Preclinical evaluation of 89Zr/177Lu/161Tb-labeled anti-CD228 monoclonal antibody for theranostics in skin cutaneous melanoma

• Immuno‑PET/CT with [ 89 Zr]Zr‑DFO‑CD228 enables specific, non‑invasive assessment of CD228 expression in SKCM models, supporting its utility for diagnosis and dynamic monitoring. • Both [ 177 Lu]Lu‑DOTA‑CD228 and [ 161 Tb]Tb‑DOTA‑CD228 exhibit significant tumor suppression with a acceptable safety profile in preclinical SKCM models. • [ 161 Tb]Tb-DOTA-CD228 inhibited tumor growth more potently than [ 177 Lu]Lu-DOTA-CD228 at the same administered activity, with preliminary mechanistic analyses suggesting that differential DNA damage, vascular responses, and immune modulation may account for the distinct anti–tumor effects of 161 Tb and 177 Lu, although further investigation is warranted. • Targeting CD228 with radiolabeled ligands for the diagnosis and treatment of SKCM is a promising approach, providing a rationale for future clinical application.