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Rational engineering of degradation tail-driven CELMoD-antibody conjugates for precision malignancy therapy
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Acta Pharmaceutica Sinica B | 2025, 15(12) : 6510 - 6528
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Acta Pharmaceutica Sinica B | 2025, 15(12): 6510-6528
• Original articles •
Rational engineering of degradation tail-driven CELMoD-antibody conjugates for precision malignancy therapy
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Published: 2025-12-25 doi: 10.1016/j.apsb.2025.09.009
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Degrader–antibody conjugates (DACs) represent a promising drug modality for targeting hematological malignancy, but still lack rational design frameworks. Here, we 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, we sought to explore the potential of cereblon E3 ligase modulators (CELMoDs) in constructing novel conjugates. 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.
Degrader-antibody conjugate  /  Antibody-drug conjugate  /  Cereblon E3 ligase modulator  /  Immunomodulatory drug  /  Molecular glue  /  Targeted protein degradation  /  Multiple myeloma  /  Hematologic malignancy
. Rational engineering of degradation tail-driven CELMoD-antibody conjugates for precision malignancy therapy. 药学学报（英文版）, 2025 , 15 (12) : 6510 -6528 . DOI: 10.1016/j.apsb.2025.09.009
. Rational engineering of degradation tail-driven CELMoD-antibody conjugates for precision malignancy therapy[J]. Acta Pharmaceutica Sinica B, 2025 , 15 (12) : 6510 -6528 . DOI: 10.1016/j.apsb.2025.09.009
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Year 2025 volume 15 Issue 12
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doi: 10.1016/j.apsb.2025.09.009
  • Receive Date：2025-02-14
  • Online Date：2026-10-25
  • Published：2025-12-25
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  • Received：2025-02-14
  • Revised：2025-06-05
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表12种不同金属材料的力学参数
科
Family		 属数
Number of
genus		 种数
Number of
species		 占总种数比例
Percentage of
total species (%)		 属
Genus		 种数
Number of
species		 占总种数比例
Percentage of total
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鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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