Pretargeted radioimmunotherapy

Pretargeted radioimmunotherapy decouples the tumour-targeting antibody from the radionuclide, injecting them separately so that they combine in vivo. The generic sequence is: (1) administer an unlabelled or non-radioactive antibody derivative that carries a bio-orthogonal handle; (2) wait, typically 24-72 hours, for the antibody to accumulate at the tumour and clear from the circulation; (3) inject a small, rapidly clearing radiolabelled ligand; (4) allow it to ligate specifically to the antibody handle at the tumour, while any unbound radioligand is excreted quickly, sharply reducing radiation exposure to blood, marrow and other normal tissue compared with a directly labelled antibody. Four mechanistic platforms have been developed historically: streptavidin-biotin, bispecific antibodies that bind both a tumour antigen and a radiolabelled hapten (including the clinically advanced anti-tumour x anti-HSG bispecific/IMP288 peptide-hapten system), complementary oligonucleotide hybridisation (including morpholino, MORF/cMORF, backbones), and bio-orthogonal click chemistry using the inverse electron-demand Diels-Alder (IEDDA) reaction between tetrazine (Tz) and trans-cyclooctene (TCO).

The bispecific-antibody/hapten route has the most extensive clinical experience, including phase I optimisation trials in colorectal cancer and CD38-bispecific pretargeting in multiple myeloma and B-cell malignancies. Click-chemistry pretargeting is the most recent and modular approach: preclinical work with the huA33 colorectal antibody and 177Lu-DOTA-PEG-tetrazine achieved tumour activity concentrations of roughly 21% injected dose per gram at a 24-hour antibody-to-radioligand interval, with a calculated effective dose of about 0.054 mSv/MBq, and 'masking agents' that inactivate residual circulating TCO have been used to further sharpen the dosimetric profile. Limitations include the added logistical complexity of two sequential injections, the need for very fast blood clearance of the radioligand to avoid background dose, and, for click chemistry, in vivo stability of the TCO/tetrazine handles.