Copper-67 as a therapeutic nuclide for radioimmunotherapy

Abstract

The application of the beta particle-emitting nuclide 67Cu 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 67Cu-labelled immunoconjugates is provided. Protocols for antibody labelling with 67Cu as well as quality control procedures for 67Cu-labelled antibodies are described. Preclinical data on the biological properties of 67Cu-labelled immunoconjugates are reported and discussed. 67Cu-labelled antibodies show higher and more persistent tumour uptake than their radioiodinated counterparts due to accumulation of labelled metabolites in tumour cells. Biodistribution of 67Cu-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 organs such as the kidney and liver indicates that, despite this improvement, intact 67Cu-labelled antibodies achieve higher tumour uptake and better therapeutic ratios than 67Cu-labelled antibody fragments and that they are at present the logical choice for clinical studies. Clinical studies using 67Cu-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 67Cu- than from 131I-labelled antibodies. The intravesical application of 67Cu-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 67Cu-labelled antibodies, it is the reliable availability of the 67Cu nuclide which is the limiting factor for their more widespread evaluation in radioimmunotherapy trials.

Generation of Radioisotopes with Accelerator Neutrons by Deuterons

“…Note that 90 Y-ibritumomab tiuxetan (Zevarin Ò ), a radiopharmaceutical agent containing a radionuclide 90 Y (T 1=2 ¼ 64 h), a pure À -ray emitter with a maximum energy of 2.28 MeV, has been used for cancer therapy. 67 Cu (T 1=2 ¼ 61:8 h) is believed to be a promising radionuclide to treat small distant metastases in RIT, 32) since 67 Cu decays to excited states of 67 Zn with their maximum À -ray energies of 0.377 MeV (57%), 0.468 MeV (22%), and 0.562 MeV (20%). Since 67 Cu emits low-energy -rays, which can be readily detected by a gamma-camera, it can be used simultaneously for diagnostic imaging and internal therapy.…”

Les anticorps radiomarqués pour le traitement des cancers

“…Le lutétium 177, émetteur β -de faible éner-gie, est aujourd'hui préféré à l'yttrium 90 pour traiter des petites lésions tumorales [33]. Le cuivre 67 est une autre option [34] qui pourra se développer grâce à de nouveaux moyens de production (cyclotrons de haute énergie et haute intensité comme Arronax, qui vient d'être installé à Nantes). Les deux images, antérieure et postérieure, révèlent les multiples métastases délimitées avec un fort contraste grâce à une technique de préciblage (AES) ciblant l'antigène carcinoembryonnaire [43].…”

Targeting of Radio-Isotopes for Cancer Therapy

“…Several Cu(II) isotopes have been investigated with 67 Cu for targeted radiation therapy being foremost. 41 The choice of BCA for Cu(II) isotopes remains an open and unresolved topic despite use of several different macrocyclic chelating agents being touted as stable and inert yet then with issues arising from transchelation of the isotope to superoxide dismutase and the isotope also being detected in patients' ceruloplasmin. 42-44 67 Cu remains an interesting isotope for therapy in regards to emission energy, half-life, and possessing imagable emissions, yet development of the chemistry remains necessarily active.…”