Trans-Cyclooctene Tag with Improved Properties for Tumor Pretargeting with the Diels鈥揂lder Reaction
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- 作者：Raffaella Rossin ; Sander M. J. van Duijnhoven ; Tilman L盲ppchen ; Sandra M. van den Bosch ; Marc S. Robillard
- 刊名：Molecular Pharmaceutics
- 出版年：2014
- 出版时间：September 2, 2014
- 年：2014
- 卷：11
- 期：9
- 页码：3090-3096
- 全文大小：282K
- ISSN：1543-8392
文摘
Radioimmunotherapy (RIT) of solid tumors is hampered by low tumor-to-nontumor (T/NT) ratios of the radiolabeled monoclonal antibodies resulting in low tumor doses in patients. Pretargeting technologies can improve the effectiveness of RIT in cancer therapy by increasing this ratio. We showed that a pretargeting strategy employing in vivo chemistry in combination with clearing agents, proceeds efficiently in tumor-bearing mice resulting in high T/NT ratios. A dosimetry study indicated that the chemical pretargeting technology, which centered on the bioorthogonal Diels鈥揂lder click reaction between a radiolabeled tetrazine probe and a trans-cyclooctene-oxymethylbenzamide-tagged CC49 antibody (CC49鈥揟CO(1)), can match the performance of clinically validated high-affinity biological pretargeting approaches in mice (Rossin J Nucl Med.ml:space="preserve"> 2013ml:space="preserve">, m>54 m>ml:space="preserve">, 1989鈭?995). Nevertheless, the increased protein surface hydrophobicity of CC49鈥揟CO(1) led to a relatively rapid blood clearance and concomitant reduced tumor uptake compared to native CC49 antibody. Here, we present the in vivo evaluation of a TCO-oxymethylacetamide-tagged CC49 antibody (CC49鈥揟CO(2)), which is highly reactive toward tetrazines and less hydrophobic than CC49鈥揟CO(1). CC49鈥揟CO(2) was administered to healthy mice to determine its blood clearance and the in vivo stability of the TCO. Next, pretargeting biodistribution and SPECT studies with CC49鈥揟CO(2), tetrazine-functionalized clearing agent, and radiolabeled tetrazine were carried out in nude mice bearing colon carcinoma xenografts (LS174T). CC49鈥揟CO(2) had an increased circulation half-life, a 1.5-fold higher tumor uptake, and a 2.6-fold improved in vivo TCO stability compared to the more hydrophobic TCO-benzamide鈥揅C49. As a consequence, and despite the 2-fold lower reactivity of CC49鈥揟CO(2) toward tetrazines compared with CC49鈥揟CO(1), administration of radiolabeled tetrazine afforded a significantly increased tumor accumulation and improved T/NT ratios in mice pretargeted with CC49鈥揟CO(2). In conclusion, the TCO-acetamide derivative represents a large improvement in in vivo Diels鈥揂lder pretargeting, possibly enabling application in larger animals and eventually humans.