MMAE-AzB-5B1-TCO

MMAE-AzB-5B1-TCO is a preclinical pretargeted antibody-radiosensitizer conjugate (ARC) developed by Memorial Sloan Kettering Cancer Center and Hunter College for the treatment of pancreatic ductal adenocarcinoma (PDAC). The conjugate consists of the fully human monoclonal antibody 5B1, which targets carbohydrate antigen 19-9 (CA19-9), conjugated to the potent cytotoxin and radiosensitizer monomethyl auristatin E (MMAE) via a hypoxia-sensitive azobenzene (AzB) linker, and further modified with trans-cyclooctene (TCO) groups. In the dense, hypoxic microenvironment of PDAC, the azobenzene linker is cleaved, selectively releasing MMAE to act as a radiosensitizer and cytotoxin. The TCO groups enable a bioorthogonal pretargeting strategy, allowing subsequent administration of radiolabeled tetrazine probes (such as [177Lu]Lu-DO3A-PEG7-Tz) to achieve highly localized radiotherapy while minimizing off-target radiation exposure to healthy tissues.