性分子の経膜的輸送を高める方法
CA1222694A (fr) Immunochimiotherapie pour tumeurs malignes, particulierement pour le cancer du pancreas
WO1993023080A1 (fr) Cytotoxicite d'especes activees ciblees
US5144012A (en) Cytotoxic drug conjugates
EP0475230A1 (fr) Méthodes de conjugaison d'actinomycine D
Sett et al. Macrophage-directed delivery of doxorubicin conjugated to neoglycoprotein using leishmaniasis as the model disease
JP2001526060A (ja) 抗感染症薬としての酵素プロドラッグの適用
EP0464135B1 (fr) Composition utile a reduire les effets secondaires d'un medicament
US7157087B2 (en) Enhancement of intracellular delivery and tissue targeting of drugs and genes
WO1992005200A1 (fr) Conjugues d'anticorps xenobiotiques
Messinger et al. Treatment of human B-cell precursor leukemia in SCID mice using a combination of the investigational biotherapeutic agent B43-PAP with cytosine arabinoside.
JPH0193540A (ja) 癌転移と増殖の予防および治療用組成物
EP3941508A1 (fr) Lieurs stables non hydrolysables, non clivables pour agents thérapeutiques de précision et leurs utilisations
WO1991000112A1 (fr) Conjugues d'anticorps-oxydase de lactate
JPH07277964A (ja) 抗腫瘍剤
JP3199081B2 (ja) 抗腫瘍剤
US20020127223A1 (en) Method for reducing side effects of a drug
US20220040338A1 (en) Alpha Emitter Compositions And Methods
JP2842888B2 (ja) リボヌクレアーゼインヒビターを有効成分とする癌細胞転移抑制剤
WO2000010610A2 (fr) Ciblage de medicament

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AT AU BB BG BR CA CH DE DK ES FI GB HU JP KP KR LK LU MG MN MW NL NO PL RO RU SD SE US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA GN ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
WD Withdrawal of designations after international publication

Free format text: US

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA