2. Academic Validation
  3. 89Zr/177Lu-Labeled Radioimmunoconjugates Targeting SORT1 for Cancer Theranostics

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

  • J Med Chem. 2026 Mar 12;69(5):6254-6265. doi: 10.1021/acs.jmedchem.6c00007.
Jingyue Gao 1,  Tianyi Cen 2,  Junyi Chen 3,  Xinwei Li 2,  Xiaowei Fan 2,  Mengxin Xu 2,  Feng Gao 1,  Zhibo Liu 4 2 3 5
Affiliations

Affiliations

  • 1 Key Laboratory for Experimental Teratology of the Ministry of Education and Center for Experimental Nuclear Medicine, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, China.
  • 2 Changping Laboratory, Beijing 102206, China.
  • 3 Beijing National Laboratory for Molecular Sciences, Radiochemistry and Radiation Chemistry Key Laboratory of Fundamental Science, Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, China.
  • 4 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), NMPA Key Laboratory for Research and Evaluation of Radiopharmaceuticals (National Medical Products Administration), Department of Nuclear Medicine, Peking University Cancer Hospital & Institute, Beijing 100142, China.
  • 5 Peking University-Tsinghua University Center for Life Sciences, Beijing 100871, China.
PMID: 41773941 DOI: 10.1021/acs.jmedchem.6c00007
Abstract

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.

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