Classifications

• • 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
  • A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
  • A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
  • A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
  • A61K47/6817—Toxins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
  • Y10S530/827—Proteins from mammals or birds
  • Y10S530/828—Cancer

Definitions

• Medicaments comprising as a combination at least one immunotoxin and at least one monovalent carboxylic ionophore.
• the present invention relates to new drugs comprising in combination at least one immunotoxin and at least one monovalent carboxylic ionophore.
• ammonium salts of potentiating the selective cytotoxic activity of immunotoxins has numerous advantages in two types of situation. a) Whenever an immunotoxin is used as a selective cytotoxic agent in vitro to destroy target cells.
• the present invention relates to the preparation of potent cytotoxic drugs using the potentiation of the selective cytotoxic effects of the immunotoxins described in the previous applications mentioned above.
• the monovalent carboxylic ionophores represent a group of substances particularly interesting for potentiating the cytotoxic effect of immunotoxins.
• carboxylic ionophores denotes natural substances isolated from strains of Streptomyces which comprise a linear hydrocarbon skeleton in which oxygenated heterocycles are included. At one end of the chain, there is always a carboxylic acid function while at the other end there are one or more alcohol functions [see B.C. Pressman: Annual Review of Biochemistry 45, 501-530, (1976)].
• monensin is used as an adjuvant in animal feed and as a coccidiostatic agent in poultry. It was also indicated [B. Ray and HC Wu, Molecular and Cellular Biology 1, 552-559, (1981)] that monensin and nigericin increase the cytotoxicity of ricin towards certain cell lines. This increase is however modest on the order of a factor of 10.
• the monovalent carboxylic ionophores used in doses where they themselves do not exhibit any specific cytotoxicity for the lines studied potentiate in an extremely significant way (factors from 7,000 to 55,000 ) the specific cytotoxicity of immunotoxins.
• Example 1 demonstrates the potentiation of the selective cytotoxicity of the anti-T-65 immunotoxin (as described in application No. 81 21836 by the applicant) with respect to human T lymphoblastoid cells of the CEM line carrying the T-65 antigen.
• the cytotoxicity was evaluated by measuring the incorporation of 14 C-leucine by the cells after 24 h of incubation at 37 ° C. in the presence of known quantities of the immunotoxin studied, or of cytotoxic substances of reference, in the absence or presence of the ionophores to be tested. 1 - Potentiation of the cytotoxic effect by ionophores.
• Figure 1 shows the effect of monensin on the inherent cytotoxicity of ricin (R) and its isolated chain (A), taken as reference substances.
• the values of the molar concentrations (IC 50) corresponding to 507. of inhibition of incorporation of the tracer are indicated in Table I.
• the four curves obtained relate respectively to: the chain A of ricin (A), a mixture of the A chain of ricin and monensin (A) + M, ricin (R) and a mixture of ricin and monensin (R) + M.
• Figures 2 and 3 show the comparative potentiating effect of the NH ion (10 mM), monensin (50 nM), nigericin (10 nM), grisorixin (50 nM) and lasalocid (l 'uM), on the cytotoxicity of the anti-T-65 immunotoxin towards cells of the CEM line.
• the values of the molar concentrations (IC 50) corresponding to 50% inhibition of incorporation of the tracer are given in Table II.
• the various curves relate respectively to the results., Obtained with: the chain A of ricin (A), the chain A of ricin mixed with monensin (A) + (M), the anti-T conjugate -65 (AT65) and the AT65 conjugate supplemented with nigericin (AT65N), monensin (AT65M), ammonium chloride (AT65C), grisorixin (AT65G) and lasalocid (AT65L).
• the WEHI 7 mouse lymphoma line with anti Thy 1.2 immunotoxin (as described in application No. 79 24655 of the applicant) at a concentration of 50 nM.
• the results are presented in FIG. 5.
• the curves relate respectively to the anti-Thy 1.2 conjugate (AT12) and to the mixture of this conjugate with monensin (AT12.M).
• mice intraperitoneally are respectively: 16.8 mg / kg for monensin , 65 mg / kg for nigericin, 15 mg / kg for grisorixine and 64 mg / kg for lasalocid.
• the combination constituted by an immunotoxin and a monovalent carboxylic ionophore can be used for the treatment of ailments, cancerous or not, which are sensitive to the antibody used for the preparation of the immunotoxin.
• the treatment should be carried out with a sufficient dose of immunotoxin associated with an amount of monovalent carboxylic ionophore which can vary from 1 to 100 mg each time the immunotoxin is administered.
• the duration of treatment should be determined in each case depending on the subject and the nature of the condition to be treated.
• the new drugs according to the invention are packaged for use by the injectable route and preferably by the intravenous route.
• constituents of the combination will be stored separately and mixed, only at the time of use, in the syringe or the perfusion solvent.

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• Health & Medical Sciences (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Engineering & Computer Science (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Chemical & Material Sciences (AREA)
• Pharmacology & Pharmacy (AREA)
• Medicinal Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• Veterinary Medicine (AREA)
• Toxicology (AREA)
• Molecular Biology (AREA)
• Immunology (AREA)
• Epidemiology (AREA)
• General Chemical & Material Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Applications Claiming Priority (2)

Publications (1)

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Family Applications (1)

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• 1982
  • 1982-02-09 FR FR8202091A patent/FR2521010B1/fr not_active Expired
• 1983
  • 1983-02-04 DE DE8383400233T patent/DE3363563D1/de not_active Expired
  • 1983-02-04 JP JP58500586A patent/JPS59500272A/ja active Granted
  • 1983-02-04 EP EP83400233A patent/EP0086152B1/fr not_active Expired
  • 1983-02-04 AT AT83400233T patent/ATE19857T1/de not_active IP Right Cessation
  • 1983-02-04 WO PCT/FR1983/000025 patent/WO1983002725A1/fr not_active Ceased
  • 1983-10-06 NO NO833641A patent/NO833641L/no unknown
• 1984
  • 1984-09-14 US US06/650,570 patent/US4767621A/en not_active Expired - Fee Related

Non-Patent Citations (3)

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