开发用于三重阴性乳腺癌 PET 成像的 [Zr]ZrDFO-amivantamab 双特异性抗体，针对 EGFR 和 c-MET。
Development of [Zr]ZrDFO-amivantamab bispecific to EGFR and c-MET for PET imaging of triple-negative breast cancer.
机构信息
Yale PET Center, Department of Radiology and Biomedical Imaging, Yale University, PO Box 208048, New Haven, CT, 06520, USA.
Department of Nutrition and Food Hygiene, Southern Medical University, Guangzhou, Guangdong, China.
出版信息
Eur J Nucl Med Mol Imaging. 2021 Feb;48(2):383-394. doi: 10.1007/s00259-020-04978-6. Epub 2020 Aug 8.
BACKGROUND
Amivantamab is a novel bispecific antibody that simultaneously targets the epidermal growth factor receptor (EGFR) and the hepatocyte growth factor receptor (HGFR/c-MET) that are overexpressed in several types of cancer including triple-negative breast cancer (TNBC). Targeting both receptors simultaneously can overcome resistance to mono-targeted therapy. The purpose of this study is to develop Zr-labeled amivantamab as a potential companion diagnostic imaging agent to amivantamab therapy using various preclinical models of TNBC for evaluation.
METHODS
Amivantamab was conjugated to desferrioxamine (DFO) and radiolabeled with Zr to obtain [Zr]ZrDFO-amivantamab. Binding of the bispecific [Zr]ZrDFO-amivantamab as well as its mono-specific "single-arm" antibody controls were determined in vitro and in vivo. Biodistribution studies of [Zr]ZrDFO-amivantamab were performed in MDA-MB-468 xenografts to determine the optimal imaging time point. PET/CT imaging with [Zr]ZrDFO-amivantamab or its isotype control was performed in a panel of TNBC xenografts with varying levels of EGFR and c-MET expression.
RESULTS
[Zr]ZrDFO-amivantamab was synthesized with a specific activity of 148 MBq/mg and radiochemical yield of ≥ 95%. Radioligand binding studies and western blot confirmed the order of EGFR and c-MET expression levels: HCC827 lung cancer cell (positive control) > MDA-MB-468 > MDA-MB-231 > MDA-MB-453. [Zr]ZrDFO-amivantamab demonstrated bispecific binding in cell lines co-expressed with EGFR and c-MET. PET/CT imaging with [Zr]ZrDFO-amivantamab in TNBC xenografted mice showed standard uptake value (SUV) of 6.0 ± 1.1 in MDA-MB-468, 4.2 ± 1.4 in MDA-MB-231, and 1.5 ± 1.4 in MDA-MB-453 tumors, which are consistent with their receptors' expression levels on the cell surface.
CONCLUSION
We have successfully prepared a radiolabeled bispecific antibody, [Zr]ZrDFO-amivantamab, and evaluated its pharmacologic and imaging properties in comparison with its single-arm antibodies and non-specific isotype controls. [Zr]ZrDFO-amivantamab demonstrated the greatest uptake in tumors co-expressing EGFR and c-MET.
背景
Amivantamab 是一种新型双特异性抗体，可同时靶向表皮生长因子受体（EGFR）和肝细胞生长因子受体（HGFR/c-MET），这些受体在多种癌症中过度表达，包括三阴性乳腺癌（TNBC）。同时靶向这两个受体可以克服对单靶治疗的耐药性。本研究的目的是开发 Zr 标记的 Amivantamab，作为 Amivantamab 治疗的潜在伴随诊断成像剂，使用各种 TNBC 的临床前模型进行评估。
方法
Amivantamab 与去铁胺（DFO）缀合，并与 Zr 标记以获得 [Zr]ZrDFO-amivantamab。在体外和体内测定双特异性 [Zr]ZrDFO-amivantamab 及其单特异性“单臂”抗体对照的结合情况。在 MDA-MB-468 异种移植瘤中进行 [Zr]ZrDFO-amivantamab 的生物分布研究，以确定最佳成像时间点。在具有不同 EGFR 和 c-MET 表达水平的 TNBC 异种移植瘤中进行 [Zr]ZrDFO-amivantamab 或其同种型对照的 PET/CT 成像。
结果
[Zr]ZrDFO-amivantamab 的比活度为 148 MBq/mg，放射化学产率≥95%。放射性配体结合研究和 Western blot 证实了 EGFR 和 c-MET 表达水平的顺序：HCC827 肺癌细胞（阳性对照）>MDA-MB-468> MDA-MB-231> MDA-MB-453。在共表达 EGFR 和 c-MET 的细胞系中，[Zr]ZrDFO-amivantamab 显示出双特异性结合。在 TNBC 异种移植瘤小鼠中进行的 [Zr]ZrDFO-amivantamab PET/CT 成像显示，MDA-MB-468 肿瘤的标准摄取值（SUV）为 6.0±1.1，MDA-MB-231 肿瘤为 4.2±1.4，MDA-MB-453 肿瘤为 1.5±1.4，与细胞表面的受体表达水平一致。
结论
我们成功制备了放射性标记的双特异性抗体 [Zr]ZrDFO-amivantamab，并将其与单臂抗体及其非特异性同种型对照进行比较，评估了其药理和成像特性。[Zr]ZrDFO-amivantamab 在共表达 EGFR 和 c-MET 的肿瘤中摄取最多。
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