Chemistry: natural resins or derivatives; peptides or proteins; – Proteins – i.e. – more than 100 amino acid residues – Blood proteins or globulins – e.g. – proteoglycans – platelet...
Patent
1995-06-30
1997-10-21
Davis, Zinna Northington
Chemistry: natural resins or derivatives; peptides or proteins;
Proteins, i.e., more than 100 amino acid residues
Blood proteins or globulins, e.g., proteoglycans, platelet...
534 14, 546264, 546306, C07D21382, A61K 3144
Patent
active
056797788
DESCRIPTION:
BRIEF SUMMARY
This is a 371 application of PCT/GB93/02259, filed Nov. 3, 1993.
The present invention concerns improvements in molecule labelling and more especially concerns novel bifunctional hydrazine derivatives which are capable of linking metal ions, particularly technetium and rhenium, to biologically useful molecules.
BACKGROUND OF THE INVENTION
Because of their high biological specificity, certain macromolecules (eg, monoclonal antibodies and fragments thereof) have been used to target radioisotopes to specific in vivo sites for the purpose of imaging and/or therapy. The use of the metastable isotope of technetium, .sup.99m Tc, in diagnostic nuclear medicine is well established and the beta-emitting isotopes of rhenium .sup.186 Re, .sup.188 Re and .sup.189 Re can be used therapeutically. A number of methods for attaching technetium to macromolecules have been described. Some of these methods involve the reduction of disulphide groups in the macromolecule (usually an immunoglubulin) to thiols and the subsequent use of these groups to bind reduced Tc (eg, McKenzie et al, International Patent Publication WO 87/04164 and Bremmer et al, EP 0 271 806 A2). Direct labelling methods of this type have several potential disadvantages. The reduction of disulphide units can lead to protein de-naturation and a subsequent loss in biological specificity. Also, the method cannot be used to label macromolecules lacking disulphide moieties.
Alternatively, .sup.99m Tc can be linked to macromolecules via bifunctional chelates such as DTPA (D. Lanteigne and D. J. Hnatowich, Int. J. Appl. Radiat. Isot., 35, 617, (1984)), chelating thiosemicarbazones (Y. Arano et al, Int. J. Nucl. Med. Biol., 12, 425, (1985)) and diamidedithiol ligands (A. Fritzberg, European Patent Appl, EP 188 256 2A). Problems associated with these methods include significant nonspecific binding of technetium (binding to the protein at sites other than the chelating group) and slow kinetics of Tc-labelling.
We have previously described, in European Patent Application EP 0 384 769 A2, a novel method of modifying biological molecules (eg, monoclonal antibodies, polyclonal human IgG and ovalbumin) and smaller molecules (eg, peptides) with 2-hydrazinopyridino moieties which react with reduced Tc, eg .sup.99m Tc.sup.v (glucoheptonate) to produce stable immunoreactive radioconjugates.
It has been demonstrated that biological molecules, (eg, monoclonal antibodies), modified to carry radioisotopes or drug molecules are metabolised in vivo and the resulting products are distributed throughout the body. In an effort to control the biodistribution of the metabolised products the chemical characteristics of the modification moiety have been altered by including hydrophilic or cleavable functionalities. Paik et al (J. Nucl. Med., 30, 1693-1701 (1989) and Antibod. Immunoconjug. and Radiopharm. 3, 127-136 (1990) have demonstrated that interposition of an ester functionality between the monoclonal antibody and the radioisotope (.sup.111 In) accelerated the isotope's blood clearance and reduced its uptake in normal organs such as muscle, kidney, liver and spleen. This faster clearance from normal organs increased the tumour
ormal organ ratios 2-3 fold. Similarly enahnced clearance in non-tumoured animals was seen by Deshapande et al (Nucl. Med. Biol, 16, 587-597 (1989), Paik et al (Nucl. Med. Biol., 16, 475-481 (1989)), Weber et al (Bioconjugate Chem., 1, 431-437 (1990)), and Gustavson et al (U.S. Pat. No. 5,112,953 (1992) for antibodies labelled with .sup.111 In or .sup.99m Tc radioisotopes via a chelator attached through an ester or disulphide function.
It is the object of the present invention to provide new bifunctional molecules having hydrazino groups and reactive groups spaced by hydrophilic and/or cleavable moieties which can be used to link metal ions, such as .sup.99m Tc, to macromolecules so as to alter advantageously the biodistribution of the radiolabelled biological molecules.
SUMMARY OF THE INVENTION
According to the invention, novel bifunctional hydrazine comp
REFERENCES:
patent: 4861869 (1989-08-01), Nicolotti et al.
patent: 5112953 (1992-05-01), Gustavson et al.
Abrams Michael J.
Bridger Gary J.
Padmanabhan Sreenivasan
Schwartz David A.
Ultee Michael E.
Davis Zinna Northington
Johnson Matthey Public Limited Company
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