CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom.
CRUK/MRC Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, Oxford, United Kingdom.
Nucl Med Biol. 2019 Mar;70:14-22. doi: 10.1016/j.nucmedbio.2019.01.010. Epub 2019 Feb 5.
While radiolabelled antibodies have found great utility as PET and SPECT imaging agents in oncological investigations, a notable shortcoming of these agents is their propensity to accumulate non-specifically within tumour tissue. The degree of this non-specific contribution to overall tumour uptake is highly variable and can ultimately lead to false conclusions. Therefore, in an effort to obtain a reliable measure of inter-individual differences in non-specific tumour uptake of radiolabelled antibodies, we demonstrate that the use of dual-isotope imaging overcomes this issue, enables true quantification of epitope expression levels, and allows non-invasive in vivo immunohistochemistry. The approach involves co-administration of (i) an antigen-targeting antibody labelled with zirconium-89 (Zr), and (ii) an isotype-matched non-specific control IgG antibody labelled with indium-111 (In). As an example, the anti-HER2 antibody trastuzumab was radiolabelled with Zr, and co-administered intravenously together with its In-labelled non-specific counterpart to mice bearing human breast cancer xenografts with differing HER2 expression levels (MDA-MB-468 [HER2-negative], MDA-MB-231 [low-HER2], MDA-MB-231/H2N [medium-HER2], and SKBR3 [high-HER2]). Simultaneous PET/SPECT imaging using a MILabs Vector4 small animal scanner revealed stark differences in the intratumoural distribution of [Zr]Zr-trastuzumab and [In]In-IgG, highlighting regions of HER2-mediated uptake and non-specific uptake, respectively. Normalisation of the tumour uptake values and tumour-to-blood ratios obtained with [Zr]Zr-trastuzumab against those obtained with [In]In-IgG yielded values which were most strongly correlated (R = 0.94; P = 0.02) with HER2 expression levels for each breast cancer type determined by Western blot and in vitro saturation binding assays, but not non-normalised uptake values. Normalised intratumoural distribution of [Zr]Zr-trastuzumab correlated well with intratumoural heterogeneity HER2 expression.
放射性标记抗体已被广泛应用于肿瘤研究中的 PET 和 SPECT 成像，但其存在一个显著的缺点，即容易在肿瘤组织中非特异性聚集。这种非特异性摄取对肿瘤总摄取的贡献程度差异很大，最终可能导致错误的结论。因此，为了可靠地测量放射性标记抗体在个体间非特异性摄取肿瘤的差异，我们证明了使用双同位素成像可以克服这个问题，能够真正定量抗原表达水平，并允许进行非侵入性的体内免疫组织化学分析。该方法涉及共给药 (i) 用锆-89（Zr）标记的靶向抗原的抗体，和 (ii) 用铟-111（In）标记的同种型匹配的非特异性对照 IgG 抗体。例如，用 Zr 标记抗 HER2 抗体曲妥珠单抗，并与具有不同 HER2 表达水平的荷人乳腺癌异种移植瘤小鼠静脉内共给药，这些异种移植瘤包括 MDA-MB-468（HER2 阴性）、MDA-MB-231（低 HER2）、MDA-MB-231/H2N（中 HER2）和 SKBR3（高 HER2）。使用 MILabs Vector4 小动物扫描仪进行的同时 PET/SPECT 成像显示，[Zr]Zr-曲妥珠单抗和 [In]In-IgG 在肿瘤内的分布存在明显差异，分别突出了 HER2 介导摄取和非特异性摄取的区域。用 [Zr]Zr-曲妥珠单抗归一化获得的肿瘤摄取值和肿瘤与血液的比值与用 [In]In-IgG 归一化获得的值与每种乳腺癌类型的 HER2 表达水平最相关（R=0.94；P=0.02），Western blot 和体外饱和结合测定法确定，但不是未归一化的摄取值。[Zr]Zr-曲妥珠单抗的肿瘤内归一化分布与肿瘤内异质性 HER2 表达具有很好的相关性。
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