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WO1999021587A1 - Complexants et immunoreactifs de ciblage - Google Patents

Complexants et immunoreactifs de ciblage Download PDF

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Publication number
WO1999021587A1
WO1999021587A1 PCT/GB1998/003102 GB9803102W WO9921587A1 WO 1999021587 A1 WO1999021587 A1 WO 1999021587A1 GB 9803102 W GB9803102 W GB 9803102W WO 9921587 A1 WO9921587 A1 WO 9921587A1
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Prior art keywords
cys
immunoreagent
group
oxy
alkoxy
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PCT/GB1998/003102
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English (en)
Inventor
Henry Wolfe
Daniel Joseph Delecki
Shi-Bao Yu
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Nycomed Imaging As
Matthews, Derek, Peter
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Filing date
Publication date
Application filed by Nycomed Imaging As, Matthews, Derek, Peter filed Critical Nycomed Imaging As
Priority to AU94521/98A priority Critical patent/AU9452198A/en
Publication of WO1999021587A1 publication Critical patent/WO1999021587A1/fr

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    • 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
    • A61K51/088—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins conjugates with carriers being peptides, polyamino acids or proteins
    • 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

Definitions

  • the present invention relates to targeting immunoreagents which find particular utility in therapeutic and diagnostic imaging compositions and methods.
  • radioactive immunoreagent i.e, reduction in tumor size by the targeting radioactive immunoreagent.
  • radioiodinated antibodies Moreover, rapid metabolism of radioiodinated antibodies allows incorporation of the iodine into the thyroid and active excretion of the iodine by the stomach and urinary tract. This dispersion of the radioactive iodine hinders imaging of specific tumors, since the tumors are hidden by background radiation .
  • EDTA and especially DTPA and derivatives thereof have remained the prevalent complexing agents to covalently bind antibody and coordinately complex metallic radionuclides .
  • the inadequacies of DTPA have been noted, for example, by Parker et al, "Implementation of Macrocycle Conjugated Antibodies for Tumor Targeting," Pure and APPI . Ch m . r 61, No. 9, 1637-41 (1989): "Conventionally the metal radionuclide has been complexed by an acyclic chelate (e.g. EDTA or DTPA) which is covalently linked to the antibody. None of the chelates is adequate because the metal tends to dissociate in vivo, ...
  • an acyclic chelate e.g. EDTA or DTPA
  • chelating agents When chelating agents are covalently bonded to proteins (such as Ab's), the proteins usually are capable of accepting far more than one molecule of the chelating agent because they contain a host of amine and sulfhydryl groups through which the chelating agents are bound. It is often very important to determine how many chelating sites are bound to each protein molecule. The most convenient way to accomplish this is by spectrophotometric means.
  • prior art chelating agents and chelates thereof have spectral absorptions that overlap with those of useful proteins, and an analytical determination of the number of chelating or chelated sites per molecule of protein cannot be made unequivocally by spectrophotometry since the overlapping spectral absorptions mask each other.
  • the chelator must be activated by a reducing agent before forming the radionuclide chelate. If the protein conjugates are to be formed prior to formation of the radionuclide chelate, then the reducing agent employed for activating the complexing agent can degrade the protein. For example, the preferred chelating agents currently used for complexing technetium (Tc) and rhenium (Re) complex to the metals via sulfur-containing groups which must be reduced with a reducing agent (dithiothreitol) to activate the chelator before forming the radionuclide chelate. If the protein conjugate containing disulfide bonds is formed prior to reduction, then the reducing agent can degrade the protein. It would be highly desirable to have chelating agents capable of forming conjugates with proteins before complexing with radionuclides .
  • the various currently available radiolabeled antibodies and chelating agents employed for making immunoreactive conjugates by covalently bonding a chelating agent to the immunoreactive protein, and radionuclide complexes thereof for use in diagnostic imaging and targeted therapeutics suffer from one or more of the following disadvantages: 1) toxicity; 2) dispersion of the reagent due to rapid metabolism; 3) inadequate emission characteristics; 4) inefficient covalent bonding with protein for conjugate preparation; 5) slow complexation with metals; 6) unstable metal complexation, e.g., with respect to temperature, time or pH; 7) inability to form conjugates and remain stable in storage until metal complexation is desired; 8) inability to spectrophotometrically analyze the radionuclide complex reagent; and 9) inability to complex without activation steps that degrade protein.
  • the targeting immunoreagents of this invention comprise a metal ion, a complexing agent which is a derivative of a pyridine, bipyridine, terpyridine, quaterpyridine, quinquepyridine, sexipyridine or phenanthroline, and an immunoreactive group covalently bonded through a protein reactive group to the complexing agent .
  • a targeting immunoreagent comprising a metal ion, a complexing agent, and an immunoreactive group covalently bonded to the complexing agent, the complexing agent having the structure A-I
  • R represents hydrogen, alkyl, alkoxy, alk lthio, alkylamino, alkylformamido, aryl, aryloxy, heterocyclyl or a protein reactive group
  • R represents hydrogen, alkyl, alkoxy, alkylthio, alkylamino, alkylformamido, aryl, aryloxy, heterocyclyl or a protein reactive group
  • R represents hydroxy, carboxy, hydroxyalkyl, thioalkyl, carbonyliminodiacetic acid, methyleneiminodiacetic acid, methylenethioethyleneiminodiacetic acid, carboxyalkythioalkyl, hydrazinylidenediacetic acid, or a salt
  • 2 of such acids, or two R groups, taken together, represent the atoms necessary to complete a macrocy ⁇ lic ring structure containing at least one heteroatom coordinating site and at least one, preferably two, alkylene groups forming part of the ring structure;
  • 3 R represents hydrogen, alkyl, alkoxy, alkylthio, alkylamino, alkylformamido, aryl, aryloxy, heterocyclyl or a protein reactive group;
  • 4 R represents hydrogen or a protein reactive group; n is 0, 1, 2, 3 or 4; o is 0 or 1; m is 0 or 1; provided that at least one of n and m is 0 and at least one of R, R 1, R3 and R4 is a protein reactive group; and said immunoreactive group is an ST binding receptor moiety.
  • the pyridines have the structure A-II
  • R, R 1, R2 and R3 are as defined above and n is 0, 1, 2,
  • the phenanthrolines have the structure A-IV
  • R 2, R3 and R4 are as defined above.
  • terpyridine quaterpyridine, quinqepyridine , and sexipyridine complexing agents having the structure A-I.
  • R 3 is alkoxy or alkyl
  • p is 0,1,2,3 or 4
  • R 6 is a protein reactive group.
  • This invention also provides therapeutic and diagnostic compositions comprising the above-described targeting immunoreagent.
  • This invention further provides a method for diagnostic imaging a site in a patient comprising a) administering to the patient an effective amount of a radioactive immunoreagent capable of targeting the site, and b) imagewise activating a radiation-sensitive element or device, such as, for example, a film or electronic sensor, with the radiation emitted from the targeted site.
  • This invention further provides a method for diagnostic imaging a site in a patient comprising a) administering to the patient an effective amount of a paramagnetic immunoreagent capable of targeting the site in a pharmaceutically acceptable carrier therefor, and b) imagewise activating a nuclear magnetic resonance detection sensor element or device which is sensitive to a change in one or more nuclear magnetic relaxation properties of an isotope such as a proton at the site of the patient while exposed to a controlled magnetic field environment such as, for example, a magnetic field in a magnetic resonance imaging instrument, which change is induced by the paramagnetic metal ion of the immunoreagent .
  • This invention further provides a method for diagnostic imaging a site in a specimen comprising a) administering to the specimen an effective amount of a fluorescent composition comprising a fluorescent immunoreagent capable of targeting a site in the specimen, b) irradiating the specimen with light, and c) imagewise activating a fluorescence emission sensor element or device, such as, for example, a film or electronic sensor with the fluorescent light emitted from the targeted site.
  • a method for treating disease sites in a patient according to this invention comprises administering to the patient or a specimen from the patient an effective amount of a therapeutic composition comprising the above-described immunoreagent capable of targeting the site and a pharmaceutically acceptable carrier therefor. It is an advantageous feature of this invention that the described targeting immunoreagents containing yttrium exhibit lower radiation toxicity, when compared to radioactive immunoreagents prepared with other yttrium chelators.
  • the targeting immunoreagents of this invention are not rapidly metabolized and do not deleteriously disperse. It is another advantageous feature that the described complexes efficiently form covalent bonds with proteins and other biological molecules.
  • immunoreagents exhibit good emission characteristics and are readily subject to spectrophotometric analysis.
  • protein conjugates of the complexing agents can be formed and stored until metal complexation is desired, and complexation can be accomplished without activation steps that degrade protein. Moreover, the complexing agents rapidly complex with metals, and the resulting chelates exhibit excellent stability with respect to time, temperature and pH.
  • Fig. 1 depicts the mass spectrum of the TMT-ST conjugate prepared in Example 1.
  • targeting immunoreagents are useful as diagnostic reagents, for example, radioimmunoelectrophoresis reagents .
  • the immunoreagents of this invention comprise a metal ion, a complexing agent, and an immunoreactive group covalently bonded to the complexing agent through a protein reactive group.
  • the complexing agent is a derivative of a pyridine, bipyridine, terpyridine, quaterpyridine, quinquepyridine, sexipyridine or phenanthroline, preferably having the structural formula A-I recited in the Summary above.
  • Each R in formula A-I independently is hydrogen; straight or branched alkyl, preferably containing from 1 to about 20 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, s-butyl, t-butyl, 2-ethylhexyl, decyl, hexadecyl, octadecyl, etc.; alkoxy, the alkyl portion of which contains from 1 to about 20 carbon atoms as described for R above; alkylthio, the alkyl portion of which contains from 1 to about 20 carbon atoms as described for R above; alkylamino, the alkyl portion of which contains from 1 to about 20 carbon atoms as described for R above; alkylformamido, the alkyl portion of which contains from 1 to about 20 carbon atoms as described for 12
  • substituted or unsubstituted aryl preferably containing from about 6 to 20 carbon atoms such as phenyl, naphthyl, phenanthryl, nitrophenyl, hydroxyphenyl, aminophenyl, hexadecylaminophenyl, octadecylaminophenyl, tolyl, xylyl, methoxyphenyl, 3-amino-4-methoxy ⁇ henyl, 4-methoxy-3- (N- methylhydrazinothioforraamido)phenyl, 3-isocyanato-4- methoxypheny1, 3-isothioc anato- -methoxyphenyl, methylthiophenyl, carboxyphenyl and alkylaryl such as alkylphenyl, the alkyl portion of which contains from 1 to about 20 carbon atoms as described for R above; aryloxy, the aryl portion of which contains from 6 to about 20 carbon
  • Each R is independently selected from the groups specified for R.
  • R preferably represents hydrogen or a protein reactive group.
  • Each R is independently selected from hydroxy; carboxy; hydroxyalkyl, the alkyl portion of which preferably contains from 1 to 4 carbon atoms, such as hydroxymethyl; carbonyliminodiacetic acid, [-CON (CH 2 COOH) 2 ] ; methyleneiminodiacetic acid, [-CH 2 N (CH 2 COOH) 2 ] ; methylenethioethyleneiminodiacetic acid - 13 -
  • salts of such acids including, for example, metal salts of such acids formed from such metals as Na, K, Li, etc., and ammonium salts such as ammonium, tetraethylammonium, and
  • two R groups taken together, represent the atoms necessary to complete a macrocyclic ring structure containing (a) at least one heteroatom coordinating site for ions, and (b) at least one, preferably two, alkylene groups forming part of the ring structure .
  • the macrocyclic ring-forming groups can be a heteroatom group substituted alkylene such as 2,2-bis-
  • oxybis (alkylene) for example oxybis (ethylene) , oxybis (ethyleneoxymethylene) , oxybis (ethyleneoxyethylene) ; alkyleneoxyalkyleneoxyalkylene, such as methyleneoxy- ethyleneoxymethylene; arylene-di (oxyalkylene) , such as 1,4- dimethyl-5, 6- ⁇ henylenebis (oxymethylene) ; 2, 6-pyridylene- bis (methyleneoxymethylene) ; 2-methoxy-5-methyl-l, 3- ⁇ henyl- enebis (methyleneoxymethylene) and 1, 10- ⁇ henanthrolin-2, 9- ylenebis (methyleneoxymethylene) ; carboxymethyliminobis [ (tri- methylene (carboxymethyl) iminomethylene] , [-CH 2 N (CH 2 COOH) (CH 2 ) 3 ⁇ N (CH 2 COOH) (CH 2 )
  • carboxylic acid containing groups including, for example, the
  • R ⁇ is methyleneiminodiacetic acid or a salt thereof.
  • Each R is independently selected from the groups
  • R preferably represents hydrogen.
  • Each R is independently selected from hydrogen or a protein reactive group.
  • At least one of the R, R 1, R3 and R4 groups present is a protein reactive group.
  • protein reactive group is meant any group which can react with any functional groups typically found on or introduced into proteins . However, it is specifically contemplated that the protein reactive group can be conjugated to nonprotein biomolecules .
  • the protein reactive groups useful in the practice of this invention include those groups which can react with any biological molecule (including carbohydrates, nucleic acids and lipids) containing a reactive group, or a specific receptor-ligand interactive group, to form a linking group between the complexing agent and the immunoreactive group.
  • Preferred protein reactive groups can be selected from, but are not limited to: (1) A group that will react directly with the amine or sulfhydryl groups on the protein or biological molecule containing the immunoreactive group, for example, active halogen containing groups including, for example, chloromethylphenyl groups and chloroacetyl [Cl-
  • the alkyl portions of the protein reactive group can contain from 1 to about 20 carbon atoms as described for R above.
  • the aryl portions of the protein reactive group can contain from about 6 to about 20 carbon atoms as described for R above.
  • Certain useful crosslinking agents such as, for example, difunctionai gelatin hardeners, bisepoxides and bisisocyanates become a part of, i * .e., a linking group in, the protein-complexing agent conjugate during the crosslinking reaction.
  • crosslinking agents facilitate the crosslinking, for example, as consumable catalysts, and are not present in the final conjugate.
  • crosslinking agents are carbodiimide and carbamoylonium crosslinking agents as disclosed in U.S. Patent 4,421,847, the disclosure of which is hereby incorporated herein by reference in its entirety, and the dication ethers of U.S. Patent 4,877,724, the disclosure of which is hereby incorporated herein by reference in its entirety.
  • one of the reactants must have a carboxyl group and the other an amine or sulfhydryl group.
  • the crosslinking agent first reacts selectively with the carboxyl group, then is split out during reaction of the "activated" carboxyl group with an amine to form an amide linkage between the protein and metal complexing agents having the structure A- I above, thus covalently bonding the two moieties.
  • An advantage of this approach i. that crosslinking of like molecules, e.g., complexing agents with comple t ing agents, avoided, whereas the reaction of difunctional crosslinking agents i_-nonselective so that unwanted crossli ed molecules are obtained.
  • Especially preferred protein reactive groups include amino and isothiocyanato .
  • Especially preferred complexing agents include species 1-59 set forth below.
  • SI Preferred classes of complexing agents for use herein include terpyridines represented by structure A-III above and phenanthrolines represented by structure A-IV above.
  • Representative preferred species of complexing agents include compounds 20-32 depicted above. The currently most preferred complexing agent is TMT isothiocyanate (compound
  • R is alkoxy or alkyl
  • p is 0,1,2,3 or 4.
  • R is a protein reactive group.
  • R ⁇ is alkyl, preferably containing from 1 to about 20, more preferably from 1 to 8 carbon atoms, such as methyl, ethyl and the like; or alkoxy, the alkyl portion of which contains- from 1 to about 20, more prefereably from 1 to 8 carbon atoms, such as methoxy, ethoxy and the like.
  • > is a protein reactive group as described above.
  • Preferred protein reactive groups include amino, alkylamino, arylamino, carbazido, semicarbazido, thiosemicarbazido, thiocarbazido, isocyanato and isothiocyanate
  • Especially preferred protein reactive groups include amino, isothiocyanato, and semicarbazido.
  • Especially preferred species include TMT (compound 21) TMT isothiocyanate (compound 24), and THT (compound 20).
  • Preferred phenanthroline complexing agents according to this invention have the structure A-IV above wherein at least one R 4 is a protein reactive group.
  • Preferred protein reactive groups include those specified for R 6 above.
  • the polypyridine and phenanthroline complexing agents having metal complexing sites, e.g. heteroatoms and iminodiacetate groups can be prepared by techniques known in the art. Suitable reaction schemes are illustrated in U.S. Patent 4,837,169, U.S. Patent
  • the targeting immunoreagent of this invention includes a metal ion.
  • the term 'metal ion 1 is intended to include any ion of an element other than hydrogen that has an oxidation state equal to or greater than 1 and which can bind to a complexing agent of this invention through interaction with sites of high electron density in the complexing agent such as at heteroatom sites.
  • preferred metal ions can be selected from, but are not limited to, ions of elements of groups ILA through VIA.
  • Preferred metals include those of atomic number 12, 13, 20, the transition elements 21 to 33, 38 to 52, 56, 72 to 84 and 88 and those of the lanthanide series (atomic nubmer 57 to 71) . Ions of yttrium and the lanthanide metals are especially preferred.
  • the immunoreagent of this invention can comprise a fluorescent metal ion.
  • the fluorescent metal ion can be selected from, but is not limited to, metals of atomic number 57 to 71. Ions of the follwing metals are preferred: La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu. Eu +3 is especially preferred.
  • Such immunoreagents comprising fluorescent metal ions such as, for example a Eu +3 ion can exhibit utility in time delayed fluorescence and assays which involve time delayed fluorescence.
  • the metal ion is a paramagnetic metal ion which is suitable for use in nuclear magnetic resonance applications which include diagnostic imaging using MRI techniques.
  • the paramagnetic element can be selected from elements of atomic number 21 to 29, 43, 44 and 57 to 71. The following elements are preferred: Cr, V, Mn, Fe, Co, Ni, Cu, La, Ce, Pr, Nd, Pm, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu. Mn, Gd and Dy are especially preferred.
  • the metal ion is a radionuclide.
  • the radionuclide can be selected, for example, from radioisotopes of Sc, Fe, Pb, Ga, Y, Bi,
  • radionuclides include 44 Sc, 64 Cu, 67 Cu, ⁇ n In, 212 Pb, 68 Ga, 90 Y, 87 Y, 153 Sm, 212 Bi, 99m Tc, 186 Re and 188 Re . Of these, especially preferred is 90 Y. Where the metal ion is a radionuclide ion the resulting immunoreagent is a targeting radioactive immunoreagent.
  • the immunoreactive group is an ST receptor binding moiety, such as ST enterotoxins or analogues thereof which bind to the ST receptors which are found only on the apical brush border membranes of the cells lining the intestinal tract of placental mammals.
  • a variety of bacteria such as Eschericia coli, Vibrio cholerae, Citrobacter freundii and Yersinia enterocolitica, which may infect the mammal gut produce homologous peptide toxins which bind to ST receptors and trigger a cascade of biochemical processes eventually leading to fluid secretion into the intestinal lumen and hence diarrhoea.
  • These ST enterotoxins are a major cause of infectious diarrhoeal disease in developing countries, the fourth leading cause of mortality and morbidity in the pediatric population worldwide.
  • These enterotoxins typically contain 18 or 19 amino acid residues, are stable to proteases and maintain their bioactivity even after incubation at 100°C for 15 minutes. Examples of such heat stable ST enterotoxins are listed in the table below:
  • E.Coli STa has disulphide bridges between the Cys residues at positions 5 and 10, 6 and 14 and 9 and 17.
  • Such cell receptor binding oligopeptides and analogues thereof are of interest both for therapeutic and diagnostic purposes.
  • an oligopeptide capable of binding to a cell surface receptor may be coupled to the complexing agents of the invention and serve as a biological vector to deliver that moiety to sites possessing such cell surface receptors.
  • radiopharmaceuticals may be caused to accumulate at body sites having the target receptors and so allow such sites to be detected and if desired mapped.
  • a cytotoxic dose of radiation can likewise be delivered to the site of concern using radiation emitting vector-bound radionuclides.
  • the ST receptors occur naturally only in the intestinal lumen and are found elsewhere in the body only as a result of metastases of colon cancers .
  • Parenteral administration of a radionuclide-tagged ST oligopeptide can be used to detect and treat such metastases (see US-A-5518888 and W095/11694) .
  • the ST receptor binding moiety can be modified or chemically altered to provide reactfive groups for attaching to the complexing agent by techniques known to those skilled in the art.
  • Such techniques include the use of linking moieties and chemical modification such as described in O-A-89/02931 and WO-A-89/02932, which are directed to modification of oligonucleotides, and U.S. Patent 4,719,182 the disclosures of all of which are hereby incorporated herein by reference in their entirety.
  • the immunoreactive group can have appended to it additional complexing agents via one of the protein reactive groups .
  • the term immunoreactive group is intended to include
  • ST receptor binding moieties having complexing agent molecules bonded thereto through one or more protein rective groups.
  • the immunoreagent of this invention can contain any ratio of metal radionuclide ion to complexing agent.
  • the mole ratio of metal ion to complexing agent is from about 1:100 to about 1:1.
  • the ratio of the complexing agent to the immunoreactive group can vary widely from about 0.5:1 to 10:1 or more. In some embodiments, the mole ratio of complexing agent to immunoreactive .groups is from about 1:1 to about 6:1:
  • the immunoreagent of this invention can be readily spectrophotometrically analyzed.
  • Example 1 Preparation of an ST-TMT conjugate Part A Preparation of Gly-Qxime Resin
  • TMT- isothiocyanate (TMT-NCS) was prepared in accordance with Preparation 6 in WO 92/08494.
  • TMT-NCS (6.4 mg) and ST peptide (4.3 mg) were charged into a siliconized plastic vial.
  • About 100 ⁇ l of acetonitrile was added to wet the solids and then 1.5 mL of borate buffer (pH 8.3) was added. The mixture was vortexed until it became a clear solution. It was left at RT overnight. MS identified the desired product from an aliquot of the reaction mixture.

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Abstract

L'invention concerne un immunoréactif de ciblage renfermant un ion métallique, un complexant et un groupe immunoréactif lié par covalence audit complexant qui présente la structure (I), ledit groupe immunoréactif étant une fraction de fixation à un récepteur de ST.
PCT/GB1998/003102 1997-10-15 1998-10-15 Complexants et immunoreactifs de ciblage WO1999021587A1 (fr)

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AU94521/98A AU9452198A (en) 1997-10-15 1998-10-15 Complexing agents and targeting immunoreagents

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US95114497A 1997-10-15 1997-10-15
US08/951,144 1997-10-15

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999039748A1 (fr) * 1998-02-06 1999-08-12 Nycomed Imaging As Immunoreactifs de ciblage utilises dans des compositions et des procedes therapeutiques et diagnostiques
WO2002070018A2 (fr) 2001-03-02 2002-09-12 Amersham Plc Conjugues peptide-chelate ameliores

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992008494A2 (fr) * 1990-11-08 1992-05-29 Sterling Winthrop Inc. Immunoreactifs de ciblage radioactifs
WO1995011694A1 (fr) * 1993-10-26 1995-05-04 Thomas Jefferson University Compositions se fixant specifiquement a des cellules cancereuses colo-rectales et procedes d'utilisation

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992008494A2 (fr) * 1990-11-08 1992-05-29 Sterling Winthrop Inc. Immunoreactifs de ciblage radioactifs
WO1995011694A1 (fr) * 1993-10-26 1995-05-04 Thomas Jefferson University Compositions se fixant specifiquement a des cellules cancereuses colo-rectales et procedes d'utilisation

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, vol. 106, no. 5, 2 February 1987, Columbus, Ohio, US; abstract no. 31032, BHATNAGAR, P. K. ET AL: "Synthesis and antigenic activity of E.coli ST and its analogs" XP002093444 *
CHEMICAL ABSTRACTS, vol. 93, no. 25, 22 December 1980, Columbus, Ohio, US; abstract no. 232989, SO, MAGDALENE ET AL: "Nucleotide sequence of the bacterial transposon Tn1681 encoding a heat-stable (ST) toxin and its identification in enterotoxigenic Escherichia coli strains" XP002093445 *
DEV. BIOL. STAND. (1986), 63(USE STAND. CHEM. DEFINED ANTIGENS), 79-87 CODEN: DVBSA3;ISSN: 0301-5149, 1986 *
PROC. NATL. ACAD. SCI. U. S. A. (1980), 77(7), 4011-15 CODEN: PNASA6;ISSN: 0027-8424, 1980 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999039748A1 (fr) * 1998-02-06 1999-08-12 Nycomed Imaging As Immunoreactifs de ciblage utilises dans des compositions et des procedes therapeutiques et diagnostiques
WO2002070018A2 (fr) 2001-03-02 2002-09-12 Amersham Plc Conjugues peptide-chelate ameliores
US7608242B2 (en) * 2001-03-02 2009-10-27 Ge Healthcare Limited Peptide-chelate conjugates

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