DOTAGA-Trastuzumab. A New Antibody Conjugate Targeting HER2/Neu Antigen for Diagnostic Purposes

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• 作者：Mathieu Moreau ; Olivier Raguin ; Jean-Marc Vrigneaud ; Bertrand Collin ; Claire Bernhard ; Xavier Tizon ; Fr茅d茅ric Boschetti ; Olivier Duchamp ; Fran莽ois Brunotte ; Franck Denat
• 刊名：Bioconjugate Chemistry
• 出版年：2012
• 出版时间：June 20, 2012
• 年：2012
• 卷：23
• 期：6
• 页码：1181-1188
• 全文大小：340K
• 年卷期：v.23,no.6(June 20, 2012)
• ISSN：1520-4812

文摘

Improved bifunctional chelating agents (BFC) are required for indium-111 radiolabeling of monoclonal antibodies (mAbs) under mild conditions to yield stable, target-specific agents. 2,2鈥?2鈥?(10-(2,6-Dioxotetrahydro-2H-pyran-3-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyl)triacetic acid (DOTAGA-anhydride) was evaluated for mAb conjugation and labeling with indium-111. The DOTA analogue was synthesized and conjugated to trastuzumab鈥攚hich targets the HER2/neu receptor鈥攊n mild conditions (PBS pH 7.4, 25 掳C, 30 min) and gave a mean degree of conjugation of 2.6 macrocycle per antibody. Labeling of this immunoconjugate with indium-111 was performed in 75% yield after 1 h at 37 掳C, and the proportion of ¹¹¹In-DOTAGA-trastuzumab reached 97% after purification. The affinity of DOTAGA-trastuzumab was 5.5 卤 0.6 nM as evaluated by in vitro saturation assays using HCC1954 breast cancer cell line. SPECT/CT imaging and biodistribution studies were performed in mice bearing breast cancer BT-474 xenografts. BT-474 tumors were clearly visualized on SPECT images at 24, 48, and 72 h postinjection. The tumor uptake of [¹¹¹In-DOTAGA]-trastuzumab reached 65%ID/g 72 h postinjection. These results show that the DOTAGA BFC appears to be a valuable tool for biologics conjugation.