89Zr/177Lu-Labeled Radioimmunoconjugates Targeting SORT1 for Cancer Theranostics

Sortilin (SORT1), a receptor overexpressed across multiple malignancies, represents a promising but untapped target for radionuclide theranostics. We utilized the SORT1-targeted antibody latozinemab to develop [89Zr]Zr-DFO-latozinemab and [177Lu]Lu-DOTA-latozinemab, providing a proof-of-concept for SORT1-targeted theranostics. Transcriptional analyses confirmed significant SORT1 upregulation across multiple malignancies, notably in melanoma. Melanoma TMA confirmed high SORT1 expression (mean H-score 189.79). The conjugates maintained picomolar affinity and demonstrated high internalization. [89Zr]Zr-DFO-latozinemab PET imaging enabled specific and high-contrast tumor visualization, with uptake peaking at 72 h in HT-1080-SORT1 models (SUVmean = 5.8 ± 0.69). In SK-MEL-28 xenografts, [177Lu]Lu-DOTA-latozinemab showed high, long tumor accumulation (39.08 ± 13.23%ID/g at 72 h) and favorable tumor-to-blood ratios (11.51 ± 6.17 at 96 h). Moreover, 11.1 MBq [177Lu]Lu-DOTA-latozinemab significantly suppressed tumor growth via induction of DNA damage, as evidenced by increased 53BP1 foci. These findings establish the first SORT1-directed theranostic radiopharmaceutical pair, exhibiting high specificity and therapeutic potency for managing SORT1-positive cancers.