A comparative evaluation of the chelators H₄octapa and CHX-A″-DTPA with the therapeutic radiometal ⁹⁰Y

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• 作者：Eric W. Price^a ; Kimberly J. Edwards^a ; Kathryn E. Carnazza^a ; Sean D. Carlin^a ; Brian M. Zeglis^a ; ^d ; Michael J. Adam^e ; Chris Orvig^f ; Jason S. Lewis^a ; ^b ; ^c ; ^{lewisj2@mskcc.org" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Yttrium-90 ; Trastuzumab ; CHX-A&Prime ; -DTPA ; H4octapa ; Radiometal ; Radioimmunotherapy
• 刊名：Nuclear Medicine and Biology
• 出版年：2016
• 出版时间：September 2016
• 年：2016
• 卷：43
• 期：9
• 页码：566-576
• 全文大小：1581 K

文摘

To compare the radiolabeling performance, stability, and practical efficacy of the chelators CHX-A″-DTPA and H₄octapa with the therapeutic radiometal ⁹⁰Y.

absSec_2">Methods

The bifunctional chelators p-SCN-Bn-H₄octapa and p-SCN-Bn-CHX-A″-DTPA were conjugated to the HER2-targeting antibody trastuzumab. The resulting immunoconjugates were radiolabeled with ⁹⁰Y to compare radiolabeling efficiency, in vitro and in vivo stability, and in vivo performance in a murine model of ovarian cancer.

absSec_3">Results

High radiochemical yields (>95%) were obtained with ⁹⁰Y-CHX-A″-DTPA-trastuzumab and ⁹⁰Y-octapa-trastuzumab after 15 min at room temperature. Both ⁹⁰Y-CHX-A″-DTPA-trastuzumab and ⁹⁰Y-octapa-trastuzumab exhibited excellent in vitro and in vivo stability. Furthermore, the radioimmunoconjugates displayed high tumoral uptake values (42.3 ± 4.0 %ID/g for ⁹⁰Y-CHX-A″-DTPA-trastuzumab and 30.1 ± 7.4 %ID/g for ⁹⁰Y-octapa-trastuzumab at 72 h post-injection) in mice bearing HER2-expressing SKOV3 ovarian cancer xenografts. Finally, ⁹⁰Y radioimmunotherapy studies performed in tumor-bearing mice demonstrated that ⁹⁰Y-CHX-A″-DTPA-trastuzumab and ⁹⁰Y-octapa-trastuzumab are equally effective therapeutic agents, as treatment with both radioimmunoconjugates yielded substantially decreased tumor growth compared to controls.

absSec_4">Conclusions

Ultimately, this work demonstrates that the acyclic chelators CHX-A″-DTPA and H₄octapa have comparable radiolabeling, stability, and in vivo performance, making them both suitable choices for applications requiring ⁹⁰Y.