An N-Acetylgalactosamino Dendron-Clearing Agent for High-Therapeutic-Index DOTA-Hapten Pretargeted Radioimmunotherapy.,Bioconjugate Chemistry

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An N-Acetylgalactosamino Dendron-Clearing Agent for High-Therapeutic-Index DOTA-Hapten Pretargeted Radioimmunotherapy.
Bioconjugate Chemistry ( IF 4.0 ) Pub Date : 2020-02-10 , DOI: 10.1021/acs.bioconjchem.9b00736
Sarah M Cheal ₁ , Mitesh Patel ₁ , Guangbin Yang ₂ , Darren Veach ₃ , Hong Xu ₄ , Hong-Fen Guo ₄ , Pat B Zanzonico ₅ , Donald B Axworthy ₆ , Nai-Kong V Cheung ₄ , Ouathek Ouerfelli ₂ , Steven M Larson _{1,

3}

Affiliation

Clearing agents (CAs) can rapidly remove nonlocalized targeting biomolecules from circulation for hepatic catabolism, thereby enhancing the therapeutic index (TI), especially for blood (marrow), of the subsequently administered radioisotope in any multistep pretargeting strategy. Herein we describe the synthesis and in vivo evaluation of a fully synthetic glycodendrimer-based CA for DOTA-based pretargeted radioimmunotherapy (DOTA-PRIT). The novel dendron-CA consists of a nonradioactive yttrium-DOTA-Bn molecule attached via a linker to a glycodendron displaying 16 terminal α-thio-N-acetylgalactosamine (α-SGalNAc) units (CCA α-16-DOTA-Y3+; molecular weight: 9059 Da). Pretargeting [177Lu]LuDOTA-Bn with CCA α-16-DOTA-Y3+ to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [177Lu]LuDOTA-Bn for blood, tumor, liver, spleen, and kidneys of 11.7, 468, 9.97, 5.49, and 13.3 cGy/MBq, respectively. Tumor-to-normal tissues absorbed-dose ratios (i.e., TIs) ranged from 40 (e.g., for blood and kidney) to about 550 for stomach.

中文翻译：

用于高治疗指数DOTA半抗原预靶向放射免疫疗法的N-乙酰半乳糖氨基树胶清除剂。

清除剂（CA）可以从循环中快速去除非定位的靶向生物分子以进行肝分解代谢，从而以任何多步预靶向策略提高随后给药的放射性同位素的治疗指数（TI），尤其是血液（骨髓）的治疗指数。在这里，我们描述了基于DOTA的预靶向放射免疫疗法（DOTA-PRIT）的完全合成的基于糖树状大分子的CA的合成和体内评估。新型树突-CA由一个非放射性钇-DOTA-Bn分子组成，该分子通过一个连接子连接到一个具有16个末端α-硫代-N-乙酰基半乳糖胺（α-SGalNAc）单元的糖胶体上（CCAα-16-DOTA-Y3+;分子量：9059 Da）。将具有CCAα-16-DOTA-Y3+的[177Lu] LuDOTA-Bn预靶向表达GPA33的SW1222人结肠直肠异种移植物非常有效，从而导致血液吸收[177Lu] LuDOTA-Bn剂量，肿瘤，肝脏，脾脏和肾脏的cGy / MBq分别为11.7、468、9.97、5.49和13.3 cGy / MBq。肿瘤与正常组织的吸收剂量比（即TIs）范围从40（例如，对于血液和肾脏而言）到大约550（对于胃）。

更新日期：2020-02-10

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