Preclinical evaluation of the theranostic potential of 89Zr/177Lu-labeled anti-TROP-2 antibody in triple-negative breast cancer model

Yitian Wu; Tuo Li; Xianzhong Zhang; Hongli Jing; Fang Li; Li Huo

doi:10.1186/s41181-023-00235-x

Preclinical evaluation of the theranostic potential of ⁸⁹Zr/¹⁷⁷Lu-labeled anti-TROP-2 antibody in triple-negative breast cancer model

EJNMMI Radiopharm Chem. 2024 Jan 9;9(1):5. doi: 10.1186/s41181-023-00235-x.

Authors

Yitian Wu^{1

2}, Tuo Li², Xianzhong Zhang¹, Hongli Jing², Fang Li³, Li Huo⁴

Affiliations

¹ Medical Science Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Beijing, 100730, China.
² Department of Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Center for Rare Diseases Research Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China.
³ Department of Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Center for Rare Diseases Research Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China. lifang@pumch.cn.
⁴ Department of Nuclear Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Center for Rare Diseases Research Beijing Key Laboratory of Molecular Targeted Diagnosis and Therapy in Nuclear Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100730, China. huolipumch@163.com.

Abstract

Background: Triple-negative breast cancer (TNBC) is one of the most lethal malignant tumors among women, characterized by high invasiveness, high heterogeneity, and lack of specific therapeutic targets such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Trophoblast cell-surface antigen-2 (TROP-2) is a transmembrane glycoprotein over-expressed in 80% of TNBC patients and is associated with the occurrence, progress, and poor prognosis of TNBC. The TROP-2 targeted immunoPET imaging allows non-invasive quantification of the TROP-2 expression levels of tumors, which could help to screen beneficiaries most likely to respond to SG and predict the response. This study aimed to develop a ⁸⁹Zr/¹⁷⁷Lu-radiolabeled anti-TROP-2 antibody (NY003) for immunoPET and SPECT imaging, as well as radioimmunotherapy (RIT) in TROP-2 (+)TNBC tumor-bearing model. Based on the camelid antibody, we developed a TROP-2 targeted recombinant antibody NY003. NY003 was conjugated with DFO and DTPA for ⁸⁹Zr and ¹⁷⁷Lu radiolabelling, respectively. The theranostic potential of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003 was evaluated through immunoPET, SPECT imaging, and RIT studies in the subcutaneous TROP-2 positive TNBC xenograft mice model.

Results: The high binding affinity of NY003 to TROP-2 was verified through ELISA. The radiochemical purity of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003 exceeded 95% and remained stable within 144h p.i. in vitro. ImmunoPET and SPECT imaging showed the specific accumulation of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003 in MDA-MB-231 tumors and gradually increased with the time tested, significantly higher than that in control groups (P < 0.05). The strongest anti-tumor efficacy was observed in the high-dose of [¹⁷⁷Lu]Lu-DTPA-NY003 group, followed by the low-dose group, the tumor growth was significantly suppressed by [¹⁷⁷Lu]Lu-DTPA-NY003, the tumor volumes of both high- and low-dose groups were smaller than the control groups (P < 0.05). Ex vivo biodistribution and histological staining verified the results of in vivo imaging and RIT studies.

Conclusion: As a drug platform for radiotheranostics, ⁸⁹Zr/¹⁷⁷Lu-radiolabeled anti-TROP-2 antibody NY003 could not only non-invasively screen the potential beneficiaries for optimizing SG ADC treatment but also suppressed the growth of TROP-2 positive TNBC tumors, strongly supporting the theranostic potential of [⁸⁹Zr]Zr-DFO-NY003/[¹⁷⁷Lu]Lu-DTPA-NY003.

Keywords: 177Lu; 89Zr; ADC; ImmunoPET; Radioimmunotherapy (RIT); TROP-2; Triple negative breast cancer (TNBC).

Abstract

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