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

Bioconjugate Chemistry
Sarah M ChealSteven M Larson

Abstract

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.

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Citations

Sep 23, 2020·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Brian H SantichNai K Cheung
May 1, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Leila Mousavifar, René Roy
Jul 31, 2021·Carbohydrate Research·Anand K AgrahariVinod K Tiwari
Aug 5, 2021·Chemical Society Reviews·Yujun KimInjae Shin
Aug 8, 2021·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Maryana HandulaYann Seimbille

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