Targeting Claudin 18.2 Using a Highly Specific Antibody Enables Cancer Diagnosis and Guided Surgery
Targeting Claudin 18.2 Using a Highly Specific Antibody Enables Cancer Diagnosis and Guided Surgery
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使用高度特异性抗体靶向 Claudin 18.2 实现癌症诊断和引导手术
DOI：
10.1021/acs.molpharmaceut.1c00947
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发表时间：
2022-03-28
影响因子：
4.9
通讯作者：
Zhu, Hua
中科院分区：
文献类型：
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作者：
Zhao, Chuanke;Rong, Zhuona;Zhu, Hua
摘要：Claudin 18.2（CLDN18.2）是一个潜在的肿瘤治疗新靶点，尤其是晚期胃癌（AGC）。分子靶向探针对于患者分层和治疗指导具有重要意义。在这里，我们探索了基于CLDN18.2特异性抗体5C 9的特异性检测和手术指导的抗体依赖性分子成像策略。合成了两种显像探针124 I-5C 9和Cy5.5- 5C 9。在具有对照的细胞实验中证明了对CLDN18.2的特异性，使用异种移植模型通过荧光成像评估诊断效用。设计了近红外荧光II成像探头FD 1080 - 5C 9，以促进病变的全面手术切除。124 I-5C 9免疫PET成像清楚地描绘了皮下CLDN18.2阳性肿瘤，峰值摄取（最大标准化摄取值; SUVmax）为2.25 +/- 0.30，而124 I-IgG组和阻断组的最高值分别为0.70 +/- 0.13和0.66 +/- 0.12。Cy5.5- 5C 9荧光成像显示类似的结果。作为诊断和引导手术（DGS）概念的证据，在原位CLDN18.2阳性肿瘤模型中同时施用124 I-5C 9和FD 1080 - 5C 9，促进肿瘤组织的全面切除。结合起来，124 I-5C 9和FD 1080 - 5C 9都是有前途的DGS工具：前者作为PET探针揭示病变中的CLDN18.2，后者可以指导手术。这些结果为基于CLDN 18. 2特异性抗体的AGC和其他癌症的特异性检测和手术指导提供了实用的分子成像策略。关键词：CLDN18.2，分子成像，免疫PET，诊断和指导治疗，近红外荧光II
ABSTRACT: Claudin 18.2 (CLDN18.2) is a new potential target for cancer therapy, especially for advanced gastric cancer (AGC). A molecular targeting probe is of importance for patient stratification and therapeutic guidance. Here, we explored an antibodydependent molecular imaging strategy for specific detection and surgery guidance based on a CLDN18.2-specific antibody, 5C9. Two imaging probes, 124I-5C9 and Cy5.5-5C9, were synthesized. The specificity to CLDN18.2 being evidenced in the cellular experiments with control, the diagnostic utility was assessed by fluorescence imaging using xenograft models. A near-infrared fluorescent II imaging probe FD1080-5C9 was designed to facilitate the comprehensive surgical removal of lesions. 124I-5C9 immuno-PET imaging clearly delineated subcutaneous CLDN18.2positive tumors, with a peak uptake (maximum standardized uptake value; SUVmax) of 2.25 +/- 0.30, whereas the highest values for the 124I-IgG and blocking groups were 0.70 +/- 0.13 and 0.66 +/- 0.12, respectively. Cy5.5-5C9 fluorescence imaging showed similar results. As proof of the diagnosis and guided surgery (DGS) concept, 124I-5C9 and FD1080-5C9 were simultaneously administered in orthotopic CLDN18.2-positive tumor models, facilitating the comprehensive resection of tumor tissue. Combined, 124I-5C9 and FD1080-5C9 are both promising DGS tools: the former reveals CLDN18.2 in lesions as a PET probe, and the latter can guide surgery. These results provide a utility molecular imaging strategy for specific detection and surgery guidance based on a CLDN18.2specific antibody both in AGC and other cancers. KEYWORDS: CLDN18.2, molecular imaging, immuno-PET, diagnosis and guiding therapy, near-infrared fluorescent II