Radioimmunotargeting of malignant glioma by monoclonal antibody D2C7 reactive against both wild-type and variant III mutant epidermal growth factor receptors.
Radioimmunotargeting of malignant glioma by monoclonal antibody D2C7 reactive against both wild-type and variant III mutant epidermal growth factor receptors.
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DOI：
10.1016/j.nucmedbio.2011.06.005
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发表时间：
2012-01
影响因子：
3.1
通讯作者：
Bigner DD
中科院分区：
文献类型：
--
作者：
Zalutsky MR;Boskovitz A;Kuan CT;Pegram CN;Ayriss J;Wikstrand CJ;Buckley AF;Lipp ES;Herndon JE 2nd;McLendon RE;Bigner DD
恶性神经胶质瘤仍然是一个重大的治疗挑战，免疫治疗可能对这些患者是一种有益的方法。针对多个分子靶点的特异性单克隆抗体 (MAb) 可以扩大可治疗的患者群体和靶向肿瘤细胞的比例，并有可能提高疗效。这激发了 MAb D2C7 的产生，它可以识别野生型表皮生长因子受体 (EGFRwt) 和肿瘤特异性突变体 EGFRvIII。 D2C7 结合亲和力通过表面等离子共振测定，并通过流式细胞术和免疫组织化学分析与 EGFRwt 特异性 EGFR.1 和 EGFRvIII 特异性 L8A4 MAb 进行比较来表征其特异性。使用 Iodogen 对 3 个 MAb 进行 125I 或 131I 标记，并在具有人类肿瘤异种移植物的无胸腺小鼠中进行配对标记内化测定和生物分布实验。 D2C7 对 EGFRwt 和 EGFRvIII 的亲和力为 5.2 × 109 M−1 和 3.6 × 109 M−1，并且通过流式细胞术记录了与这两种受体的细胞表面反应性。免疫组织化学分析显示 D2C7 与 101 名患者中的 90 名的恶性神经胶质瘤组织有反应。对表达 EGFRwt 的 WTT 细胞和表达 EGFRvIII 的 NR6M 细胞进行的内化测定表明，与 131 I 标记的 EGFR 相比， 125 I 标记的 D2C7 的降解降低了三倍。1。 NR6M 异种移植物中 125I 标记的 D2C7 的摄取（第 3 天为 52.45 ∀ 13.97% ID/g）是 131I 标记的 L8A4 的两倍多；与 131I 标记的 EGFR.1 相比，在 WTT 异种移植小鼠中发现了三到五倍的肿瘤递送优势。这些结果表明，D2C7 值得进一步评估，以开发针对表达 EGFRwt 和 EGFRvIII 的癌症的基于 MAb 的疗法。
Malignant glioma remains a significant therapeutic challenge and immunotherapeutics might be a beneficial approach for these patients. A monoclonal antibody (MAb) specific for multiple molecular targets could expand the treatable patient population and the fraction of tumor cells targeted, with potentially increased efficacy. This motivated the generation of MAb D2C7, which recognizes both wild-type epidermal growth factor receptor (EGFRwt) and a tumor-specific mutant, EGFRvIII. D2C7 binding affinity was determined by surface plasmon resonance and its specificity characterized through comparison to EGFRwt-specific EGFR.1 and EGFRvIII-specific L8A4 MAbs by flow cytometry and immunohisochemical analysis. The 3 MAbs were labeled with 125I or 131I using Iodogen, and paired-label internalization assays and biodistribution experiments in athymic mice with human tumor xenografts were performed. The affinity of D2C7 for EGFRwt and EGFRvIII was 5.2 × 109 M−1 and 3.6 × 109 M−1, and cell-surface reactivity with both receptors was documented by flow cytometry. Immunohistochemical analyses revealed D2C7 reactivity with malignant glioma tissue from 90 of 101 patients. Internalization assays performed on EGFRwt-expressing WTT cells and EGFRvIII-expressing NR6M cells indicated a threefold lower degradation of 125I-labeled D2C7 compared with 131I-labeled EGFR.1. Uptake of 125I-labeled D2C7 in NR6M xenografts (52.45 ∀ 13.97% ID/g on Day 3) was more than twice that of 131I-labeled L8A4; a threefold to fivefold tumor delivery advantage was seen when compared to 131I-labeled EGFR.1 in mice with WTT xenografts. These results suggest that D2C7 warrants further evaluation for the development of MAb-based therapeutics against cancers expressing EGFRwt and EGFRvIII.
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影响因子：
8
作者：
Davies, G. C.;Ryan, P. E.;Lipkowitz, S.
通讯作者：
Lipkowitz, S.
影响因子：
4.7
作者：
Liu, L;Bäcklund, LM;Nilsson, BR;Grandér, D;Ichimura, K;Goike, HM;Collins, VP
通讯作者：
Collins, VP
影响因子：
11.5
作者：
Brandes, Alba A.;Franceschi, Enrico;Stupp, Roger
通讯作者：
Stupp, Roger
影响因子：
4.8
作者：
Faillot, T;Magdelenat, H;Delattre, JY
通讯作者：
Delattre, JY
影响因子：
4.8
作者：
Johns, TG;Adamas, TE;Scott, AM
通讯作者：
Scott, AM