2. Academic Validation
  3. Chimeras co-targeting antigens and FcγRIIb trigger degradation of extracellular soluble proteins and pathological aggregates

Chimeras co-targeting antigens and FcγRIIb trigger degradation of extracellular soluble proteins and pathological aggregates

  • Nat Commun. 2025 Dec 10. doi: 10.1038/s41467-025-67207-4.
Mingjuan Du # 1,  Na Li # 2 3,  Tianqi Li # 2 3,  Zhuoqian Zhao # 1,  Huanzhen Liu # 1,  Xin Li # 2,  Nanxin Gong 2 3,  Baoxin Duan 2,  Wenli Wang 2,  Yi Jian 2,  Wenxuan Ma 2,  Xiaoqi Zhang 2,  Yi Wang 2,  Zhaoyuan Zhang 2,  Yiyang Bai 2,  Xiaoqian Wang 2,  Chunlei Wang 2,  Jinming Liu 2,  Xiangchen Guan 2,  Feilong Zhou 2,  Wei Wang 1,  Lili Li 4,  Xingping Zhu 5,  Ying Lei 1,  Yinkai Duan 1,  Guoge Han 6,  Pinghui Wei 6,  Shan Gao 6,  Sheng Wang 7,  Ancheng Chen 7,  Yi Huang 8,  Haitao Yang 9,  Xue Xue 10 11,  Hongkai Zhang 12 13 14
Affiliations

Affiliations

  • 1 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, PR China.
  • 2 State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and College of Pharmacy, Nankai University, Tianjin, PR China.
  • 3 Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, PR China.
  • 4 Beijing Institute of Biological Products Co., Ltd, Beijing, PR China.
  • 5 EVIDENT(Shanghai) Co., Ltd, Shanghai, PR China.
  • 6 Tianjin Eye Hospital, Tianjin Key Laboratory of Ophthalmology and Visual Science and Nankai University affliated Tianjin Eye Hospital, Tianjin, PR China.
  • 7 Shanghai Zelixir Biotech Company Ltd, Shanghai, PR China.
  • 8 Analytical Science Department, Shanghai Tanshi Biotech Company Ltd, Shanghai, PR China.
  • 9 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, PR China. [email protected].
  • 10 State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and College of Pharmacy, Nankai University, Tianjin, PR China. [email protected].
  • 11 Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, PR China. [email protected].
  • 12 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, PR China. [email protected].
  • 13 State Key Laboratory of Medicinal Chemical Biology, College of Life Sciences and College of Pharmacy, Nankai University, Tianjin, PR China. [email protected].
  • 14 Academy for Advanced Interdisciplinary Studies, Nankai University, Tianjin, PR China. [email protected].
  • # Contributed equally.
PMID: 41372196 DOI: 10.1038/s41467-025-67207-4
Abstract

While the clinical utility of conventional antibody therapies is undeniable, their therapeutic potential is often constrained high antigen loads and the recycling of antibody-antigen complexes via neonatal Fc receptor (FcRn). Here, we present a platform, based on a design similar to bispecific antibodies, FcγRIIb-Targeting Chimeras (FcRTAC). These constructs recognise antigens with one arm and bind FcγRIIb with the Other arm to harness the unique endocytic properties of FcγRIIb to direct the recognized pathogenic antigens to lysosomes for irreversible degradation. The FcRTAC platform demonstrates broad therapeutic potential across multiple disease-relevant targets, including IgE, proprotein convertase subtilisin/kexin type 9 (PCSK9) and Amyloid-β (Aβ). Notably, a single intravenous administration of blood brain barrier (BBB)-penetrating adeno-associated viral vector (AAV) encoding an Aβ-targeting FcRTAC construct achieves sustained therapeutic effects, establishing proof-of-concept for AAV-mediated delivery of an Aβ degrader as a strategy for Alzheimer's disease treatment. Our comprehensive investigation of binding properties of FcRTACs reveals critical molecular determinants of function and enables development of optimized engineering approaches. In summary, our approach represents a versatile therapeutic platform for treating diverse diseases ranging from autoimmune disorders to neurodegenerative conditions, while simultaneously serving as a user-friendly, plug-and-play research tool for extracellular protein knockout in basic biological research.

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