Abstract 4600: Preclinical evaluation and clinical translation of 68Ga/177Lu-JH12, a novel CXCR4-targeting radioligand

Abstract Introduction: C-X-C motif chemokine receptor 4 (CXCR4) is highly expressed by many kinds of tumors. Radiolabeled Pentixafor/Pentixather as typical targeting CXCR4 radioligands have been widely used in clinical practice, while there still remains barriers such as inadequate tumor uptake and high retention in blood or liver. Therefore, we designed a novel CXCR4-targeted agent, JH12. This research evaluated the specificity, biodistribution, pahrmacokinetics, and dosimetry of 68Ga/177Lu-JH12 in preclinical and preliminary clinical studies, using 68Ga-Pentixafor/177Lu-Pentixather as references. Methods: HT1080-CXCR4 cell line was used in cellular and small animal experiments. The in vitro binding affinities to CXCR4 were evaluated and presented as IC50 values. The specificity of 68Ga/177Lu-JH12 was assessed using PET/SPECT imaging, compared with 68Ga-Pentixafor/177Lu-Pentixather. Ex-vivo biodistribution studies were performed to obtain tumor uptake of 177Lu-JH12. Besides, the biodistribution and radiation dosimetry of 68Ga-JH12 were evaluated in 5 patients with oligometastatic tumors. We also conducted a head-to-head comparison to assess the diagnostic performance of 68Ga-JH12 and 68Ga-Pentixafor PET/CT in 3 patients. Results: 68Ga-JH12 exhibited excellent radiochemical purity and stability both in vitro and in vivo. The lower IC50 values on cellular level was observed in JH12 (18.79 nM) than Pentixafor (400.3 nM) and Pentixather (148 nM). In small animal PET imaging, the tumor uptake of 68Ga-JH12 was 3.29 times than 68Ga-Pentixafor at 1 hour post-injection. In small animal SPECT imaging and the ex-vivo distribution, 177Lu-JH12 showed significantly higher tumor uptake (approximately 2 times) while lower accumulation in liver (approximately 10 times) than those of 177Lu-Pentixather. Furthermore, clinical PET/CT imaging of 68Ga-JH12 demonstrated remarkably higher tumor radiotracer uptake than 68Ga-Pentixafor (SUVmax: 60 minutes, 27.44 ± 14.75 vs. 12.98 ± 7.41, P<0.05). Ultimately, based on the results of 68Ga-JH12 dosimetry in 5 patients with tumor, the mean dose of 68Ga-JH12 in liver, kidney and red marrow was 2.31E-02 ± 3.25E-03 mGy/MBq, 7.57E-02 ± 2.12E-02 mGy/MBq and 3.03E-02 ± 1.34E-02 mGy/MBq respectively. The effective dose of 68Ga-JH12 was 2.01E-02 ± 6.66E-03 mGy/MBq. Conclusion: JH12 appears to perform better in tumor visualization and retention, which might be a promising biological radio-tracer in CXCR4-targeting imaging and treatment. Citation Format: Tianrui Kang, Yuxin Lai, Hongfei Cheng, Xiuting Lin, Yaoming Yu, Jian Zhan, Yueguang Sun, Eric Wang, Haihua Yu, Kevin Wang, Jinqiu He, Guochang Wang, Weibing Miao. Preclinical evaluation and clinical translation of Ga/Lu-JH12, a novel CXCR4-targeting radioligand [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4600.