Advantage of a residualizing iodine radiolabel in the therapy of a colon cancer xenograft targeted with an anticarcinoembryonic antigen monoclonal antibody.
Advantage of a residualizing iodine radiolabel in the therapy of a colon cancer xenograft targeted with an anticarcinoembryonic antigen monoclonal antibody.
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残留碘放射性标记在抗癌胚抗原单克隆抗体靶向结肠癌异种移植物治疗中的优势。
DOI：
10.1158/1078-0432.ccr-04-2100
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发表时间：
2005
期刊：
影响因子：
--
通讯作者：
Goldenberg,DavidM
中科院分区：
文献类型：
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作者：
Stein,Rhona;Govindan,SerengulamV;Hayes,Marianne;Griffiths,GaryL;Hansen,HansJ;Horak,IvanD;Goldenberg,DavidM
目的：放射性核素在靶细胞内的滞留时间短是传统的放射性碘标记的单抗用于肿瘤治疗的缺点。为了解决这个问题，我们最近开发了一种将放射性碘引入抗体的方法，该方法使用一种由氨基多羧酸二乙三胺五乙酸(IMP-R4)上的非代谢多肽组成的加合物，命名为IMP-R4。这种加合物使放射性碘在抗体分解代谢后被困在溶酶体中。实验设计：将131I-IMP-R4标记的抗癌胚抗原人源化单抗HMN-14与131I-HMN-14(131I-HMN-14)在表达CEA的人结肠癌细胞株LoVo和LS174T以及荷瘤裸鼠体内进行了比较。结果：与125I-HMN-14相比，125I-IMP-R4-HMN-14在细胞系中的滞留率显著增加(3d后为61.5%)。使用131I-IMP-R4-HMN-14可显著改善肿瘤的放射性标记生长，从而导致治疗效果的显著提高。治疗8周后，131I-IMP-R4-HMN-14和131I-HMN-14组小鼠的平均肿瘤体积分别为0.16±0.19和1.99±1.35cm3，其中27%的小鼠完全缓解，与传统的131I标记抗体相比，非using131I-hMN-14.Conclusion:131I-IMP-R4-hMN-14具有显著的治疗优势。这种标记方法能够用于临床规模的标记，人源化的抗CEA单抗对CEA表达的癌症的广泛适用性，以及最近显示的针对小体积和微小残留病的抗CEA单抗的放射免疫治疗的临床益处，使131I-IMP-R4-HMN-14成为一种有前途的放射免疫治疗的新药物。
Purpose:A disadvantage of conventionally radioiodinated monoclonal antibodies (mAb) for cancer therapy is the short retention time of the radionuclide within target cells. To address this issue, we recently developed a method in which radioiodine is introduced onto antibodies using an adduct consisting of a nonmetabolizable peptide attached to the aminopolycarboxylate diethylenetriaminepentaacetic acid, designated IMP-R4. This adduct causes the radioiodine to become trapped in lysosomes following antibody catabolism. Clinical-scale production of131I-IMP-R4-labeled antibodies is possible using a recently developed facile method.Experimental Design:The properties of131I-IMP-R4-labeled anticarcinoembryonic antigen (CEA) humanized mAb hMN-14 were compared with the directly radioiodinated hMN-14 (131I-hMN-14) in CEA-expressing human colon cancer cell lines, LoVo and LS174T, and in nude mice bearing established LoVo tumor xenografts.Results:125I-IMP-R4-hMN-14 retention in the cell lines was significantly increased (61.5% after 3 days) compared with125I-hMN-14.In vivo, a significant improvement in tumor accretion of radiolabel was obtained using131I-IMP-R4-hMN-14, which led to a marked improvement in therapeutic efficacy. Eight weeks post-treatment, mean tumor volumes were 0.16 ± 0.19 and 1.99 ± 1.35 cm3in mice treated with131I-IMP-R4-hMN-14 and131I-hMN-14, respectively, with complete remissions observed in 27% of mice treated with131I-IMP-R4-hMN-14 and none using131I-hMN-14.Conclusion:131I-IMP-R4-hMN-14 provides a significant therapeutic advantage in comparison to the conventionally131I-labeled antibody. The ability of this labeling method to lend itself to clinical-scale labeling, the broad applicability of a humanized anti-CEA mAb for CEA-expressing cancers, and the clinical benefits of radioimmunotherapy with anti-CEA mAb shown recently for small-volume and minimal residual disease combine to make131I-IMP-R4-hMN-14 a promising new agent for radioimmunotherapy.