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124I-labeled anti-CD147 antibody for noninvasive detection of CD147-positive pan-cancers: construction and preclinical studies

Acta Pharmacologica Sinica volume 45, pages 436–448 (2024)Cite this article

Abstract

Extracellular matrix metalloproteinase inducer CD147 is a glycoprotein on the cell surface. There is minimal expression of CD147 in normal epithelial and fetal tissues, but it is highly expressed in a number of aggressive tumors. CD147 has been implicated in pan-cancer immunity and progression. With the development of CD147-targeting therapeutic strategy, accurate detection of CD147 expression in tumors and its changes during the therapy is necessary. In this study we constructed a novel radiotracer by labeling the anti-CD147 mAb with radionuclide 124/125I (124/125I-anti-CD147) for noninvasive detection of CD147 expression in pan-cancers, and characterized its physicochemical properties, affinity, metabolic characteristics, biodistribution and immunoPET imaging with 124I-IgG and 18F-FDG as controls. By examining the expression of CD147 in cancer cell lines, we found high CD147 expression in colon cancer cells LS174T, FADU human pharyngeal squamous cancer cells and 22RV1 human prostate cancer cells, and low expression of CD147 in human pancreatic cancer cells ASPC1 and human gastric cancer cells BGC823. 124/125I-anti-CD147 was prepared using N-bromine succinimide (NBS) as oxidant and purified by PD-10 column. Its radiochemical purity (RCP) was over 99% and maintained over 85% in saline or 5% human serum albumin (HSA) for more than 7 d; the RCP of 125I-anti-CD147 in blood was over 90% at 3 h post injection (p.i.) in healthy mice. The Kd value of 125I-anti-CD147 to CD147 protein was 6.344 nM, while that of 125I-IgG was over 100 nM. 125I-anti-CD147 showed much greater uptake in CD147 high-expression cancer cells compared to CD147 low-expression cancer cells. After intravenous injection in healthy mice, 125I-anti-CD147 showed high initial uptake in blood pool and liver, the uptake was decreased with time. The biological half-life of distribution and clearance phases in healthy mice were 0.63 h and 19.60 h, respectively. The effective dose of 124I-anti-CD147 was estimated as 0.104 mSv/MBq. We conducted immunoPET imaging in tumor-bearing mice, and demonstrated a significantly higher tumor-to-muscle ratio of 124I-anti-CD147 compared to that of 124I-IgG and 18F-FDG in CD147 (+) tumors. The expression levels of CD147 in cells and tumors were positively correlated with the maximum standardized uptake value (SUVmax) (P < 0.01). In conclusion, 124/125I-anti-CD147 displays high affinity to CD147, and represents potential for the imaging of CD147-positive tumors. The development of 124I-anti-CD147 may provide new insights into the regulation of tumor microenvironment and formulation of precision diagnosis and treatment programs for tumors.

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Fig. 1: CD147 expression in different cell lines and the activity analysis of natI-anti-CD147.
Fig. 2: Quality control and in vitro stability test of 124/125I-anti-CD147.
Fig. 3: Binding affinity and cell uptake study of 125I-anti-CD147 and 125I-IgG.
Fig. 4: Pharmacokinetics and biodistribution of tracers in mice.
Fig. 5: ImmunoPET/CT imaging, ROIs and T/NT analysis of tumor models.
Fig. 6: Immunohistochemistry results of the tumor in mice.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (No. 82102092, 82171973 and 82171980), Beijing Municipal Hospital Management Center’s "Young Seedlings" Project (QML20231111), Capital’s Funds for Health Improvement and Research (No. 2022-2Z-2154 and 2022-2Z-2155), National Science and Technology Major Project (No. 2022YFC2406901), Beijing Hospitals Authority Dengfeng Project (DFL20191102), and Guizhou Provincial Science and Technology Department Basic Project Fund (ZK [2021]471).

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  1. These authors contributed equally: Xiao-kun Ma, Te-li Liu

Authors and Affiliations

  1. State Key Laboratory of Holistic Integrative Management of Gastrointestinal Cancers, Beijing Key Laboratory of Carcinogenesis and Translational Research, 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

    Xiao-kun Ma, Te-li Liu, Ya-nan Ren, Xiao-pan Ma, Yuan Yao, Xing-guo Hou, Jin Ding, Feng Wang, Hua Zhu & Zhi Yang

  2. Medical College, Guizhou University, Guiyang, 550025, China

    Ya-nan Ren & Xiao-pan Ma

  3. Department of Orthopaedics, Guizhou Provincial People’s Hospital, Guiyang, 550002, China

    Hai-feng Huang

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Contributions

A collaborative effort between ZY and HZ led to the design of the project and funding for its implementation. XKM wrote the manuscript, conducted animal studies, imaging, in vitro studies and data analysis. TLL conducted antibody radiolabelings and in vivo experiments. YNR, YY and XPM performed the pharmacokinetics and biodistribution of the probes. FW, XGH and JD produced and purified radionuclide 124I. XKM, TLL and HFH conducted the literature review and participated in the revision of the manuscript. ZY, HZ and TLL contributed to the study design and conceptualization, supervision, and manuscript revision.

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Correspondence to Hua Zhu or Zhi Yang.

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Ma, Xk., Liu, Tl., Ren, Yn. et al. 124I-labeled anti-CD147 antibody for noninvasive detection of CD147-positive pan-cancers: construction and preclinical studies. Acta Pharmacol Sin 45, 436–448 (2024). https://doi.org/10.1038/s41401-023-01162-y

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