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Updated: Mar 4, 2026
The Bioconjugation and Radiosynthesis of 89Zr-DFO-labeled Antibodies
Published on: February 12, 2015
89Zr/177Lu-Labeled Radioimmunoconjugates Targeting SORT1 for Cancer Theranostics
Jingyue Gao1, Tianyi Cen2, Junyi Chen3
1Key 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.
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.
Insights
Sortilin (SORT1) targeted antibody latozinemab was used to create novel theranostic radiopharmaceuticals. These agents show high specificity and therapeutic potential for SORT1-positive cancers, including melanoma.
Area of Science:
- Oncology
- Radiopharmaceutical Science
- Molecular Imaging
Background:
- Sortilin (SORT1) is overexpressed in several cancers, making it a potential target for cancer therapy and diagnostics.
- Current therapeutic strategies targeting SORT1 are limited, necessitating the development of novel approaches.
Purpose of the Study:
- To develop and validate a theranostic pair targeting Sortilin (SORT1) for cancer treatment.
- To evaluate the efficacy of SORT1-targeted radiopharmaceuticals in preclinical cancer models.
Main Methods:
- Development of [89Zr]Zr-DFO-latozinemab for PET imaging and [177Lu]Lu-DOTA-latozinemab for therapy.
- Assessment of SORT1 expression in various malignancies using transcriptional analysis and tissue microarrays.
- Evaluation of radiopharmaceutical binding affinity, internalization, tumor uptake, and therapeutic efficacy in vitro and in vivo.
Main Results:
- High SORT1 expression confirmed in melanoma and other malignancies.
- [89Zr]Zr-DFO-latozinemab demonstrated specific tumor visualization with high contrast.
- [177Lu]Lu-DOTA-latozinemab exhibited significant tumor accumulation and suppressed tumor growth through DNA damage induction.
Conclusions:
- The study establishes the first Sortilin (SORT1)-directed theranostic radiopharmaceutical pair.
- These agents show high specificity and therapeutic potency for SORT1-positive cancers, offering a promising new avenue for cancer management.
