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Micron-Scale 2D Antibody Arrays for HER2 Signaling Blockade and Cancer Therapy
Mingming Du1, Xiang Zhong1, Tingfeng Yao1
1CAS Key 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.
Abstract:
Monoclonal antibodies (mAbs) targeting the human epidermal growth factor receptor 2 (HER2) are widely used in the treatment of breast, gastric, and other solid tumors. However, rapid HER2 endocytosis and recycling contribute to low response rates and treatment resistance. Here, we introduce RhuA-P, a self-assembling protein that forms uniform, micron-sized 2D arrays (2.4 × 2.4 μm) featuring spatially addressable Protein G sites for mAb conjugation. This design allows control over antibody density (22-274 molecules per array) and intermolecular spacing (57-230 nm). We show that trastuzumab (TmAb) arrays templated on RhuA-P inhibit HER2 dimerization, cluster HER2 into micron-scale inactive domains dictated by the 2D TmAb geometry, and prolong receptor membrane retention by blocking endocytosis. This sustained blockade of HER2 signaling induces oxidative stress and triggers potent apoptosis. In a murine breast cancer model, TmAb arrays exhibited superior antitumor efficacy compared to free TmAb. Moreover, the modular design of RhuA-P makes it a versatile platform for assembling other clinically relevant mAbs─such as anti-PD-1 and anti-PD-L1 antibodies─offering a generalized strategy for enhancing antibody-based therapies.
Insights
This study introduces RhuA-P, a novel protein platform that creates 2D antibody arrays. These arrays enhance cancer therapy by blocking HER2 receptor signaling, leading to improved antitumor efficacy.
Area of Science:
- Biotechnology
- Cancer Biology
- Immunotherapy
Background:
- Monoclonal antibodies (mAbs) targeting human epidermal growth factor receptor 2 (HER2) are crucial for treating solid tumors.
- Rapid HER2 endocytosis and recycling limit the efficacy of current HER2-targeted therapies, contributing to resistance.
Purpose of the Study:
- To develop a novel protein-based platform, RhuA-P, for creating spatially controlled 2D antibody arrays.
- To investigate the therapeutic potential of RhuA-P-templated trastuzumab (TmAb) arrays in enhancing HER2-targeted cancer therapy.
Main Methods:
- RhuA-P self-assembly into uniform micron-sized 2D arrays with Protein G sites for mAb conjugation.
- Control over antibody density and intermolecular spacing on the arrays.
- In vitro assays to assess HER2 dimerization, clustering, endocytosis blockade, and apoptosis induction.
- In vivo evaluation of TmAb array efficacy in a murine breast cancer model.
Main Results:
- RhuA-P arrays enabled precise control over TmAb density and spacing.
- TmAb arrays effectively inhibited HER2 dimerization and clustered HER2 into inactive domains.
- Arrays prolonged HER2 membrane retention by blocking endocytosis, inducing oxidative stress and apoptosis.
- TmAb arrays demonstrated superior antitumor efficacy compared to free TmAb in a preclinical model.
Conclusions:
- RhuA-P is a versatile platform for assembling antibody arrays, offering a generalized strategy to enhance antibody-based therapies.
- Spatially controlled antibody arrays can overcome limitations of free mAbs by modulating receptor dynamics and signaling.
- This approach holds promise for improving treatment outcomes in HER2-positive cancers and potentially other antibody-treatable diseases.
