Pretargeted alpha radioimmunotherapy

Directly labelled antibodies carrying alpha emitters are attractive because alpha particles are extremely damaging over a very short range, but full-length antibodies circulate for days, so a directly labelled alpha antibody keeps irradiating blood and marrow long after most of it has left the tumour. Pretargeting separates the two steps: a bispecific antibody (one arm binds the tumour antigen, the other binds a small hapten) is given first and allowed to clear from circulation over hours to days, then a small radiolabelled hapten is injected and rapidly binds the antibody already sitting on the tumour, or clears from the body within hours if unbound.

The approach has a long clinical history with beta and gamma emitters going back over thirty years, including phase I/II trials of iodine-131 and lutetium-177 pretargeting in medullary thyroid cancer, small-cell lung cancer and CEA-positive colorectal cancer, but it has never reached market approval; a 2017 review notes that pretargeted lutetium-177/CEA trials in colorectal cancer were disappointing because tumour retention was too fast relative to lutetium-177's multi-day half-life. That mismatch is exactly why alpha emitters, most of which have half-lives of minutes to hours (bismuth-213, astatine-211), are now seen as a better fit for pretargeting's fast hapten kinetics. Preclinical proof of concept for alpha-pretargeting exists: a 2025 study from Memorial Sloan Kettering used a three-step regimen (anti-HER2/anti-DOTA bispecific antibody, a clearing agent, then actinium-225-labelled DOTA) to achieve complete responses in 20/20 HER2-positive breast cancer xenografts with tumour-to-kidney dose ratios of roughly 60:1 and no chronic nephrotoxicity at curative doses.

No alpha-emitter pretargeting regimen has yet been tested in patients; all current human experience with actinium-225 or bismuth-213 antibody therapy uses direct labelling (for example anti-CD33 225Ac antibodies in acute myeloid leukaemia).