A tetravalent bispecific protein enables targeted degradation of VCAM-1 and VEGFR for treatment of choroidal neovascularization
5 affiliations
- 1School of Nano-Tech and Nano-Bionics, University of Science and Technology of China, Hefei 230026, China
- 2Key Laboratory of Nano-Bio Interface, Jiangsu Key Laboratory of Organoid Engineering and Precision Medicine, Division of Nanobiomedicine and i-Lab, Suzhou Institute of Nano-Tech and Nano-Bionics, Chinese Academy of Sciences, Suzhou 215123, China
- 3Department of Ophthalmology, The First Affiliated Hospital of Soochow University, Suzhou 21006, China
- 4School of Chemistry and Chemical Engineering, Shanghai Jiao Tong University, Shanghai 200240, China
- 5Global Institute of Future Technology, Shanghai Jiao Tong University, Shanghai 200240, China
Abstract
Wet age-related macular degeneration (AMD), a leading cause of irreversible vision loss, is driven by pathological choroidal neovascularization (CNV). Although anti-vascular endothelial growth factor (anti-VEGF) therapies remain the clinical standard, their utility is constrained by incomplete responses in nearly 50% of patients and off-target risks—such as geographic atrophy—stemming from non-specific VEGF blockade. Here, we identify a robust correlation between vascular cell adhesion molecule-1 (VCAM-1) and VEGF/VEGF receptor (VEGFR) expression in aqueous humor from AMD patients and in murine CNV models. Thus, we engineered a tetravalent bispecific protein, RHV, by functionalizing an L-rhamnulose-1-phosphate aldolase scaffold with peptides that selectively bind VCAM-1 and the VEGFR on neovessels. The tetravalent design confers high apparent affinity, enhancing pathological endothelial targeting while sparing healthy retinal vasculature. RHV induces concurrent internalization and lysosomal degradation of both VCAM-1 and VEGFR via a head-to-tail binding mode, leading to sustained inhibition of the VEGF/VEGFR, PI3K/AKT and Apelin/APJ signaling pathways. In murine CNV models, a single intravitreal injection of RHV exhibits superior ocular retention and lesion penetration, achieving therapeutic efficacy comparable to aflibercept [a ligand-trap fusion protein for VEGF-A, VEGF-B and placental growth factor (PIGF)] at one-quarter of the molar dose. This dual-receptor degradation-based strategy represents a targeted and durable approach for treating ocular neovascularization.
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BibTeX
@article{zhang2026tetravalent,
title = {{A tetravalent bispecific protein enables targeted degradation of VCAM-1 and VEGFR for treatment of choroidal neovascularization}},
author = {Jialun Zhang and Mingming Du and Lingying Ge and Yuheng Cao and Jiang Jiang and Xue Yin and Guangcun Chen and Qiangbin Wang},
journal = {Proceedings of the National Academy of Sciences of the United States of America},
year = {2026},
month = nov,
doi = {10.1073/pnas.2613631123},
url = {https://doi.org/10.1073/pnas.2613631123},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - A tetravalent bispecific protein enables targeted degradation of VCAM-1 and VEGFR for treatment of choroidal neovascularization
AU - Jialun Zhang
AU - Mingming Du
AU - Lingying Ge
AU - Yuheng Cao
AU - Jiang Jiang
AU - Xue Yin
AU - Guangcun Chen
AU - Qiangbin Wang
PY - 2026
DA - 2026/11/04
JO - Proceedings of the National Academy of Sciences of the United States of America
DO - 10.1073/pnas.2613631123
UR - https://doi.org/10.1073/pnas.2613631123
AB - Wet age-related macular degeneration (AMD), a leading cause of irreversible vision loss, is driven by pathological choroidal neovascularization (CNV). Although anti-vascular endothelial growth factor (anti-VEGF) therapies remain the clinical standard, their utility is constrained by incomplete responses in nearly 50% of patients and off-target risks—such as geographic atrophy—stemming from non-specific VEGF blockade. Here, we identify a robust correlation between vascular cell adhesion molecule-1 (VCAM-1) and VEGF/VEGF receptor (VEGFR) expression in aqueous humor from AMD patients and in murine CNV models. Thus, we engineered a tetravalent bispecific protein, RHV, by functionalizing an L-rhamnulose-1-phosphate aldolase scaffold with peptides that selectively bind VCAM-1 and the VEGFR on neovessels. The tetravalent design confers high apparent affinity, enhancing pathological endothelial targeting while sparing healthy retinal vasculature. RHV induces concurrent internalization and lysosomal degradation of both VCAM-1 and VEGFR via a head-to-tail binding mode, leading to sustained inhibition of the VEGF/VEGFR, PI3K/AKT and Apelin/APJ signaling pathways. In murine CNV models, a single intravitreal injection of RHV exhibits superior ocular retention and lesion penetration, achieving therapeutic efficacy comparable to aflibercept [a ligand-trap fusion protein for VEGF-A, VEGF-B and placental growth factor (PIGF)] at one-quarter of the molar dose. This dual-receptor degradation-based strategy represents a targeted and durable approach for treating ocular neovascularization.
SN - 0027-8424
SN - 1091-6490
ER -