EP0593452A1 - Verfahren zur herstellung eines mit metallradionuklid markierten proteins - Google Patents

Verfahren zur herstellung eines mit metallradionuklid markierten proteins

Info

Publication number
EP0593452A1
EP0593452A1 EP91902555A EP91902555A EP0593452A1 EP 0593452 A1 EP0593452 A1 EP 0593452A1 EP 91902555 A EP91902555 A EP 91902555A EP 91902555 A EP91902555 A EP 91902555A EP 0593452 A1 EP0593452 A1 EP 0593452A1
Authority
EP
European Patent Office
Prior art keywords
group
protein
radionuclide
sulphonated
bifunctional agent
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.)
Withdrawn
Application number
EP91902555A
Other languages
English (en)
French (fr)
Other versions
EP0593452A4 (de
Inventor
Wilhelmus Theodorus Goedemans
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.)
Mallinckrodt Inc
Original Assignee
Mallinckrodt Medical Inc
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 Mallinckrodt Medical Inc filed Critical Mallinckrodt Medical Inc
Publication of EP0593452A4 publication Critical patent/EP0593452A4/de
Publication of EP0593452A1 publication Critical patent/EP0593452A1/de
Withdrawn legal-status Critical Current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
    • A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
    • A61K51/10—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
    • A61K51/1093—Antibodies or immunoglobulins; Fragments thereof, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody conjugates with carriers being antibodies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2123/00—Preparations for testing in vivo

Definitions

  • the invention relates to a method of preparing a metal- radionuclide - labelled protein or proteinaceous materia which is intended for diagnostic or therapeutic application.
  • Radionuclide- labelled compounds may be used for diagnostic examination, for example, into deviations in shape and function of internal organs and into the presence and location of pathological processes in the body.
  • a composition in which the radioactive compound is present is administered to the patient, for example, in the form of an injectable liquid.
  • suitable detection apparatus for example, a gamma camera
  • pictures of, e.g. , the organ or the pathological process in which the radioacti ve compound'has been incorporated can be obtained by recording the emitted radiation ("scanning").
  • Radioactive- labelled biological materials in particular proteins and proteinaceous materials, e.g. , blood cells, immunoglobulins , glycopeptides , monoclonal antibodies like anti yosin and monoclonals against tumour antigens, peptides, aminofunctions -containing hormones like somatosta- tin and ACTH, and other proteins suitable for this purpose, such as plasmin and plasmin derivatives, e.g. , iniplasmin and tissue plasminogen activator, present interesting perspectives for diagnostic application.
  • proteins have a very large target organ specificity and, after having been introduced into the patient's body, can react very selectively with biological macromolecules present therein; good example thereof is the selective reaction of antibodies or antibody fragments with antigens present in the body.
  • SUBSTITUTE SHEET Various metal- radionuclides , provided they are bound to tumour-selective biological macromolecules, such as the glycopeptide bleomycin, can be used successfully for controlling tumours, and thus form a powerful tool in radiotherapy.
  • the macromolecules used thus serve as vehicles for the transportation of the desired radiation dose, i.e. , the metal- radionuclide , to the tumour to be exposed to radiation.
  • the direct labelling of a protein or a proteina ⁇ ceous material with a metal-radionuclide has two disadvan ⁇ tages.
  • the biologically active site of the protein necessary for a good target organ specificity or selectivi ⁇ ty, may easily be blocked by this reaction, so that the normal behaviour of the biological macromolecule is distur ⁇ bed.
  • the affinity between metal-radionuclide an macromolecule often is insufficient, as a result of which th formed bond is not sufficiently stable to remain intact unde physiological conditions.
  • the administered material then is no longer useful, neither as diagnostic - the behaviour of the protein in the body can no longer be traced - nor as therapeutic - the radiation dose is no longer transported to the desired site but causes an undesired radiation burden elsewhere !
  • the biological behaviour of the original macromolecule must be maintained as well as possibl by this modification.
  • the chelator or the bifunctional agent with which the metal-radionuclide is boun to the protein may not to be too bulky, certainly not when used for comparatively small protein molecules.
  • th usually extremely sensitive protein or proteinaceous materia must be exposed as little as possible to damaging conditions during the coupling with chelator or bifunctional agent, which may adversely influence the properties of the macromo ⁇ lecule. Long-lasting incubations, treatments at elevated temperatures, the presence of organic solvents or conditions of acidity differing from the physiological pH , reactions in the presence of oxidizing or reducing agents, all these treatments should be avoided as much as possible.
  • the selected bifunctional agent should ensure a strong bond between the protein or proteinaceous material on the one hand and the metal-radionuclide on the
  • chelators or bifunctional agents described in the above-mentioned patent publications are not satisfactory with regard to one or more of the requirements mentioned hereinbefore.
  • a comparatively bulky chelator is
  • SUBSTITUTE SHEET used in US 4479930, US 4511550, US 4652519, US 4678667 and 188256.
  • conditions which are damaging to the protein during the coupling reaction are applied in the methods described in US 4652440, EP 173629, WO 85/03231 and WO 86/03010.
  • the bond between protein and metal - radionuclide is not sufficiently strong in the proteins labelled according to US 4479930 and WO 85/03231.
  • the labelling method is laborious and purification afterwards of the labelled protein is necessary: US 4652440, EP 83129, EP 188256, NL 8204108, WO
  • SAMSA S-acetylmer capto succinic anhydride
  • This object can be achieved by performing the coupling reaction with a bifunctional agent which consists at least substantially of a thio compound of the general formula
  • X is a halogenated or non-halogenated alkanoyl group having 2-5 carbon atoms or a substituted or non-substituted benzoyl group
  • R is an optionally substituted hydrocarbon radical having 1-10 carbon atoms
  • Y is at least one terminal reactive group which is capable of reacting with a free amino group or mercapto group in the protein or the proteinace ⁇ ous material ; and by then reacting the formed protein conjugate with the
  • Metal -radionuclides suitable for use in the method according to the invention are Tc-99m, Re-186, Re- 188, As-72 and As-77. Of these radionuclides Tc-99m and As - 72 may be used for diagnostic purposes, the other radionu ⁇ clides are paricularly useful in therapeutically active compositions .
  • the derivatisation of the protein or the protein ceous material may be carried out in a very simple manner in a neutral medium (pH between 6.5 and 8) and at room tempera ⁇ ture.
  • a neutral medium pH between 6.5 and 8
  • the desired radionu- elide is presented to the protein conjugate in the form of salt or preferable in the form of a chelate bound to comparatively weak chelators, for example, a pyrophosphate, phosphonate or a polyphosphonate , an oxinate, a carboxylate, a hydroxycarboxylate , an aminocarboxylate , an enolate or a mixture thereof, likewise in a neutral medium.
  • the desired complex is formed via the principle of ligand exchange, in which the sulphur atom of the thio compound forms a strong chelate bond with the metal - radionu ⁇ clide .
  • a mercapto-protecting group X is very important because for that reason polymerisation of the protein conjugate during the preparation is avoided. It has been found surprisingly that an extra reduction step to form free mercapto groups before carrying out the reaction with the radionuclide is not necessary.
  • the formed protein conjugate may directly be labelled with the desired metal- radionuclide , which means a considerable advantage in particular when supplied in the form of a kit. Examples of
  • EET suitable protecting groups X for the mercapto group are: acetyl, halogenated acetyl and substituted or non-substitu ⁇ ted benzoyl, in which in particular eleetrons -withdrawing groups, such as nitro, halogen and sulpho are to be conside- red as substituents .
  • a bifunctional agent which consists at least substantially of a thio compound of the general formula
  • Y' - R - S - X (II) wherein X and R have the meanings given hereinbefore; and Y' is an isocyanate group, a formyl group, a diazonium group, an isothiocyanato group, an ' epoxyethylene group, a trichloro- s - triazinyl group, an ethylene imino group, a halocarbonyl group, a halosulphonyl group, a maleimido group, sulphonated or non-sulphonated alkylcarbonyl- oxycarbonyl group, a sulphonated or non-sulphona ted alkylcarbonyliminocarbonyl group, a 2,4- dinitrophenoxycarbonyl group, or a sulphonated o non-sulphonated nitrogen-containing heterocyclic five- or six-membered ring which is bound to R with the ring nitrogen via a carbonyl group or oxycarbon
  • alkylcarbonyloxycarbonyl groups and of alkylcarbonyliminocarbonyl groups are radicals derived
  • Suitable protective groups X are: acetyl, halogenated acetyl such as trifluoroacetyl , and benzoyl whether or not substituted with nitro, halogen or sulp-ho.
  • substituent Y' the following groups are to be preferred: a 2,4-dinitro- phenoxycarbonyl group or a sulphonated or non-sulphonated nitrogen-containing heterocyclic five- or six-membered ring which is bound to R with the ring-nitrogen via a carbonyl group or oxycarbonyl group and which is substituted in the ortho position with an oxo function or a thioxo function.
  • Z is a hydrogen atom or a fluorine atom
  • R' is a methylene group or an ethylene group
  • Y' ' ' is a sulphonated or non- sulphonated succini- mido-oxy group or a 2 - thioxo - thiazolidin- 3 -yl group .
  • the last-mentioned preferred compound according to the invention is excellently suitable for use in the preparation of labelled proteins or proteinaceous materials. It has been found surprisingly that the use of an extra reduction step preceding the radioactive labelling of the protein -conjugate formed with this preferred compound is not only superfluous but is even undesired. The labelling efficiency is considerably higher without a reduction, as will become apparent from the specific examples. As already explained hereinbefore, this means a considerable advantage
  • A is hydrogen or an alkali- (or ammonium- )sulphonate group, and n. is 1 or 2.
  • the invention also relates to a metal-radionu- clide- labelled protein or proteinaceous material obtained by using the method as described hereinbefore, and to a radiopharmaceutical composition which comprises, in addition to a pharamaceutically acceptable liquid carrier material, a metal-radionuclide- labelled protein or proteinaceous material.
  • a radiopharmaceutical composition which comprises, in addition to a pharamaceutically acceptable liquid carrier material, a metal-radionuclide- labelled protein or proteinaceous material.
  • SUBSTITUTE SHEET proteinaceous material may be used directly as a radiopharm ceutical composition. If necessary, the solution may be brought into a form which is better suitable for intravenou or subcutaneous administration, for example, by the additio of a pharmaceutically acceptable liquid carrier material, preferably a physiological saline solution.
  • a pharmaceutically acceptable liquid carrier material preferably a physiological saline solution.
  • the solution should be sterile for intravenous or subcutaneous administration.
  • composition for carrying out a radiodiagnostic examination the composition, as described hereinbefore, optionally after dilution with a pharmaceutically acceptable liquid, prefera ⁇ bly a physiological saline solution, may be administered to warmblooded living being in a quantity from lOO Ci to 30 mCi, preferably from 0.5 to 10 mCi, per 70 kg of body weight after which the radioactive radiation emitted by the living being is recorded.
  • a pharmaceutically acceptable liquid prefera ⁇ bly a physiological saline solution
  • composition is to be used for a radiothe- rapeutic treatment, a suitable metal- radionuclide should be selected for the labelling reaction, as indicated hereinbe- fore.
  • the composition optionally after dilution with a pharmaceutically acceptable liquid, is administered to a warmblooded living being in a quantity effective for combating or controlling tumours.
  • the radiopharmaceutical composition according to the invention can so easily and simply be prepared, said preparation can particularly readily be carried out by the user himself.
  • the invention therefore also relates to a so-called "kit", as described hereinbe-
  • SUBSTITUTE SHEET fore, comprising (1) in an optionally dry condition a composition of a protein conjugate, which is formed by reaction of a protein or a proteinaceous material with a bifunctional agent, consisting at least substantially of a thio compound as defined hereinbefore, (2) a solution of a salt or chelate of a metal-radionuclide , and (3) instructi ⁇ ons for use with a prescription for reacting the ingredients present in the kit.
  • a protein hereafter is to be understood to mean a protein including a proteineous material.
  • the desired radionuclide is preferably presented to the protein conjugate in the form of a chelate bound to comparatively weak chela ⁇ tors, for example, a pyrophosphate, and phosphonate or polyphosphonate , an oxinate, a carboxylate, a hydroxycar- boxylate, an aminocarboxylate , an enolate or a mixture there ⁇ of, in which the reaction can take place in a neutral medium.
  • a chelate bound to comparatively weak chela ⁇ tors for example, a pyrophosphate, and phosphonate or polyphosphonate , an oxinate, a carboxylate, a hydroxycar- boxylate, an aminocarboxylate , an enolate or a mixture there ⁇ of, in which the reaction can take place in a neutral medium.
  • Suitable chelators for the radionuclide are 8- hydroxyquinoline or derivatives thereof; dicarboxylic acids, polycarboxylic acids or hydroxycarboxylic acids, for example, oxalic acid, malonic acid, succinic acid, maleic acid, orthophthalic acid, malic acid, lactic acid, tartaric acid, citric acid, ascorbic acid, salicylic acid or derivatives of these acids; pyrophosphates ; phosphonates or polyphosphona- tes, for example, methylene diphosphonate , hydroxyethylene diphosphonate or hydroxymethylene diphosphonate; or enolates, for example with a ⁇ -diketone such as acetyl acetone, furoyl acetone, thenoyl acetone, benzoyl acetone, dibenzoyl methane, tropolone or derivatives of these diketones.
  • dicarboxylic acids for example, oxalic acid, malonic acid,
  • the supplied kit may also comprise the constituents mentioned sub (1) with instruction for use, whereas the solution of the metal - radionuclide defined sub (2) , having a limited shelf life, may be supplie to the user separately.
  • the kit according to the invention is equipped so as to comprise the following ingredients: (1) in an optionally dry condition a composition of a protein conjugate, which is formed by reaction of a protein with a bifunctional agent consisting at least substantially of a thio compound as defined hereinbefore; (2) a chelator as described hereinbe ⁇ fore and a reducing agent; and (3) instructions for use with a prescription for reacting the ingredients of the kit with technetium- 99m in the form of a pertechnetate solution.
  • the composition should comprise a reducing agent to reduce the pertechnetate , for example, a dithionite or stannous ions.
  • a kit is intended for the preparation of a Tc-99m- labelled pharmaceutical composition.
  • the pertechnetate solution can simply be obtained by the user from a molybde ⁇ num- technetium generator available to him.
  • a similar kit may be used for the preparation of a pharmaceutical composition labelled with Re-186 or Re-188, in which the perrhenate solution must also be reduced with a suitable reducing agent, for example, a dithionite or stannous ions.
  • a suitable reducing agent for example, a dithionite or stannous ions.
  • the ingredients defined above sub (1) and (2) may be combined, provided they are compatible.
  • Such a kit, in which the combined ingredients are preferably lyophilized, is extremel suitable for being reacted by the user with the radionuclide solution in a simple manner.
  • the kit according to the invention is equipped so as to comprise (1) in an optionally dry condition a bifuncti ⁇ onal agent, consisting at least substantially of a thio compound as defined hereinbefore, as well as a chelator as described hereinbefore and a reducing agent, and (2) instructions for use with a prescription for reacting the ingredients mentioned sub (1) , which are preferably accomoda ted in one vial, with a protein which is separately supplied to the user, and then with technetium- 99m in the form of a pertechnetate solution or with rhenium-186 or rhenium-188 in the form of a perrhenate solution.
  • a bifuncti ⁇ onal agent consisting at least substantially of a thio compound as defined hereinbefore, as well as a chelator as described hereinbefore and a reducing agent
  • instructions for use with a prescription for reacting the ingredients mentioned sub (1) which are preferably accomoda ted in one vial, with a protein which is separately supplied to the user,
  • the kit according to the invention comprises (1) a bifunctional agent as defined hereinbefore, (2) a solution of a salt or chelate of a metal-radionuclide , and (3) instructions for use with a prescription for reacting the ingredient sub (1) with a protein and then with the ingre ⁇ washer mentioned sub 2.
  • a metallic reducing agent for example, Sn(II),
  • Fe(II), Cu(I), Ti(III) or Sb(III), is preferably used as a reducing agent for the kits mentioned hereinbefore; Sn(II) is excellently suitable.
  • the constituent of the above-mentioned kits stated sub (1) may be supplied as a solution, for example, in the form of a physiological saline solution, or in some buffer solution or other, but is preferably ' present in a d condition, for example, in a lyophilized condition.
  • a component for an injection liquid it should be steril in which, if the constituent is present in a dry condition, the user should use a sterile physiological saline solutio as a solvent.
  • the above-mentioned constituent be stabilised in the usual manner with suitable stabiliser or may comprise other auxiliary means like fillers, e.g, glucose, lactose, raannitol, and the like.
  • Starting material is 1 ml of humane IgG (immuno ⁇ globulin G) in a concentration of 20 mg/ml in 15 mM of an ammonium bicarbonate buffer solution.
  • N-succinimidyl-S -acet thioacetate (SATA) is dissolved in the same buffer solution and added to the IgG solution in a molar ratio of 25 : 1
  • the first fraction (“A") is labelled directly with technetium- 99m by adding successively 0.25 ml of tin tartra solution (approximately 5 mg of Sn-II) and 0.5 ml of Tc-99m pertechnetate solution (6.7 mCi).
  • the other fractions are first treated with 50 ml, 100 ml and 300 ml, respectively, 1% hydroxylaraine solution (0.5 rag, 1.0 mg and 3.0 mg) as a reducing- agent : fractions "B", "C", and "D” , respectively.
  • the labelling yields are determined after 20 * an 80 min by means of gel chromatography .
  • the results are recorded in the table below.
  • the labelling yield in the absence of a reducing agent is significantly higher than in the presence thereof.
  • the formed protein conjugate, i.e. , the IgG treated with SATA yields the desired technetium-99m-labelled protein directl in a very high labelling efficiency and in a very short period of time.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Physics & Mathematics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Optics & Photonics (AREA)
  • Immunology (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)
EP91902555A 1989-11-30 1990-11-28 Verfahren zur herstellung eines mit metallradionuklid markierten proteins Withdrawn EP0593452A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
NL8902956 1989-11-30
NL8902956 1989-11-30
PCT/US1990/006977 WO1991007991A1 (en) 1989-11-30 1990-11-28 Method for preparing a metal-radionuclide-labelled protein

Publications (2)

Publication Number Publication Date
EP0593452A4 EP0593452A4 (de) 1992-08-31
EP0593452A1 true EP0593452A1 (de) 1994-04-27

Family

ID=19855723

Family Applications (1)

Application Number Title Priority Date Filing Date
EP91902555A Withdrawn EP0593452A1 (de) 1989-11-30 1990-11-28 Verfahren zur herstellung eines mit metallradionuklid markierten proteins

Country Status (5)

Country Link
EP (1) EP0593452A1 (de)
JP (1) JPH05504763A (de)
AU (1) AU654663B2 (de)
CA (1) CA2069868A1 (de)
WO (1) WO1991007991A1 (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5879657A (en) * 1993-03-30 1999-03-09 The Dupont Merck Pharmaceutical Company Radiolabeled platelet GPIIb/IIIa receptor antagonists as imaging agents for the diagnosis of thromboembolic disorders
WO1994025488A1 (en) * 1993-05-03 1994-11-10 Mallinckrodt Medical, Inc. Method for preparing a metal-radionuclide-labelled protein
WO1997025069A1 (en) * 1996-01-11 1997-07-17 Techniclone, Inc. Antibodies with reduced net positive charge
US5990286A (en) * 1996-12-18 1999-11-23 Techniclone, Inc. Antibodies with reduced net positive charge

Family Cites Families (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS59116232A (ja) * 1982-12-24 1984-07-05 Teijin Ltd 細胞毒性複合体及びその製造法
US4707352A (en) * 1984-01-30 1987-11-17 Enzo Biochem, Inc. Method of radioactively labeling diagnostic and therapeutic agents containing a chelating group
US4897255A (en) * 1985-01-14 1990-01-30 Neorx Corporation Metal radionuclide labeled proteins for diagnosis and therapy
US4732974A (en) * 1986-03-05 1988-03-22 Mallinckrodt, Inc. Metal ion labeling of carrier molecules
US4861869A (en) * 1986-05-29 1989-08-29 Mallinckrodt, Inc. Coupling agents for joining radionuclide metal ions with biologically useful proteins
US4970303A (en) * 1988-02-03 1990-11-13 Xoma Corporation Linking agents and methods
EP0401302B1 (de) * 1988-02-09 1995-06-28 Mallinckrodt, Inc. Verfahren zur herstellung eines mit metall-radionuklid-markierten proteins
GB8809616D0 (en) * 1988-04-22 1988-05-25 Cancer Res Campaign Tech Further improvements relating to drug delivery systems
ATE120454T1 (de) * 1988-06-14 1995-04-15 Cetus Oncology Corp Kupplungsmittel und sterisch gehinderte, mit disulfid gebundene konjugate daraus.
US5218128A (en) * 1988-06-15 1993-06-08 Centocor, Inc. Bifunctional coupling agents and radionuclide labeled compositions prepared therefrom

Also Published As

Publication number Publication date
WO1991007991A1 (en) 1991-06-13
AU7156691A (en) 1991-06-26
AU654663B2 (en) 1994-11-17
JPH05504763A (ja) 1993-07-22
EP0593452A4 (de) 1992-08-31
CA2069868A1 (en) 1991-05-31

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