WO2001054734A2 - Produit radiopharmaceutique utilise en therapie tumorale radio-isotopique - Google Patents

Produit radiopharmaceutique utilise en therapie tumorale radio-isotopique Download PDF

Info

Publication number
WO2001054734A2
WO2001054734A2 PCT/EP2001/000714 EP0100714W WO0154734A2 WO 2001054734 A2 WO2001054734 A2 WO 2001054734A2 EP 0100714 W EP0100714 W EP 0100714W WO 0154734 A2 WO0154734 A2 WO 0154734A2
Authority
WO
WIPO (PCT)
Prior art keywords
radiopharmaceutical
thio
isotope
glucose
organism
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/EP2001/000714
Other languages
English (en)
Other versions
WO2001054734A3 (fr
Inventor
Pedro Ortiz Armua
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Molypharma SA
Original Assignee
Molypharma SA
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 Molypharma SA filed Critical Molypharma SA
Priority to AU39226/01A priority Critical patent/AU3922601A/en
Publication of WO2001054734A2 publication Critical patent/WO2001054734A2/fr
Publication of WO2001054734A3 publication Critical patent/WO2001054734A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
    • A61K51/04—Organic compounds
    • A61K51/0491—Sugars, nucleosides, nucleotides, oligonucleotides, nucleic acids, e.g. DNA, RNA, nucleic acid aptamers

Definitions

  • TITLE A radiopharmaceutical for radionuclide tumor therapy
  • the present invention relates to a radiopharmaceutical for radionuclide tumor therapy; a composition for radionuclide therapy comprising the radiopharmaceutical; and a method of preparing the radiopharmaceutical.
  • a cytotoxic agent such as a radionuclide (radioactive isotope)
  • a radioactive conjugate comprising an antibody labeled with a radioactive isotope.
  • the objective of such a strategy is generally to identify an antiboby which specifically recognizes special tumor cells with the aim to direct the cytotoxic radioactive isotope to these tumor cells. See e.g.
  • the problem to be solved by the present invention is to provide a radiopharmaceutical suitable for radionuclide tumor therapy and which should be generally applicable to the majority of the different types of tumors related to the different types of cancer, such as lung cancer, testicle cancer, uterus cancer, pancreatic cancer, etc.
  • the solution is a novel complex comprising a 5-thio-D-Glucose molecule labeled with a 188 Re isotope.
  • the invention relates to a radiopharmaceutical comprising a 5-thio-D-Glucose molecule labeled with a 188 Re isotope for use in medical therapy; and in a second aspect the invention relates to use of a radiopharmaceutical comprising a 5-thio-D-Glucose molecule labeled with a 18g Re isotope for the manufacture of a medicament for radionuclide tumor therapy.
  • a radiopharmaceutical is capable of directing the cytotoxic 188 Re isotope to tumor cells in a preferentially manner, i.e.
  • the tumor tissue takes up the radiopharmaceutical at a must higher frequency that other normal tissue within the organism.
  • the working example is performed in a mice. Mice is known to be a very good model for a human. Accordingly, these data demonstrate that the radiopharmaceutical as described herein is very suitable for radionuclide tumor therapy.
  • radiopharmaceutical is that it is more general applicable that radiopharmaceuticals which use antibodies as a vector molecule to direct the radioactive isotope to the tumor cell. This is due to that the antibody only recognizes the specific tumor cells which they are constructed to bind.
  • the 5-thio-D-Glucose used as a vector molecule in a radiopharmaceuticical as described herein is more general useable since the tumor uptake of the radiopharmaceutical is related to the general D-Glucose transport pathway within the body.
  • a theory behind the preferential uptake of the radiopharmaceutical is that tumor tissue is a region of low oxygen tension and decreased availability of oxygen causes an increased extraction of glucose via an anaerobic pathway.
  • the final result is that a radiopharmaceutical as described herein is preferentially taken of by a tumor cell independently of which specific cancer disease the tumor relates to.
  • a radiopharmaceutical as described herein exhibits a perfect balance between an adequate biological half-life within the tumor tissue and a good clearance effect.
  • the invention in a third aspect relates to a composition for radionuclide therapy comprising a 5-thio-D-Glucose molecule labeled with a 188 Re isotope and a pharmaceutically acceptable solvent
  • a method of preparing a radiopharmaceutical comprising a 5-thio-D-Glucose molecule labeled with a 188 Re isotope comprising the step of combining 5-thio-D-Glucose, stannous ions, and a solution of 188 Re isotope in a pharmaceutically acceptable solvent.
  • tumor therapy should herein be understood in its general sense, i.e. that the objective is to significantly reduce the size the tumors within the organism. Preferably the tumors should be completely eliminated.
  • radiopharmaceutical comprising a 5-thio-D-Glucose molecule labeled with a 188 Re isotope for the manufacture of a medicament for radionuclide tumor therapy:
  • the radiopharmaceutical of the second aspect of the invention is preferably used for tumor therapy, wherein tumors are disseminated at different places within the organism. Due to that the radiopharmaceutical directs itself to tumors cell in general, it is perfectly suitable to treat tumors situated at different places in the organism in a one time treatment, i.e. the radiopharmaceutical is delivered to the organism, it finds it way to the different tumors, and performs the cytotoxic killing of these.
  • the tumors to be treated are relatively small tumors of less than 8 mm in diameter, preferably less than 5 mm in diameter.
  • the 188 Re isotope has a ⁇ - radiation of 2 MeV which makes it highly suitable to treat such tumors.
  • radiopharmaceutical as described herein, may also be used to treat more bulky tumors, such as tumors of more than 1 cm in diameter.
  • the amount of radiopharmaceutical delivered to the organism is from 25 MBq to 750 MBq per kilogram body weight of the organism, more preferably from 50 MBq to 400 MBq per kilogram body weight of the organism, even more preferably from 75 MBq to 250 MBq per kilogram body weight of the organism, and most preferably from 90 MBq to 150 MBq per kilogram body weight of the organism.
  • 1 ft ft radiopharmaceutical is capable of directing the cytotoxic Re isotope to tumor cells in a preferentially manner, i.e. the tumor tissue takes up the radiopharmaceutical at a must higher frequency that other normal tissue within the organism.
  • the working example is performed in a mice and since mice is known to be a very good model for a human it is reasonably expected that a radiopharmaceutical, as described herein, can be effectively employed with any mammalian species, including humans.
  • the preferred organism to be treated is a human.
  • the Radiopharmaceutical may be delivered to the organism by a number of conventional routes, such as by an intraperitoneal route, an intrathecal route, or an intravesical route. See (Chatal J-F et al, Chapter 84 "Therapeutic use of radio labeled antibodies”; in the book “Nuclear Medicine, Clinical Diagnostic and Treatment, Editor: Murray I.P.C, Ell Peter, Hong Kong 1998”) for further details in relation to the routes of delivery.
  • the radiopharmaceutical is delivered by an intravenously route.
  • a composition for radionuclide therapy comprising a 5-thio-D-Glucose molecule labeled with a 188 Re isotope and a pharmaceutically acceptable solvent.
  • a preferred composition of the third aspect of the invention is wherein at least 90% of the 5-thio-D-Glucose present in the composition is labeled with a lg8 Re isotope.
  • an embodiment of the invention relates to the composition of the third aspect of the invention, which further comprises stannous ions, and more preferably, wherein the stannous ions is supplied as stannous tin, stannous chloride dihydrate, and/or stannous flouride.
  • a pharmaceutically acceptable solvent may e.g. be normal saline. However it is anticipated that any pharmaceutically acceptable carrier in which the complex is soluble may be used as a suitable solvent.
  • a method of preparing a radiopharmaceutical comprising a 5-thio-D-Glucose molecule labeled with a 188 Re isotope comprising the step of combining 5-thio-D-Glucose, stannous ions, and a solution of . 188 ⁇ Re isotope in a pharmaceutically acceptable solvent.
  • 188 Re-5TG 5-thio-D-glucose
  • the 188 Re-5TG complex thus prepared was found to exhibit high stability. Stability is measured by the percentage of 5TG that is labeled with 188 Re after 24 hours from the time that the complex was prepared. Preferably, at least 90% of the 5TG is labeled with 188 Re after 24 hours. More preferably, at least
  • the complex of the present invention is preferably prepared by dissolving 5-thio-D-glucose in a suitable solvent such as normal saline (0.85 M NaCl) with low dissolved oxygen, adding a stannous ion source such as stannous chloride or stannous tin, for example, and lyophilizing the mixture to form a solid that can be conveniently 15 stored and readily reconstituted when needed.
  • a suitable solvent such as normal saline (0.85 M NaCl) with low dissolved oxygen
  • a stannous ion source such as stannous chloride or stannous tin, for example
  • lyophilizing the mixture to form a solid that can be conveniently 15 stored and readily reconstituted when needed.
  • an antioxidant such as gentisic acid can be included in the mixture to be lyophilized.
  • the lyophilized solid is preferably reconstituted with between 185 and 555 MBq [ 188 Re] in isotonic saline per milligram 5-thio-D-glucose to form the desired 5-thioglucose and 188 Re complex. It is anticipated that any pharmaceutically acceptable carrier in which the complex is soluble may be used in the 25 present invention.
  • One of skill in the art would recognize that one could prepare the 188 Re-labeled 5TG by combining a solution of 5-TG and stannous ions together with a solution of 188 Re without first lyophilizing the 5-TG and stannous ion solution.
  • a preparation of 188 Re-labeled 5TG was prepared by reconstituting lyophilized 5-TG and stannous ions with a 188 Re solution
  • the incubation should be at least 5 minutes long, and more preferably the incubation should be at least 10 minutes long.
  • 188 Re-TG was prepared using 74 ⁇ g stannous tin, 20 mg 5-Thio-D-glucose
  • the labeling reaction can be performed using the same stannous reduction method and a formulation having suitable ratios of 10 mg 5-thio-D-glucose and stannous ions, such as a composition comprising about 10 mg 5-thio-D-glucose and between about 0.01 mg and 2 mg stannous tin as stannous chloride dihydrate or stannous fluoride.
  • mice Tumor localization experiments were performed in 5 nude mice. 3 of the mice were C57BL/6 strain male mice bearing MC26 colon carcinoma and 2 were female nude mice bearing breast cancer. 0.25 mCi (9.25 MBq) of 188 Re-TG was injected into the tail vein of the mice. Each mice weighted around 29 g. Consequently the dose was around 318 MBq per kilogram body weight of the mice.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Biotechnology (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Physics & Mathematics (AREA)
  • Medicinal Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un produit radiopharmaceutique contenant une molécule 5-thio-D-Glucose marquée avec un isotope 188Re destiné à être utilisé en thérapie tumorale radio-isotopique. En outre, cette invention concerne une composition de thérapie radio-isotopique contenant un produit radiopharmaceutique; et un procédé de préparation d'un radiopharmaceutique, consistant à mélanger 5-thio-D-Glucose, des ions stanneux, et une solution de l'isotope 188Re dans un solvant acceptable sur le plan pharmaceutique. Ce produit radiopharmaceutique s'applique généralement à la plupart des différents types de tumeurs liées aux différents types de cancers, lequel produit est éliminé efficacement du corps après son utilisation thérapeutique.
PCT/EP2001/000714 2000-01-28 2001-01-23 Produit radiopharmaceutique utilise en therapie tumorale radio-isotopique Ceased WO2001054734A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU39226/01A AU3922601A (en) 2000-01-28 2001-01-23 A radiopharmaceutical for radionuclide tumor therapy

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP00200293.9 2000-01-28
EP00200293 2000-01-28

Publications (2)

Publication Number Publication Date
WO2001054734A2 true WO2001054734A2 (fr) 2001-08-02
WO2001054734A3 WO2001054734A3 (fr) 2001-12-06

Family

ID=8170952

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2001/000714 Ceased WO2001054734A2 (fr) 2000-01-28 2001-01-23 Produit radiopharmaceutique utilise en therapie tumorale radio-isotopique

Country Status (2)

Country Link
AU (1) AU3922601A (fr)
WO (1) WO2001054734A2 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1268464A4 (fr) * 2000-03-21 2003-05-21 Moon Dae Hyuk Complexes de derives de glucose marques par radio-isotopes et ensembles de fabrication de ces complexes

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE69721820T2 (de) * 1996-12-18 2004-02-26 Nihon Medi-Physics Co. Ltd., Nishinomiya Nitrid-heterokomplexe von radioaktiven übergangsmetallen
WO1999020316A1 (fr) * 1997-10-20 1999-04-29 Board Of Regents, The University Of Texas System Radiotraceurs d'emission monophotonique et leurs methodes d'utilisation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1268464A4 (fr) * 2000-03-21 2003-05-21 Moon Dae Hyuk Complexes de derives de glucose marques par radio-isotopes et ensembles de fabrication de ces complexes

Also Published As

Publication number Publication date
AU3922601A (en) 2001-08-07
WO2001054734A3 (fr) 2001-12-06

Similar Documents

Publication Publication Date Title
US4454106A (en) Use of metal chelate conjugated monoclonal antibodies
Houghton et al. Establishment of the in vivo efficacy of pretargeted radioimmunotherapy utilizing inverse electron demand Diels-Alder click chemistry
Zalutsky et al. Astatination of proteins using an N-succinimidyl tri-n-butylstannyl benzoate intermediate
Maxon III et al. Rhenium-188 (Sn) HEDP for treatment of osseous metastases
US5219556A (en) Stabilized therapeutic radiopharmaceutical complexes
Visser et al. Optimal quality 131I-monoclonal antibodies on high-dose labeling in a large reaction volume and temporarily coating the antibody with IODO-GEN
CN107530456A (zh) 具有优异特性的放射性药物溶液
US20080279772A1 (en) Methods for detecting pathological sites
CN114748471A (zh) 放射性标记的伊文思蓝衍生物药物的制备方法及用途
AU2004228746B2 (en) Microwave method for preparing radiolabelled gallium complexes
CN118852044A (zh) 一种肽脲素衍生物、含其的药物组合物及其应用
US5759514A (en) Composition for delivery of toxic radioisotopes to the cell nucleus and use
Pedraza-López et al. Preparation of 166Dy/166Ho-EDTMP: a potential in vivo generator system for bone marrow ablation
Vaalburg et al. Evaluation of carbon-11 labelled phenylglycine and phenylalanine for pancreas scintigraphy
WO2001054734A2 (fr) Produit radiopharmaceutique utilise en therapie tumorale radio-isotopique
Pervez et al. 188 Rhenium-EDTMP: A potential therapeutic bone agent
JP3812680B2 (ja) 放射性医薬用途のペプチド類およびタンパク質類の安定化
AU743696B2 (en) Imaging methods and compositions
Vaidyanathan et al. 3-[211At] astato-4-fluorobenzylguanidine: a potential therapeutic agent with prolonged retention by neuroblastoma cells
WO2023202730A2 (fr) Solution aqueuse pharmaceutique dérivée de bleu d'evans radioactif, son procédé de préparation et son utilisation
WO1993009816A1 (fr) Procede de diagnostic et de traitement du cancer
CN114796532A (zh) 放射性标记的伊文思蓝衍生物药物水溶液及其用途
US4894218A (en) Therapy agents, methods of preparation, and methods of use
EP0842668B1 (fr) Méthode ex-corpore pour le traitement des cellules sanguines
US4970061A (en) Therapy agents, methods of preparation, and methods of use

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CR CU CZ DE DK DM DZ EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NO NZ PL PT RO RU SD SE SG SI SK SL TJ TM TR TT TZ UA UG US UZ VN YU ZA ZW

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): GH GM KE LS MW MZ SD SL SZ TZ UG ZW AM AZ BY KG KZ MD RU TJ TM AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE TR BF BJ CF CG CI CM GA GN GW ML MR NE SN TD TG

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: JP