EP0592549A1 - Agents d'imagerie specifiques aux tissus comprenant des anticorps anti-idiotypiques permettant de produire des images internes - Google Patents

Agents d'imagerie specifiques aux tissus comprenant des anticorps anti-idiotypiques permettant de produire des images internes

Info

Publication number
EP0592549A1
EP0592549A1 EP92914741A EP92914741A EP0592549A1 EP 0592549 A1 EP0592549 A1 EP 0592549A1 EP 92914741 A EP92914741 A EP 92914741A EP 92914741 A EP92914741 A EP 92914741A EP 0592549 A1 EP0592549 A1 EP 0592549A1
Authority
EP
European Patent Office
Prior art keywords
idiotypic antibody
recombinant
fragmented
warm
whole
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Withdrawn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
EP92914741A
Other languages
German (de)
English (en)
Other versions
EP0592549A4 (fr
Inventor
Raghavan Rajagopalan
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 EP0592549A1 publication Critical patent/EP0592549A1/fr
Publication of EP0592549A4 publication Critical patent/EP0592549A4/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
    • 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
    • A61K51/1078—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 the antibody being against an immunoglobulin, i.e. being an (anti)-anti-idiotypic antibody
    • 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 present invention relates generally to the use of labeled anti-idiotypic antibodies for diagnostic imaging and, more particularly, to labeled anti-idiotypic antibodies for use as agents to image in vivo receptors in biological systems for diagnostic use.
  • Jerne Jerne, N.K., Anals . Inst. Pasteur Paris 125c, 372 proposes that the variable regions of antibodies (i.e. idiotypes) act as immunogens to give rise to a secondary set of antibodies called "anti-idiotypes".
  • anti-idiotypes a secondary set of antibodies
  • the resulting anti-idiotypic population may contain antibodies that will likewise bind to the same receptor due to each the ligand and the anti- idiotypic antibody having similar topological features.
  • the anti-idiotypic antibody mimics the ligand.
  • Jerne has led to the development of a number of anti-idiotypic antibodies such as those against acetylcholine, TSH, glucocorticoid, adenosine and similar such compounds, without ever having to isolate and purify the natural receptor (Erlanger, B.F., Inter. Rev. Immunol . , 5, 1989, 131) which can be quite difficult.
  • radiographic imaging agents for the visualization of skeletal structures, organs, or tissues is also well known in the area of biological and medical research and diagnostic procedures.
  • the procedure whereby such imaging is accomplished generally involves the preparation of radioactive agents, which, when introduced to the biological subject, are localized in the specific skeletal structures, organs, or tissues to be studied.
  • the localized radioactive agents may then be traced, plotted, or scintiphotographed by radiation detectors such as traversing scanners or scintillation cameras.
  • the distribution and relative intensity of the detected radiation indicates the position of the agent in the tissue and also shows the presence of aberrations, pathological conditions and the like.
  • the density and distribution of the receptors being so imaged depends on the pathological state of that particular tissue.
  • the particular anti- idiotypic antibodies of the present invention provide many advantages when used as diagnostic agents to provide a means of imaging biological receptors without having to isolate and purify the natural receptor.
  • the present invention employs the use of anti- idiotypic antibodies for site specific diagnostic imaging of biological receptors without having to isolate and purify the natural receptor.
  • An anti-idiotypic antibody refers to an antibody raised against a first antibody which specifically binds to the antibody binding site or CDR of the first antibody.
  • the antibody binding site or CDR of an antibody is that portion thereof which specifically binds to the recognized epitope.
  • the anti-idiotypic antibodies of the present invention are made by developing antibodies against a first antibody that binds specifically to a certain desired ligand directed at the receptor within the body. The resulting anti-idiotypic antibody binds to the same receptor due to its topological similarity with the ligand.
  • the whole, fragmented, recombinant anti-idiotypic antibody or recombinant fragment may be labeled with a radionuclide such as Tc-99m using a chelate approach wherein one of the preferred chelates is a multidentate organic compound with three amide nitrogen atoms and one thiolate sulfur atom (N 3 S chelate) bonded to a metal radionuclide, 99m Tc, which is also bonded to one oxygen atom to form an anti-idiotypic antibody complex.
  • a radionuclide such as Tc-99m
  • one of the preferred chelates is a multidentate organic compound with three amide nitrogen atoms and one thiolate sulfur atom (N 3 S chelate) bonded to a metal radionuclide, 99m Tc, which is also bonded to one oxygen atom to form an anti-idiotypic antibody complex.
  • the anti-idiotypic antibody complex is then injected into a warm-blooded animal for site specific diagnostic imaging of the particular tissue area desired by means of imaging the labeled receptors thereof.
  • the anti-idiotypic antibody employed in the present invention is may be made according to the well established hybridoma technology as exemplified by European Patent
  • the novel approach of utilizing the anti-idiotypic antibodies for imaging specific receptors within a desired tissue area has two major advantages over the conventional methods described above. First, it avoids having to use purified receptors to develop the anti-receptor antibodies. Often it is difficult and sometimes impossible to isolate pure, stable receptors for this type of immunization. Secondly, the attachment of a small molecule for labeling, e.g., molecules having a molecular weight of approximately 1000 of less, to a large anti-idiotypic antibody should not perturb its receptor binding capability significantly. In contrast, the classical bifunctional approach of attaching metal complexes directly to small effector substances, such as drugs or hormones for example, essentially blocks the receptor binding capabilities.
  • Diagnostically or therapeutically useful radionuclide elements which may be used to label the anti-idiotypic antibody include technetium, indium, rhenium, yttrium, gadolinium, gallium, bismuth, fluorine, iodine and the like which can be coupled to the whole, fragmented or recombinant anti-idiotypic antibodies or recombinant fragments thereof by any one of the several methods known in the art.
  • Example methods that may be used in the present invention are disclosed in European Patent Application assigned publication number 0 284 071 and U.S. Patent Numbers 4,659,839; 4,732,974; 4,837,003 and 4,965,392, each incorporated herein by reference.
  • either the whole, fragmented or recombinant anti-idiotypic antibody or recombinant fragments thereof can be labeled with radionuclide chelates in a non-selective manner wherein the chelate is either bound at any location on the anti- idiotypic antibody or by a site-selective technique.
  • the radionuclide chelate is bound distally from the receptor binding site of the anti- idiotypic antibody by using, for example, a bifunctional coupling agent which reacts with a free sulfhydryl group generally found in the fragmented or anti-idiotypic antibody and is used to label the target biological receptors.
  • a standard method for preparing anti-idiotypic antibody fragments is by the enzymatic digestion of the whole antibody with papain or pepsin as described by Parham, et al., J. Immunol . Methods , 1982, 53, 133.
  • the anti-idiotypic antibody or fragments thereof can likewise be iodinated directly with a sodium iodide/chloramine-T procedure or can be attached via covalently bound bifunctional moieties such as those illustrated in Formula I below:
  • X is selected from the group consisting of isocyanate, isothiocyanate, imidate, maleimido, succinimidyloxycarbonyl, acid chloride and sulfonyl chloride.
  • Fluorines which are potentially useful for fluorine magnetic resonance imaging (MRI) or for positron emission tomography (PET) can likewise, for example, be conjugated to the antibody via a bifunctional molecule as illustrated by Formula II below:
  • Metal ions such as technetium, rhenium, indium, yttrium, gadolinium, bismuth and the like can be joined to either the whole, fragmented or recombinant anti-idiotypic antibody or recombinant fragments thereof in a selective manner using a bifunctional molecule that contains an appropriate ligand and a coupling group that reacts specifically with the protein sulfhydryl groups such as a maleimido group as illustrated in Scheme I below.
  • the bifunctional molecule contains the ligand and a coupling moiety selected from the group consisting of succinimidyloxycarbonyl, isocyanate, imidate, isothiocyanate, acid chloride and sulfonyl chloride such as illustrated in Scheme 2 below.
  • the maleimido ligand 3, the succinimido ligand 6, and the method of labeling the conjugated proteins 4 and 7 with indium-111 or technetium-99m have been described in detail by Nicolotti, et al., U.S. Patent No. 4,732,974, incorporated herein by reference.
  • the present invention is therefore not restricted to radiographic imaging, and may be applied to any imaging modality.
  • the anti-idiotypic antibody of the present invention may be likewise labeled through fluorination or by labeling with a paramagnetic metal chelate.
  • the antibody conjugate in Example 4 below can complex gadolinium or europium for MRI or immunofluorescence applications respectively.
  • the internal image antibody i.e., anti-idiotypic antibody is directed at the digoxin receptor in the myocardium and is labeled with technetium-99m. It is believed that the labeled digoxin internal image antibodies may be useful in the diagnosis of some coronary disorders and may supplement the information gained from the use of myocardial perfusion agents such as thallium-201.
  • novel imaging agents of this invention can be formulated into diagnostic compositions containing sufficient amount of labeled anti-idiotypic antibody for imaging, together with a pharmaceutically acceptable buffer such as phosphate, citrate, or tris(hydroxymethyl)amino-methane; balanced ionic solutions containing chloride and bicarbonate salts of blood plasma cations such as Ca 2+ , N 2+ , K + , Mg 2+ , saline and the like.
  • concentration of the imaging agent according to the present invention should be sufficient to provide satisfactory imaging, c.a. 1 to 50 millicuries.
  • the imaging agent should be administered so as to remain in the patient for 1 to 3 hours, although both longer and shorter time periods are acceptable.
  • Imaging may be carried out in the normal manner, for example by injecting a sufficient amount of the imaging composition to provide adequate imaging and then scanning with a suitable machine, such as a gamma camera.
  • a suitable machine such as a gamma camera.
  • the anti-idiotypic antibodies and the corresponding radionuclide conjugates can be prepared in accordance with the examples set forth below, which are not intended to be limiting.
  • Monoclonal antibodies were produced by the hybridoma technology well known in the art. Two AJ mice were immunized with murine (Balb-C) monoclonal anti-digoxin antibody (Medex Laboratories). A booster injection was given 3 weeks after the primary immunization and the spleens were removed after 3 days. Mouse myeloma and the spleen cells were washed three times with Dulbecco's Eagle Medium (DME) and suspended in DME (10ml). A 5 mL portion of each of these cell suspensions were mixed and centrifuged.
  • DME Dulbecco's Eagle Medium
  • a 75 ⁇ L portion of affinity purified goat anti-mouse antibody (2 mg/mL) was diluted with PBS buffer (150 mL). In each well was placed 200 ⁇ L of the above antibody and the plates were incubated at 37°C for 4 hours. The plates were washed with water (3 times), treated with 3% BSA solution (200 ⁇ L), and incubated for 1 hour. The wells were washed again with water (3 times) and then treated with the supernatants from the cell culture (150 ⁇ L) and allowed to incubate at ambient temperature for about 18 hours. The plates were washed with water (3 times), treated with 125 I labeled goat anti-digoxin (100 ⁇ L) and incubated for 4 hours. Thereafter, the plates were washed and the wells were counted. A total of 39 positive wells were identified.
  • Ascites fluid is obtained in the usual manner by the injection of the hybridoma cells from Example 2 into mouse peritoneum. It is purified by three successive precipitation with ammonium sulfate using 20mM phosphate buffer, pH 6.8. Thereafter, the protein is dialyzed exhaustively using 20 mM phosphate buffer, pH 6.8. The monoclonal antibody is purified by ion-exchange chromatography (Whatman C-52 column, 0 to 500 mM NaCl gradient in pH 6.8 phosphate buffer). The desired fraction is collected and stored in the same buffer at 4°C.
  • the desired amount of antibody (absorbance of 1% solution at 280 nm is 14.4) and cysteine-free papain (Worthington, 2 times crystallized) in the ratio of 1:20 are incubated at 37°C using 10 times the volume of digestion buffer (100 mM sodium acetate, 3 mM disodium EDTA, pH 5,5) until the reaction is complete (3-16 hours) as determined by SDS-PAGE.
  • the digestion mixture is diafiltered (Amicon flow cell, PM-10 membrane) at 4oC using TRIS buffer, pH 7.2. It is then applied to the Whatman DE- 52 ion-exchange resin, previously equilibrated in the same buffer, to remove the anioni ⁇ F c fragment.
  • the eluent which consists of (F ab ,) 2 and inactivated papain, is purified by Sephadex G-100 size exclusion chromatography using TRIS buffer, pH 7.2.
  • the desired antibody fragment elutes in the void volume and is characterized by SDS-PAGE. It is stored as frozen aliquots at -70oC.
  • the dimer thus obtained by papain digestion of the whole antibody is then further cleaved to the desired F ab , fragment using thiol reagents such as cysteine or dithiothreitol.
  • thiol reagents such as cysteine or dithiothreitol.
  • the dimer in 25 mM phosphate buffer, pH 7.4, containing 2 mM disodium EDTA and 0.02% (w/v) sodium azide is incubated at room temperature with either cysteine or dithiothreitol until the reaction is complete as determined by SDS-PAGE (usually 1-4 hours). Excess reducing agent and other low molecular weight fragments are quickly removed by Sephadex G-25 column using PBS.
  • the F ab fragment thus obtained should be used as soon as possible in order to prevent the oxidation of the sulfhydryl groups.
  • a mixture of the F ab , fragment and about 20 fold excess of the ligand shown in Scheme 1 is incubated in labeling buffer (50 mM MES, pH 6.0) for 2-4 hours. Excess ligand and other low molecular weight impurities are quickly removed by Sephadex G-25 column using the labeling buffer.
  • the antibody fragment conjugated with the ligand is then labeled with radioactive indium chloride as described below.
  • a mixture of 111 InCl 3 (80 ⁇ L) and 4,5-dihydroxy-1,3- benzenedisulfonic acid (40 ⁇ L, 10 mM) in 0.2 M MES buffer (80 ⁇ L) is treated with the conjugated F ab , fragment and the entire mixture is incubated at room temperature for 1 hour.
  • the reaction mixture is treated with 0.2 M EDTA (40 ⁇ L) to remove excess indium.
  • the indium labeled antibody is then purified by Sephadex G-50 column using 0.15 M NaCl as eluent.
  • a mixture of the F ab , fragment and about 25 fold excess of the ligand shown in Scheme 2 is incubated in 25 mM phosphate buffer, pH 7.4 at room temperature for about 30 minutes. Excess ligand and other low molecular weight impurities are quickly removed by Sephadex G-25 column using the same buffer. Thereafter, the conjugated F ab . solution was treated with 15 ⁇ L 99m Tc-saccharic acid and the mixture is incubated at 37°C for about 30 minutes. The technetium labeled antibody is then purified by Sephadex G- 25 column using the same buffer.
  • a preparation of the present invention using either whole, fragmented, or recombinant anti-idiotypic antibodies or a recombinant fragment thereof is administered to the patient, for example, in the form of an injectable liquid.
  • suitable detectors e.g., a gamma camera
  • images can be obtained by recording the emitted radiation of the organ or the pathological process in which the labeled anti- idiotypic antibody has been incorporated, which in the present case is biological receptors.
  • the anti-idiotypic antibody of the present invention or a fragment or recombinant derivative thereof prepared as described above provides a means of in vivo diagnostic imaging of receptors which provides many advantages over prior known procedures which involve cellular secretions.
  • the composition is used with a pharmaceutically acceptable carrier in a method of performing a diagnostic imaging procedure using a gamma camera or like device which involves injecting or administering to a warm-blooded animal an effective amount of the present invention and then exposing the warm-blooded animal to an imaging procedure as described above, thereby imaging at least a portion of the body of the warm-blooded animal.
  • Pharmaceutically acceptable carriers include those that are suitable for injection such as aqueous buffer solutions, e.g., tris(hydroxymethyl)aminomethane (and its salts), phosphate, citrate, bicarbonate, etc., sterile water for injection, physiological saline, and balanced ionic solutions containing chloride and/or bicarbonate salts of normal blood plasma cations such as Ca 2+ , Na + , K + and Mg 2+ .
  • Other buffer solutions are described in Remington's Practice of Pharmacy, Eleventh Edition, for example on page 170.
  • the carriers may contain a chelating agent, e.g., a small amount of ethylenediaminetetraacetic acid, calcium disodium salt, or other pharmaceutically acceptable chelating agents.
  • concentration of the labeled anti-idiotypic antibodies in the pharmaceutically acceptable carrier for example an aqueous medium, varies with the particular field of use. A sufficient amount is present in the pharmaceutically acceptable carrier in this particular case when satisfactory visualization of the receptor
  • composition is administered to the warm-blooded animal so that the composition remains in the living animal body for about 6 to 7 hours, although shorter and longer residence periods are normally acceptable.
  • the labeled anti-idiotypic antibodies may be used in the usual way in imaging procedures. For example, with the present invention when imaging biological receptors, a sufficient amount of the labeled anti-idiotypic antibody must be intravenously administered to the warm-blooded animal to provide adequate visualization; the animal or a portion thereof is then scanned with a suitable imaging machine such as a gamma camera.
  • a suitable imaging machine such as a gamma camera.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Optics & Photonics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Physics & Mathematics (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Composition diagnostique pouvant être administrée à un animal à sang chaud et comprenant un anticorps anti-idiotyique entier, fragmenté ou recombiné, marqué par un chélate, la composition pouvant être injectée à un animal par voie intraveineuse afin de produire une image fiable de récepteurs biologiques.
EP92914741A 1991-07-01 1992-06-29 Agents d'imagerie specifiques aux tissus comprenant des anticorps anti-idiotypiques permettant de produire des images internes Withdrawn EP0592549A4 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US72422891A 1991-07-01 1991-07-01
US724228 1991-07-01
PCT/US1992/005500 WO1993000934A1 (fr) 1991-07-01 1992-06-29 Agents d'imagerie specifiques aux tissus comprenant des anticorps anti-idiotypiques permettant de produire des images internes

Publications (2)

Publication Number Publication Date
EP0592549A1 true EP0592549A1 (fr) 1994-04-20
EP0592549A4 EP0592549A4 (fr) 2000-10-25

Family

ID=24909565

Family Applications (1)

Application Number Title Priority Date Filing Date
EP92914741A Withdrawn EP0592549A4 (fr) 1991-07-01 1992-06-29 Agents d'imagerie specifiques aux tissus comprenant des anticorps anti-idiotypiques permettant de produire des images internes

Country Status (5)

Country Link
EP (1) EP0592549A4 (fr)
JP (1) JPH06509102A (fr)
AU (1) AU2307092A (fr)
CA (1) CA2110819A1 (fr)
WO (1) WO1993000934A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030031627A1 (en) 2001-07-31 2003-02-13 Mallinckrodt Inc. Internal image antibodies for optical imaging and therapy

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0208531A2 (fr) * 1985-07-05 1987-01-14 Immunomedics, Inc. Matériaux pour Lymphographie et pour obtenir l'Image des Organes et Kit
GB2189810A (en) * 1986-04-28 1987-11-04 Antibody Technology Ltd Antibodies their preparation and use and products containing them
EP0247866A1 (fr) * 1986-05-29 1987-12-02 Mallinckrodt, Inc. (a Delaware corporation) Agents de couplage pour la préparation de protéines marquées par la radioactivité
EP0248506A1 (fr) * 1986-03-05 1987-12-09 Mallinckrodt, Inc. (a Delaware corporation) Marquage de molécules de support par les ions métalliques
EP0270340A2 (fr) * 1986-12-05 1988-06-08 Cancer Biologics, Inc. Utilisation d'un conjugué d'anticorps pour la détection de tissu nécrotique malin et pour la thérapie associée
US4859450A (en) * 1984-08-13 1989-08-22 The General Hospital Corporation Method of NMR imaging using antibody to cardiac myosin
EP0434257A2 (fr) * 1989-12-05 1991-06-26 Immunomedics, Inc. Anticorps chimérique pour la détection et thérapie de lésions infectieuses et inflammatoires

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4606855A (en) * 1982-07-26 1986-08-19 Mex Research Associates C/O Leon Reimer Monoclonal antibody to digoxin
US4659839A (en) * 1984-10-10 1987-04-21 Mallinckrodt, Inc. Coupling agents for radiolabeled antibody fragments

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4859450A (en) * 1984-08-13 1989-08-22 The General Hospital Corporation Method of NMR imaging using antibody to cardiac myosin
EP0208531A2 (fr) * 1985-07-05 1987-01-14 Immunomedics, Inc. Matériaux pour Lymphographie et pour obtenir l'Image des Organes et Kit
EP0248506A1 (fr) * 1986-03-05 1987-12-09 Mallinckrodt, Inc. (a Delaware corporation) Marquage de molécules de support par les ions métalliques
GB2189810A (en) * 1986-04-28 1987-11-04 Antibody Technology Ltd Antibodies their preparation and use and products containing them
EP0247866A1 (fr) * 1986-05-29 1987-12-02 Mallinckrodt, Inc. (a Delaware corporation) Agents de couplage pour la préparation de protéines marquées par la radioactivité
EP0270340A2 (fr) * 1986-12-05 1988-06-08 Cancer Biologics, Inc. Utilisation d'un conjugué d'anticorps pour la détection de tissu nécrotique malin et pour la thérapie associée
EP0434257A2 (fr) * 1989-12-05 1991-06-26 Immunomedics, Inc. Anticorps chimérique pour la détection et thérapie de lésions infectieuses et inflammatoires

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
CURTET C ET AL: "MAGNETIC RESONANCE IMAGING USING NMR CONTRAST AGENT GADOLINIUM LABELED MONOCLONAL ANTIBODIES, GD-DTPA-MAB 73.3 AND 19.9 DIRECTED AGAINST CRC HUMAN TUMOR AND GD-DTPA-MAB OC 125 DIRECTED AGAINST HUMAN OVARIAN TUMOR" INTERNATIONAL JOURNAL OF RADIATION APPLICATIONS AND INSTRUMENTATION PART B: NUCLEAR MEDICINE AND BIOLOGY,US,ELSEVIER SCIENCE PUBLISHERS, NEW YORK, NY, vol. PART B/16, no. 2, 1989, page 180 XP000008061 ISSN: 0883-2897 *
D.W. SECCOMBE ET AL.: "A study into the nature and organ source of digoxin-like immunoreactive substance(s) in the perinatal period." BIOLOGY OF THE NEONATE., vol. 56, no. 3, 1989, pages 136-146, XP000866111 KARGER, BASEL., CH ISSN: 0006-3126 *
DEAN SHERRY A ET AL: "STABILITY CONSTANTS FOR GD3+ BINDING TO MODEL DTPA-CONJUGATES AND DTPA-PROTEINS: IMPLICATIONS FOR THEIR USE AS MAGNETIC RESONANCE CONTRAST AGENTS" MAGNETIC RESONANCE IN MEDICINE,US,ACADEMIC PRESS, DULUTH, MN, vol. 8, no. 2, 1 October 1988 (1988-10-01), pages 180-190, XP000035617 ISSN: 0740-3194 *
FUJIBAYASHI Y ET AL: "High myocardial accumulation of radioiodinated digoxin derivative: a possible sodium, potassium-ATPase imaging agent" J. NUCL. MED., 1992, VOL. 33, NO. 4, PAGE(S) 545-9, XP002127223 *
R KOHN ET AL: "ENDOGENOUS DIGITALIS-LIKE FACTOR IN PATIENTS WITH ACUTE MYOCARDIAL INFARCTION" COR ET VASA,CZ,CZECH MEDICAL SOCIETY, PRAGUE, vol. 34, no. 3, 1992, page 227-237 XP002081545 ISSN: 0010-8650 *
See also references of WO9300934A1 *
STROSBERG A.D. ET AL: "Poly and monoclonal anti-idiotypic antibodies interact with beta-adrenergic receptors" FEDERATION PROCEEDINGS, 1984, VOL. 43, NO. 6, PAGE(S) 1742, NO. 1902, XP000938475 *
VENTER J C ET AL: "MONOCLONAL AND ANTI-IDIOTYPIC ANTIBODIES AS PROBES FOR RECEPTOR STRUCTURE AND FUNCTION" FEDERATION PROCEEDINGS,US,BETHESDA, MD, vol. 43, no. 10, July 1984 (1984-07), page 2532-2539 XP000670907 *
WILLIAMS W V ET AL: "ANTIBODY GEOMETRY AND FORM: THREE-DIMENSIONAL RELATIONSHIPS BETWEEN ANTI-IDIOTYPIC ANTIBODIES AND EXTERNAL ANTIGENS" TRENDS IN BIOTECHNOLOGY,GB,ELSEVIER PUBLICATIONS, CAMBRIDGE, vol. 8, no. 9, September 1990 (1990-09), pages 256-263, XP000142295 ISSN: 0167-7799 *

Also Published As

Publication number Publication date
AU2307092A (en) 1993-02-11
EP0592549A4 (fr) 2000-10-25
CA2110819A1 (fr) 1993-01-21
WO1993000934A1 (fr) 1993-01-21
JPH06509102A (ja) 1994-10-13

Similar Documents

Publication Publication Date Title
Goodwin et al. Pre-targeted immunoscintigraphy of murine tumors with indium-111-labeled bifunctional haptens
Khaw et al. Monoclonal antibody to cardiac myosin: imaging of experimental myocardial infarction
FI82379B (fi) Radioaktivt maerkta monoklonala antikroppar samt en komposition innehaollande dessa och anvaendbar som diagnostiskt radiofarmaseutiskt medel.
US4634586A (en) Reagent and method for radioimaging leukocytes
US5153118A (en) Monoclonal antibodies having binding specificity to human prostate tumor-associated antigens and methods for employing the same
US6375925B1 (en) Methods and reagents for non-invasive imaging of atherosclerotic plaque
Bernhard et al. Localization of 111In-and 125I-labeled monoclonal antibody in guinea pigs bearing line 10 hepatocarcinoma tumors
JPS6336794A (ja) モノクロ−ナル抗体、これを産生するハイブリド−マ並びにこれを用いた腎細胞癌腫の検出及び映像化方法
JPH0684315B2 (ja) ヒト腫瘍治療用注射組成物
Steis et al. Toxicity, immunogenicity, and tumor radioimmunodetecting ability of two human monoclonal antibodies in patients with metastatic colorectal carcinoma.
Primus et al. Immunological considerations in the use of goat antibodies to carcinoembryonic antigen for the radioimmunodetection of cancer
Sfakianakis et al. Radioimmunodiagnosis and radioimmunotherapy, 1982
EP0163041B1 (fr) Réactif diagnostique pour les maladies de coeur et son utilisation
Carney et al. Dual isotope study of iodine-125 and indium-111-labeled antibody in athymic mice
EP0228243A1 (fr) Anticorps monoclonaux à spécificité de liaison contre les antigènes associés à des tumeurs humaines de la prostate
US5084266A (en) Method for tumor imaging utilizing a labelled tumor specific antibody and a non-tumor reactive antibody
WO1998021581A1 (fr) Procedes et reactifs destines a l'imagerie non invasive d'une plaque d'atherosclerose
Britton et al. Radiolabelled monoclonal antibodies in oncology I. Technical aspects
Haber et al. Detection and quantification of myocardial cell death: application of monoclonal antibodies specific for cardiac myosin
EP0592549A1 (fr) Agents d'imagerie specifiques aux tissus comprenant des anticorps anti-idiotypiques permettant de produire des images internes
US5208008A (en) Regioselective chemical modification of monoclonal antibodies
EP0090025A1 (fr) Marquage specifique de glandes mammaires
Haber et al. Monoclonal Antibodies Specific for Cardiac Myosin: In Vivo and in Vitro Diagnostic Tools in Myocardial Infarction
Gomibuchi et al. Radioimmunodetection of human melanoma tumor xenografts with human monoclonal antibodies
Sfakianakis et al. Radioantibodies for the diagnosis and treatment of cancer; radioimmunoimaging (RAI) and radioimmunotherapy (RAT)

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

17P Request for examination filed

Effective date: 19940110

AK Designated contracting states

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

RIC1 Information provided on ipc code assigned before grant

Free format text: 7A 61K 49/02 A, 7A 61K 37/04 B, 7C 07K 13/00 B, 7C 07K 15/28 B, 7A 61K 49/00 B

A4 Supplementary search report drawn up and despatched

Effective date: 20000907

AK Designated contracting states

Kind code of ref document: A4

Designated state(s): AT BE CH DE DK ES FR GB GR IT LI LU NL SE

RAP1 Party data changed (applicant data changed or rights of an application transferred)

Owner name: MALLINCKRODT, INC.

17Q First examination report despatched

Effective date: 20011210

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN

18D Application deemed to be withdrawn

Effective date: 20020423