Targeting breast carcinoma with radioiodinated anti-HER2 Nanobody

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• 作者：Marek Pruszynski^a ; Eftychia Koumarianou^a ; Ganesan Vaidyanathan^a ; Hilde Revets^b ; Nick Devoogdt^c ; Tony Lahoutte^c ; Michael R. Zalutsky^a ; ^d ; ^{zalut001@mc.duke.edu}
• 关键词：HER2 ; Nanobody ; Breast cancer ; VHH ; Radioiodination ; IB-Mal-d-GEEEK
• 刊名：Nuclear Medicine and Biology
• 出版年：2013
• 出版时间：January, 2013
• 年：2013
• 卷：40
• 期：1
• 页码：52-59
• 全文大小：436 K

文摘

4 class=""h4"">Introduction4>With a molecular weight an order of magnitude lower than antibodies but possessing comparable affinities, Nanobodies (Nbs) are attractive as targeting agents for cancer diagnosis and therapy. An anti-HER2 Nb could be utilized to determine HER2 status in breast cancer patients prior to trastuzumab treatment. This provided motivation for the generation of HER2-specific 5F7GGC Nb, its radioiodination and evaluation for targeting HER2 expressing tumors.4 class=""h4"">Methods4>

5F7GGC Nb was radioiodinated with ¹²⁵I using Iodogen and with ¹³¹I using the residualizing agent N^?-(3-[¹³¹I]iodobenzoyl)-Lys⁵-N^¦Á-maleimido-Gly¹-GEEEK ([¹³¹I]IB-Mal-d-GEEEK) used previously successfully with intact antibodies. Paired-label internalization assays using BT474M1 cells and tissue distribution experiments in athymic mice bearing BT474M1 xenografts were performed to compare the two labeled Nb preparations.4 class=""h4"">Results4>

The radiochemical yields for Iodogen and [¹³¹I]IB-Mal-d-GEEEK labeling were 83.6 ¡À 5.0 % (n = 10) and 59.6 ¡À 9.4 % (n = 15), respectively. The immunoreactivity of labeled proteins was preserved as confirmed by in vitro and in vivo binding to tumor cells. Biodistribution studies showed that Nb radiolabeled using [¹³¹I]IB-Mal-d-GEEEK, compared with the directly labeled Nb, had a higher tumor uptake (4.65 ¡À 0.61 % ID/g vs. 2.92 ¡À 0.24 % ID/g at 8 h), faster blood clearance, lower accumulation in non-target organs except kidneys, and as a result, higher concomitant tumor-to-blood and tumor-to-tissue ratios.4 class=""h4"">Conclusions4>

Taken together, these results demonstrate that 5F7GGC anti-HER2 Nb labeled with residualizing [¹³¹I]IB-Mal-d-GEEEK had better tumor targeting properties compared to the directly labeled Nb suggesting the potential utility of this Nb conjugate for SPECT (¹²⁹I) and PET imaging (¹²⁴I) of patients with HER2-expressing tumors.