Copper-67 as a therapeutic nuclide for radioimmunotherapy

The application of the beta particle-emitting nuclide Cu-67 in radioimmunotherapy is reviewed. The production of the nuclide is outlined, and different production modes are discussed with an emphasis on cyclotron production. A short survey of copper chelators currently used for antibody labelling and their impact on the pharmacokinetics of Cu-67-labelled immunoconjugates is provided. Protocols for antibody labelling with Cu-67 as well as quality control procedures for Cu-67-labelled antibodies are described. Preclinical data on the biological properties of Cu-67-labelled immunoconjugates are reported and discussed. Cu-67-labelled antibodies show higher and more persistent tumour uptake than their radioiodinated counterparts due to accumulation of labelled metabolites in tumour cells. Biodistribution of Cu-67-labelled antibody fragments has been improved by selection of negatively charged chelators and peptide linkers. Pharmacokinetic analysis of the accumulated dose in tumour and critical or-ans such as the kidney and C liver indicates that, despite this improvement, intact Cu-67-Iabelled antibodies achieve higher tumour uptake and better therapeutic ratios than Cu-67-labelled antibody fragments and that they are at present the logical choice for clinical studies. Clinical studies using Cu-67-labelled antibodies in lymphoma, colon carcinoma and bladder cancer patients are reviewed. Some of the advantages over radioiodinated antibodies found in the preclinical work, such as higher tumour uptake and better tumour/blood ratios, have also been found with systemic application in lymphoma and colon carcinoma. However, in both lymphoma and colon carcinoma patients, the radiation dose to the liver has been found to be higher from Cu-67- than from I-131-labelled antibodies. The intravesical application of Cu-67-labelled antibody has been shown to be a promising approach for targetting cytotoxic radiation to superficial bladder tumours, without detectable systemic absorption. Given the favourable properties of Cu-67-labelled antibodies, it is the reliable availability of the Cu-67 nuclide which is the limiting factor for their more widespread evaluation in radioimmunotherapy trials.