https://doi.org/10.1016/j.apsb.2025.09.009
This new article publication from
Acta Pharmaceutica Sinica B, discusses rational engineering of degradation tail-driven CELMoD–antibody conjugates for precision malignancy therapy.
Degrader–antibody conjugates (DACs) represent a promising drug modality for targeting hematological malignancy but still lack rational design frameworks. The authors of this article show the strategies of reasonable antibody-degrader compatibility and degradation tail-derived conjugatability through a systematic exploration. Inspired by the success of IKZF1/3 degraders, the potential of cereblon E3 ligase modulators (CELMoDs) in constructing novel conjugates were explored. By combining a modular library with neo-substrate screening and further conjugatable derivation,
I034 was identified, a potent CELMoD payload with picomolar degradation activity and antiproliferative effects. Through linker chemistry,
I034-based DACs were constructed and demonstrated superior efficacy and safety compared to auristatin-based conjugates both
in vitro and
in vivo, with the CD38-targeting Dara-VA-
I034 achieving complete tumor eradication at low doses. Mechanistic insights revealed distinct positive feedback regulation of CD38 conjugates, highlighting the need for compatibility between payloads and antigens. These results demonstrate that the approach could provide a framework for discovering CELMoD payloads and advancing DACs for treating multiple myeloma and other malignancies.
Keywords: Degrader–antibody conjugate, Antibody–drug conjugate, Cereblon E3 ligase modulator, Immunomodulatory drug, Molecular glue, Targeted protein degradation, Multiple myeloma, Hematologic malignancy
Graphical Abstract: available at
https://ars.els-cdn.com/content/image/1-s2.0-S2211383525006069-ga1_lrg.jpg
Rationally engineered CELMoD–antibody conjugates (Dara-VA-I034) enable complete tumor eradication
via CD38-targeted degradation with a unique positive-feedback loop, outperforming auristatin-based ADCs in efficacy and safety.
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The Journal of the
Institute of Materia Medica, the Chinese Academy of Medical Sciences and the
Chinese Pharmaceutical Association.
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https://www.journals.elsevier.com/acta-pharmaceutica-sinica-b/
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CiteScore: 24.3
Impact Factor: 14.6 (Top 6 journal in the category of Pharmacology and pharmacy)
JIF without self-citation: 13.8
ISSN 2211-3835
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Yu Guo, Yi Song, Hanlin Wang, Yang Lu, Jingyu Zhang, Zheyuan Shen, Weijuan Kan, Yuxian Wang, Haiting Duan, Shuangshuang Geng, Bo Wang, Shaoting Li, Bizhi Li, Xi Chen, Shanshan Pei, Luo Fang, Jia Li, Yubo Zhou, Jinxin Che, Xiaowu Dong, Rational engineering of degradation tail-driven CELMoD–antibody conjugates for precision malignancy therapy, Acta Pharmaceutica Sinica B, Volume 15, Issue 12, 2025, Pages 6510-6528, ISSN 2211-3835,
https://doi.org/10.1016/j.apsb.2025.09.009