An N-acetylgalactosamino dendron-clearing agent for high-therapeutic-index DOTA-hapten pretargeted radioimmunotherapy Journal Article


Authors: Cheal, S. M.; Patel, M.; Yang, G.; Veach, D.; Xu, H.; Guo, H. F.; Zanzonico, P. B.; Axworthy, D. B.; Cheung, N. K. V.; Ouerfelli, O.; Larson, S. M.
Article Title: An N-acetylgalactosamino dendron-clearing agent for high-therapeutic-index DOTA-hapten pretargeted radioimmunotherapy
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.
Journal Title: Bioconjugate Chemistry
Volume: 31
Issue: 3
ISSN: 1043-1802
Publisher: American Chemical Society  
Date Published: 2020-03-18
Start Page: 501
End Page: 506
Language: English
DOI: 10.1021/acs.bioconjchem.9b00736
PUBMED: 31891487
PROVIDER: scopus
PMCID: PMC7212493
DOI/URL:
Notes: Article -- Source: Scopus
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MSK Authors
  1. Nai-Kong Cheung
    650 Cheung
  2. Darren Veach
    98 Veach
  3. Ouathek Ouerfelli
    102 Ouerfelli
  4. Pat B Zanzonico
    357 Zanzonico
  5. Guangbin Yang
    28 Yang
  6. Hong Xu
    54 Xu
  7. Steven M Larson
    959 Larson
  8. Sarah Marie Cheal
    49 Cheal
  9. Hong-Fen Guo
    74 Guo
  10. Miteshkumar V Patel
    15 Patel