Preclinical evaluation of anti-HER2 Affibody molecules site-specifically labeled with ¹¹¹In using a maleimido derivative of NODAGA

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• 作者：Mohamed Altai^a ; Anna Perols^b ; Amelie Eriksson Karlströ ; m^b ; Mattias Sandströ ; m^c ; Frederic Boschetti^d ; Anna Orlova^e ; Vladimir Tolmachev^a ; ^{vladimir.tolmachev@bms.uu.se}
• 关键词：HER2 ; Affibody molecules ; Radionuclides ; Receptor targeting ; Molecular imaging ; Indium-111 ; Maleimido-NODAGA
• 刊名：Nuclear Medicine and Biology
• 出版年：2012
• 期刊代码：43_09698051
• 类别：ph
• 出版时间：May, 2012
• 卷：39
• 期：4
• 页码：518-529
• 文件大小：733 K

摘要

Introduction

Affibody molecules have demonstrated potential for radionuclide molecular imaging. The aim of this study was to synthesize and evaluate a maleimido derivative of the 1,4,7-triazacyclononane-1-glutaric acid-4,7-diacetic acid (NODAGA) for site-specific labeling of anti-HER2 Affibody molecule.

Methods

The maleimidoethylmonoamide NODAGA (MMA-NODAGA) was synthesized and conjugated to Z_HER2:2395 Affibody molecule having a C-terminal cysteine. Labeling efficiency, binding specificity to and cell internalization by HER2-expressing cells of [¹¹¹In-MMA-NODAGA-Cys⁶¹]-Z_HER2:2395 were studied. Biodistribution of [¹¹¹In-MMA-NODAGA-Cys⁶¹]-Z_HER2:2395 and [¹¹¹In-MMA-DOTA-Cys⁶¹]-Z_HER2:2395 was compared in mice.

Results

The affinity of [MMA-NODAGA-Cys⁶¹]-Z_HER2:2395 binding to HER2 was 67 pM. The ¹¹¹In-labeling yield was 99.6%卤0.5%after 30 min at 60掳C. [¹¹¹In-MMA-NODAGA-Cys⁶¹]-Z_HER2:2395 bound specifically to HER2-expressing cells in vitro and in vivo. Tumor uptake of [¹¹¹In-MMA-NODAGA-Cys⁶¹]-Z_HER2:2395 in mice bearing DU-145 xenografts (4.7%卤0.8%ID/g) was lower than uptake of [¹¹¹In-MMA-DOTA-Cys⁶¹]-Z_HER2:2395 (7.5%卤1.6%ID/g). However, tumor-to-organ ratios were higher for [¹¹¹In-MMA-NODAGA-Cys⁶¹]-Z_HER2:2395 due to higher clearance rate from normal tissues.

Conclusions

MMA-NODAGA is a promising chelator for site-specific labeling of targeting proteins containing unpaired cysteine. Appreciable influence of chelators on targeting properties of Affibody molecules was demonstrated.