SEZ6-Targeted PET Imaging and Alpha-Particle Radioimmunotherapy is Effective for Detection and Treatment of Small Cell Lung Cancer.

Small cell lung cancer (SCLC) remains one of the most lethal malignancies, with a five-year survival of <10% despite advances in treatment. Seizure-related gene 6 (SEZ6), a type I transmembrane protein preferentially expressed in neuroendocrine tumors, has recently emerged as a promising therapeutic target, supported by clinical activity of SEZ6-targeted antibody-drug conjugates in relapsed SCLC. Here, we developed and evaluated a humanized anti-SEZ6 monoclonal antibody for SEZ6-targeted positron emission tomography (PET) imaging and α-particle radioimmunotherapy. Immunohistochemistry of patient tissues confirmed strong, stage-independent SEZ6 expression. Cell-based studies demonstrated high SEZ6 receptor densities, supporting high-affinity antibody binding and rapid receptor-mediated internalization. [89Zr]Zr-DFO-SEZ6-Ab administered at low antibody mass exhibited rapid hepatosplenic clearance with minimal tumor uptake despite high intratumoral levels. This pattern was consistent with active ectodomain shedding and local accumulation of soluble antigen within the tumor microenvironment, creating an extracellular antigen sink and limiting effective target engagement. Increasing the antibody mass overcame this barrier, dramatically increasing tumor uptake in xenografts. Treatment with [225Ac]Ac-Macropa-SEZ6-Ab induced complete tumor regression, while co-administration of the ATR inhibitor berzosertib enhanced efficacy at lower radioactivity doses without added toxicity. Together, these findings identify tumor-localized SEZ6 shedding as a biological barrier to SEZ6-targeted therapy, define dosing strategies to overcome it, and demonstrate potent antitumor activity of SEZ6-directed α-particle radioimmunotherapy in SCLC.