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

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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Publication Details

Journal
Nature Communications
Published
2025-12-10
DOI
https://doi.org/10.1038/s41467-025-67207-4
Primary Topic
Monoclonal and Polyclonal Antibodies Research
Type
article
Field-Weighted Citation Impact
0.00

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article

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

Pinghui Wei, Haitao Yang, Nanxin Gong, Zhaoyuan Zhang et al.
Nature Communications
Monoclonal and Polyclonal Antibodies Research
article

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

Pinghui Wei, Haitao Yang, Nanxin Gong, Zhaoyuan Zhang, Ying Lei, Feilong Zhou, Mingjuan Du, Huanzhen Liu, Guoge Han, Zhuoqian Zhao, Xue Xue, Chunlei Wang, Yinkai Duan, Lili Li, Yi Wang, Na Li, Sheng Wang, Wei Wang, Xin Li, Yi Jian, Jinming Liu, An Chen, Xiaoqian Wang, Hongkai Zhang, Xiaoqi Zhang, Tianqi Li, Xing-Ping Zhu, Yanjun Bai, Shan Gao, Yi Huang, Xiangchen Guan, Baoxin Duan, Wenli Wang
article en

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.

Nature CommunicationsVol. 17(1)
Nankai University (CN), ShanghaiTech University (CN), National Vaccine and Serum Institute (CN), Evive Biotech (China) (CN), Tianjin Medical University Eye Hospital (CN), Viva Biotech (China) (CN), Tianjin Medical University (CN)
National Natural Science Foundation of China, Natural Science Foundation of Tianjin City
Openalex Percentile: Top 46%
Monoclonal and Polyclonal Antibodies Research
DOIOpen Access PDFOpenAlex
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