Bivalent hapten-bearing peptides designed for iodine-131 pretargeted radioimmunotherapy
Bivalent hapten-bearing peptides designed for iodine-131 pretargeted radioimmunotherapy
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DOI：
10.1021/bc970083h
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发表时间：
1997-07-01
影响因子：
4.7
通讯作者：
GruazGuyon, A
中科院分区：
文献类型：
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作者：
JanevikIvanovska, E;Gautherot, E;GruazGuyon, A
用双特异性抗体预靶向已经成功地用于肿瘤检测，并且现在被考虑用于放射免疫疗法。二价半抗原的优点已经在这方面得到了证明。一系列的二价分子，允许有效的标记与放射性碘已被设计用于这项新技术。它们是基于组胺-半琥珀酸半抗原并通过固相肽合成制备的。当两个半抗原基团连接到由单个氨基酸分开的赖氨酸残基的侧链上时，两个抗体分子可以同时结合到一个二价半抗原，并且空间位阻低。半抗原和癌胚抗原的双特异性抗体显示介导半抗原与肿瘤细胞的体外特异性结合。这些实验表明，具有赖氨酰-D-酪氨酰-赖氨酸连接链的二价半抗原AG 3.0具有最佳结合特性。该肽用于将碘-125靶向裸鼠中的人结肠癌异种移植物。观察到高肿瘤摄取和肿瘤与正常组织的比率。因此，该肽似乎是进一步开发的良好候选物。还制备了具有一个组胺-半琥珀酸酯和一个二亚乙基三胺五乙酸基团的不对称二价半抗原，并显示其能够同时结合两个特异性抗体分子。这些肽应可用于将放射性碘靶向以表达两种不同抗原标记物为特征的细胞。
Pretargeting with bispecific antibodies has been used successfully for tumor detection and is now considered for radioimmunotherapy. The advantages of bivalent haptens have been demonstrated in this context. A series of bivalent molecules allowing efficient labeling with radioactive iodine has been designed for use with this new technology. They were based on the histamine-hemisuccinate hapten and prepared by solid phase peptide synthesis. Simultaneous binding of two antibody molecules to one bivalent hapten was possible with low steric hindrance when the two hapten groups were attached to the lateral chains of lysine residues separated by a single amino acid, Bispecific antibodies to the hapten and to carcinoembryonic antigen were shown to mediate specific binding of the haptens to tumor cells in vitro. These experiments demonstrated that the bivalent hapten AG3.0, with a lysyl-D-tyrosyl-lysine connecting chain, possessed the best binding properties. This peptide was used to target iodine-125 to human colon cancer xenografts in nude mice. High tumor uptake and tumor to normal tissue ratios were observed. This peptide thus appears as a good candidate for further development. Asymmetric bivalent haptens, with one histamine-hemisuccinate and one diethylenetriaminepentaacetic acid group, have also been prepared and shown to be capable of binding simultaneously two specific antibody molecules. These peptides should be useful to target radioiodine to cells characterized by the expression of two different antigenic markers.