Open AccessAn N-Acetylgalactosamino Dendron-Clearing Agent for High-Therapeutic-Index DOTA-Hapten Pretargeted Radioimmunotherapy
Author(s) -
Sarah M. Cheal,
Mitesh Patel,
Guangbin Yang,
Darren R. Veach,
Hong Xu,
Hong-Fen Guo,
Pat Zanzonico,
Donald B. Axworthy,
NaiKong V. Cheung,
Ouathek Ouerfelli,
Steven M. Larson
Publication year - 2019
Publication title -
bioconjugate chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.279
H-Index - 172
eISSN - 1520-4812
pISSN - 1043-1802
DOI - 10.1021/acs.bioconjchem.9b00736
Subject(s) - pretargeting , dota , radioimmunotherapy , chemistry , dendrimer , pharmacology , immunology , biochemistry , chelation , medicine , antibody , monoclonal antibody , organic chemistry
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-Y 3+ ; molecular weight: 9059 Da). Pretargeting [ 177 Lu]LuDOTA-Bn with CCA α-16-DOTA-Y 3+ to GPA33-expressing SW1222 human colorectal xenografts was highly effective, leading to absorbed doses of [ 177 Lu]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.