Alice Harrison

The in vivo release of 90Y from cyclic and acyclic ligand-antibody conjugates

Yttrium binding ligands DOTA, caDTPA and CT-DTPA were each conjugated to monoclonal antibody B72.3, labelled with 90Y and injected into mice in order to assess the in vivo inertness of the antibody-linked 90Y-ligand complexes. Levels of 90Y in femur shafts of the DOTA-B72.3 mice were low, being approximately 7 and 44%, respectively, of levels in the femur shafts of the caDTPA-B72.3 and CT-DTPA-B72.3 treated mice. This finding demonstrates the greater inertness and by implication the greater suitability for immunotherapy of the DOTA-90Y complex.

Synthesis of a kinetically stable yttrium-90 labelled macrocycle–antibody conjugate

Lysine is a precursor for the synthesis of an aminobutyl C-functionalised tetra-azacyclododecane tetra-acid which has been linked to B72.3 antibody and may be labelled with 90Y to form a kinetically stable complex of potential use in radioimmunotherapy.

Towards tumour imaging with indium-111 labelled macrocycle–antibody conjugates

C-Functionalised triazacyclododecane and triazacyclononane triacid macrocycles have been covalently attached to a monoclonal antibody and may be labelled with 111In to form kinetically inert radiolabelled complexes.

Towards tumour targeting with copper-radiolabelled macrocycle–antibody conjugates: synthesis, antibody linkage, and complexation behaviour

A set of four tetra-azamacrocyclic ligands bearing aminomethylphenyl substituents have been prepared and may be attached to a monoclonal antibody via an intermediate thiol-specific vinylpyridine linker molecule. The resultant conjugates may be efficiently radiolabelled with 64Cu or 67Cu at pH 4 to minimise non-specific protein binding, and the copper labelled antibody-conjugate is stable with respect to copper loss in vivo. The forward rate of copper binding has been optimised through a kinetic analysis using stopped-flow spectrophotometry. In succinate buffer, anionic copper species Cu(succ)22–(log β= 4.35) and HCu(succ)2–(log β= 9.64) are the kinetically significant copper species in the pH range 3.6–5.6.

Synthesis and structure of stable indium and gallium complexes of (R)-1,4,7-tris(2′-methylcarboxymethyl)-triazacyclononane

Abstract The title ligand forms stable neutral complexes with gallium and indium and the structure of the latter has been studied by X-ray crystallography.

Nuclear magnetic resonance, luminescence and structural studies of lanthanide complexes with octadentate macrocyclic ligands bearing benzylphosphinate groups

The solution and solid-state structures of lanthanide complexes of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetryltetramethylenetetra(benzylphosphinate), L1a, and of its o-, m- and p-methoxybenzyl analogues (L2, L3, L4) have been investigated by NMR, relaxometry, crystallographic and photophysical methods. It has been shown that the number of proximate water molecules is dependent on the size of the bound lanthanide ion: the complex [LaL1a]– is nine-co-ordinate and adopts a twisted square-antiprismatic structure with one bound water molecule. The analogous [YL1a]–, [YbL1a]–, [GdL1a]– and [EuL1a]– complexes also adopt a twisted square-antiprismatic geometry, but are eight-co-ordinate, with no metal-bound water. Relaxivity studies with the gadolinium complexes showed that they are purely ‘outer-sphere’ contrast agents, but they associate strongly with proteins leading to a pronounced relaxivity enhancement. Detailed biodistribution studies with [GdL1a]– revealed avid biliary uptake at low doses and a well defined tendency for the complex to be cleared more slowly from tumour tissue, allowing tissue differentiation.

Towards tumour targeting with copper-radiolabelled macrocycle–antibody conjugates

Tetra-aza-macrocycles covalently attached to a monoclonal antibody may be efficiently radiolabelled with 64Cu or 67Cu at pH 4, minimising non-specific binding to the protein, giving a kinetically stable conjugate in vivo.

Antibody labelling with functionalised cyclam macrocycles

Functionalised ‘cyclam’ macrocyclic ligands have been selectively attached to thiol residues on a monoclonal antibody and form kinetically inert complexes with Cu2+ and TcV.

Synthesis and biodistribution of 111In, 67Ga and 153Gd-radiolabelled conjugates of nitroimidazoles with bifunctional complexing agents: imaging agents for hypoxic tissue?

Abstract Conjugates of the putative hypoxia-selective agent 2-nitroimidazole with bifunctional complexing agents have been prepared and radiolabelled with 111In, 67Ga or 153Gd. Although some evidence for tumour localisation was found control experiments revealed that the gallium and indium labelled complexes of the simple ligand 1,4,7-triazacyclononane-triacetate are themselves promising tumour-imaging agents.

Improved tumour targeting with recombinant antibody–macrocycle conjugates

Linkage of a macrocyclic complexing agent to a spaced tri-maleimide allows formation of a recombinant trivalent antibody by reaction with a Δ-Cys Fab fragment of an engineered human antibody.