{"entity":{"id":"pretargeted-radioimmunotherapy","kind":"technology","name":"Pretargeted radioimmunotherapy","aka":["PRIT","pretargeting"],"tldr":"Instead of attaching radioactivity directly to a slow-moving antibody, doctors first inject the antibody alone, let it find the tumour and clear from the blood over some days, then inject a small fast-clearing radioactive tag that clicks onto the antibody only where it has stuck to the tumour.","summary":"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).\n\nThe 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.","asOf":"2026-09-22","links":[{"label":"Pretargeted imaging and therapy (J Nucl Med 2017 mini-review)","url":"https://jnm.snmjournals.org/content/58/10/1553"},{"label":"Current landscape in clinical pretargeted radioimmunotherapy (PMC 2021)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC8882889/"},{"label":"Towards optimisation of click-mediated pretargeted radioimmunotherapy (Mol. Pharm. 2019)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC7047588/"},{"label":"Pretargeting for imaging and therapy in oncological nuclear medicine (EJNMMI review 2017)","url":"https://pmc.ncbi.nlm.nih.gov/articles/PMC5824696/"}],"tags":["chemistry","radioimmunotherapy","click chemistry"],"related":["radioimmunotherapy","sarcophagine-chelation","b7h3","cd20","lu-177"],"indications":[],"sections":[],"technologies":[],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":["radioimmunotherapy","sarcophagine-chelation"],"notes":[],"principle":"The tumour-targeting antibody and the radionuclide are injected separately: the antibody carries a chemical handle and is given time to accumulate at the tumour and clear from blood, then a small, fast-clearing radiolabelled partner molecule is injected and binds specifically to the handle wherever the antibody has settled, while unbound radioligand is rapidly excreted.","strengths":[],"limitations":[],"since":"Concept introduced 1985 (Reardan et al.); first clinical bispecific-antibody trials from the early 1990s; IEDDA click-chemistry pretargeting from 2010"},"route":"/technologies/pretargeted-radioimmunotherapy/","neighbours":{"technology":[{"id":"radioimmunotherapy","kind":"technology","name":"Radio-antibody & radio-ADC","route":"/technologies/radioimmunotherapy/"},{"id":"sarcophagine-chelation","kind":"technology","name":"Sarcophagine chelation","route":"/technologies/sarcophagine-chelation/"}],"target":[{"id":"b7h3","kind":"target","name":"B7-H3","route":"/targets/b7h3/"},{"id":"cd20","kind":"target","name":"CD20","route":"/targets/cd20/"}],"isotope":[{"id":"lu-177","kind":"isotope","name":"Lutetium-177","route":"/isotopes/lu-177/"}]}}