A novel nanobody-based HER2-targeting antibody exhibits potent synergistic antitumor efficacy in trastuzumab-resistant cancer cells

• Published in: Frontiers in immunology Vol. 14; p. 1292839
• Main Authors: Liu, Xinlin, Luan, Linli, Liu, Xi, Jiang, Dingwen, Deng, Junwen, Xu, Jiazhen, Yuan, Yang, Xing, Jiyao, Chen, Bingguan, Xing, Dongming, Huang, Haiming
• Format: Journal Article
• Language: English
• Published: Frontiers Media S.A 25.10.2023
• Subjects: Fc fusion; HER2; Immunology; ligand-dependent heterodimerization; nanobody; synergistic efficacy; trastuzumab-resistance
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2023.1292839

Human epithelial growth factor receptor-2 (HER2) plays an oncogenic role in numerous tumors, including breast, gastric, and various other solid tumors. While anti-HER2 therapies are approved for the treatment of HER2-positive tumors, a necessity persists for creating novel HER2-targeted agents to resolve therapeutic resistance. Utilizing a synthetic nanobody library and affinity maturation, our study identified four anti-HER2 nanobodies that exhibited high affinity and specificity. These nanobodies recognized three distinct epitopes of HER2-ECD. Additionally, we constructed VHH-Fc and discovered that they facilitated superior internalization and showed moderate growth inhibition. Compared to the combination of trastuzumab and pertuzumab, the VHH-Fc combos or their combination with trastuzumab demonstrated greater or comparable antitumor activity in both ligand-independent and ligand-driven tumors. Most remarkably, A9B5-Fc, which targeted domain I of HER2-ECD, displayed significantly enhanced trastuzumab-synergistic antitumor efficacy compared to pertuzumab under trastuzumab-resistant conditions. Our findings offer anti-HER2 nanobodies with high affinity and non-overlapping epitope recognition. The novel nanobody-based HER2-targeted antibody, A9B5-Fc, binding to HER2-ECD I, mediates promising receptor internalization. It possesses the potential to serve as a potent synergistic partner with trastuzumab, contributing to overcoming acquired resistance.