My research focuses on the development of a theranostic platform approach for pretargeted radioimmunotherapy (PRIT) of solid human tumors. We call this strategy “DOTA-PRIT,” which is short for “DOTA ligand bound radionuclide-based pretargeted radioimmunotherapy.” In principle, DOTA-PRIT consists of three sequential administrations of three reagents: (i) the bi-specific Ab construct IgG-scFv (bsAb), which has high specificity and affinity for both a tumor antigen through the IgG and a radiolabeled hapten through the scFv; (ii) a clearing agent to eliminate unbound construct from the blood; and (iii) the imaging/therapeutic radioligand. The tumor targeting is separated from the payload-delivery step, thereby offering greater therapeutic indices (TIs) compared to conventional radioimmunodetection/radioimmunotherapy with directly labeled antibodies. Significant improvement in TIs permits high therapeutic doses of administered radioisotopes with minimal to no bystander side effects. In close collaboration with the lab of Nai-Kong Cheung at MSK and Dane Wittrup at MIT, we have successfully applied this platform in three preclinical tumor models: GPA33 antigen (colorectal cancer); GD2 antigen (neuroblastoma); and the HER2/neu receptor (breast cancer).
Illustration of three-step DOTA-PRIT based on targeting with an IgG-scFv bispecific antibody (e.g., huA33-C825 for detection and treatment of colorectal cancer) with dual specificity for a tumor-associated antigen (e.g., GPA33) and M-DOTA haptens (e.g., 177Lu-DOTA).