Dual membrane receptor degradation via folate receptor targeting chimera

Zhen Wang, Zhixin Li, Jenny Högström, Hiroyuki Inuzuka, Rui Jing, Peiqiang Yan, Tao Hou, Yihang Qi, Daoyuan Huang, Jingchao Wang, Ting Wu, Xiaoying Shi, Bolin Liu, Taru Muranen, Dingpeng Zhang () and Wenyi Wei ()
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Zhen Wang: Harvard Medical School
Zhixin Li: Dana-Farber Cancer Institute
Jenny Högström: Harvard Medical School
Hiroyuki Inuzuka: Harvard Medical School
Rui Jing: Houston Methodist Cancer Center/Weill Cornell Medicine
Peiqiang Yan: Harvard Medical School
Tao Hou: Harvard Medical School
Yihang Qi: Harvard Medical School
Daoyuan Huang: Harvard Medical School
Jingchao Wang: Harvard Medical School
Ting Wu: Boston Children’s Hospital
Xiaoying Shi: Brigham and Women’s Hospital
Bolin Liu: LSU Health Sciences Center
Taru Muranen: Harvard Medical School
Dingpeng Zhang: Harvard Medical School
Wenyi Wei: Harvard Medical School

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract Cancer drug resistance poses a significant challenge in oncology, often driven by intricate cross-talk among membrane-bound receptors that compromise mono-targeted therapies. We develop a dual membrane receptor degradation strategy leveraging Folate Receptor α (FRα) to address this issue. Folate Receptor α Targeting Chimeras-dual (FolTAC-dual) are engineered degraders designed to selectively and simultaneously degrade distinct receptor pairs: (1) EGFR/HER2 and (2) PD-L1/VISTA. Through modular optimization of modality configurations and geometries, we identify the “string” format as the most effective construct. Mechanistic studies demonstrate an ~85% increase in EGFR-binding affinity compared to the conventional knob-into-hole design, likely contributing to the improved efficiency of dual-target degradation. Proof-of-concept studies reveal that EGFR and HER2 FolTAC-dual effectively counteracts resistance in Trastuzumab/Lapatinib-resistant HER2-positive breast cancer models, while PD-L1 and VISTA FolTAC-dual rejuvenates immune responses in PD-L1 antibody-resistant syngeneic mouse models. These findings establish FolTAC-dual as a promising dual-degradation platform for clinical translation.

Date: 2025
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DOI: 10.1038/s41467-025-63882-5

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