Preclinical Evaluation of B7−H3-Targeted ADC-Based Molecular Imaging in Lung and Triple-Negative Breast Cancer

IF 4.9 2区医学 Q2 MEDICINE, RESEARCH & EXPERIMENTAL

Molecular Pharmaceutics Pub Date : 2026-10-05 Epub Date: 2026-09-23 DOI:10.1021/acs.molpharmaceut.6c00454

Jiayu Sui, Jingjie Qin, Jessica C. Hsu, Rachel J. Saladin, Todd E. Barnhart, Jonathan W. Engle, Xudong Hu, Jinming Yu, Weibo Cai, Yuchun Wei

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Abstract

B7−H3 is widely expressed in multiple solid tumors but shows minimal expression in normal tissues, making it an ideal target for molecular imaging; however, its systematic investigation remains limited. In this study, we utilized the clinically investigated B7−H3-targeted antibody−drug conjugate (ADC) HS-20093 to develop and evaluate a novel immuno-positron emission tomography (immuno-PET) tracer, [⁸⁹Zr]Zr-DFO-HS-20093, for accurate imaging of B7−H3 expression in lung cancer and triple-negative breast cancer models. [⁸⁹Zr]Zr-DFO-HS-20093 was synthesized with high radiochemical purity (98.2 ± 0.6%). Cellular uptake assays revealed significantly higher tracer uptake in A549 cells than in 4T1 cells at 1, 2, and 4 h (all P < 0.0001), which was markedly reduced by blocking with excess unlabeled antibody. Immunofluorescence revealed predominant membrane localization of B7−H3 in 4T1 cells, whereas A549 cells exhibited pronounced intracellular distribution, suggesting enhanced internalization. In tumor-bearing mice, [⁸⁹Zr]Zr-DFO-HS-20093 positron emission tomography (PET)/CT enabled clear tumor visualization, with peak uptake at 24 h post-injection in both A549 and 4T1 xenografts (9.63 ± 1.97 and 7.15 ± 3.14 μCi/mL, respectively), supporting its potential for tumor imaging. Ex vivo biodistribution data corroborated the PET findings, showing significantly higher tracer uptake in A549 tumors (5.01 ± 1.19 % ID/g) than in blocked tumors (2.89 ± 0.43 % ID/g) and 4T1 tumors (1.89 ± 0.47 % ID/g) (P = 0.034 and P = 0.003, respectively). Immunohistochemical analysis of A549 xenografts showed strong B7−H3 expression (3+), whereas 4T1 tumors exhibited lower expression levels (1−2+), further confirming that B7−H3 expression patterns were consistent with the imaging results. [⁸⁹Zr]Zr-DFO-HS-20093 enables sensitive immuno-PET imaging of B7−H3 and reveals tumor-type-dependent differences in B7−H3 expression and intracellular behavior.

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B7−h3靶向adc分子成像在肺癌和三阴性乳腺癌中的临床前评价

B7−H3在多种实体瘤中广泛表达，但在正常组织中表达量极少，是分子成像的理想靶点；然而，对其系统的调查仍然有限。在本研究中，我们利用临床研究的B7−H3靶向抗体-药物偶联物（ADC） HS-20093，开发并评估了一种新的免疫正电子发射层析成像（免疫- pet）示踪剂[89Zr] zr - dfos -HS-20093，用于准确成像肺癌和三阴性乳腺癌模型中B7−H3的表达。[89Zr]Zr-DFO-HS-20093具有较高的放射化学纯度（98.2±0.6%）。细胞摄取测定显示，A549细胞在1、2和4小时的示踪剂摄取明显高于4T1细胞（P < 0.0001），过量的未标记抗体阻断可显著降低示踪剂摄取。免疫荧光显示B7−H3在4T1细胞中以膜定位为主，而A549细胞表现出明显的细胞内分布，表明内化增强。在荷瘤小鼠中，[89Zr]Zr-DFO-HS-20093正电子发射断层扫描(PET)/CT能够清晰地显示肿瘤，在注射后24小时，A549和4T1异种移植物的摄取峰值分别为9.63±1.97和7.15±3.14 μCi/mL，支持其在肿瘤成像中的潜力。离体生物分布数据证实了PET的发现，A549肿瘤的示踪剂摄取（5.01±1.19% ID/g）明显高于阻断肿瘤（2.89±0.43% ID/g）和4T1肿瘤（1.89±0.47% ID/g）（P = 0.034和P = 0.003）。免疫组化分析显示，A549异种移植物的B7−H3表达较强（3+），而4T1肿瘤的表达水平较低（1−2+），进一步证实了B7−H3表达模式与影像学结果一致。[89Zr]Zr-DFO-HS-20093能够对B7−H3进行敏感的免疫pet成像，揭示B7−H3表达和细胞内行为的肿瘤类型依赖性差异。

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来源期刊

Molecular Pharmaceutics 医学-药学

CiteScore

8.00

自引率

6.10%

发文量

391

审稿时长

2 months

期刊介绍： Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development. Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.