Biological targeting agents

Details Biological targeting agents Biological targeting agents

1996-07-11

1998-01-06

Kight, John

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

530300, 424 111, 424 165, A61K 5100, A61M 3614

Patent

active

057051437

DESCRIPTION:

BRIEF SUMMARY
PRIOR ART

The conjugation of chelating groups to proteins and polypeptides and subsequent complex formation with various radiometals is an established method of radiopharmaceutical design. The chelating group is conventionally attached by reaction of suitable functional groups in the ligand with either amine or thiol groups of the protein. Ligands incorporating such functionality are described as `bifunctional chelates`.
U.S. Pat. No. 4,479,930 discloses that DTPA bis anhydride can be used to attach DTPA to proteins or polypeptides. The acid anhydride group is ring-opened by the protein amine groups to generate the ligand in situ. DTPA-protein conjugates are not ideal for technetium labelling since non-specific binding to the protein is observed, i.e. the ligand is not sufficiently avid for the radiometal. Further developments have led to bifunctional thiol-containing ligands, since thiols have a higher affinity for certain metals (e.g. technetium) than the free --NH.sub.2, --OH or --CO.sub.2 H groups of the protein backbone.
Various functional groups have been used for conjugation to the protein amine or thiol groups and include:


______________________________________ active ester e.g. US 4897255 isothiocyanate maleimide e.g. US 4659839 thiolactone e.g. US 5095111 and US 4434151 ______________________________________
U.S. Pat. No. 4,741,900 discloses that protein carbohydrate residues can be oxidised to generate aldehyde moieties which can be derivatised with amine-functionalised ligands to give imine-linked conjugates. The imine linkage can be reduced to an amine to increase stability.
U.S. Pat. No. 5,234,820 discloses site-specific labelling of proteins/peptides at the C-terminus using peptidases, with the emphasis on protein labelling. The C-terminus is said to be useful as a site remote from the active site of the protein. Example 10 makes clear that the basis of the invention is transamidation, i.e. the terminal amino acid is exchanged (e.g. for a labelled one). This is significantly different from simple attachment to a terminal carboxyl group. No chelate conjugates are described.
Recent interest has shifted from high molecular weight proteins or monoclonal antibodies to much smaller peptides as targeting entities for radiopharmaceuticals.
As described above, a range of bifunctional chelating group functionality has been developed for conjugation to protein amine or thiol groups. Custom and practice was therefore to use the same bifunctional ligands to couple to peptide amine groups. This approach is reinforced by conventional solid phase peptide synthetic methods. These normally anchor an amino acid carboxyl group to the resin, leaving the amine group free to react with a second (N-protected) amino acid. Deprotection of the resulting resin-bound peptide permits sequential build up of the desired peptide chain. The resin-bound carboxyl is thus effectively protected, although it is not completely unreactive. For example, treatment of the resin with a strong solution of an organic amine (RNH.sub.2 for a prolonged period results in amide formation, i.e. release of peptide-CONHR.
GB 2225579 uses conventional protecting group technology to ensure that the chelating group is attached to the terminal amine of a somatostatin peptide, rather than the lysine residue which is known to be implicated in receptor binding. WO 93/15770 achieves the desired selectivity by control of pH during the conjugation reaction.
WO 91/01144 describes a range of chelate conjugates of peptides, hormones, growth factors, etc. In all cases the ligand is linked to an amine group of the peptide.
Macke et al.sup.(19) disclose chelate conjugates of the somatostatin analogue octreotide. Again, the ligands are linked to the peptides via peptide amine groups.
EP 515313 discloses further somatostatin analogues having a variety of chelating groups attached at the terminal amine position of the peptide.
In both WO 91/01144 and GB 2225579 a wide range of spacer groups between the peptide and ligand are claimed, but no particular

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