一种基于纳米抗体的新型 HER2 靶向抗体在曲妥珠单抗耐药癌细胞中表现出强大的协同抗肿瘤功效。
A novel nanobody-based HER2-targeting antibody exhibits potent synergistic antitumor efficacy in trastuzumab-resistant cancer cells.
发表日期：2023
作者：
Xinlin Liu, Linli Luan, Xi Liu, Dingwen Jiang, Junwen Deng, Jiazhen Xu, Yang Yuan, Jiyao Xing, Bingguan Chen, Dongming Xing, Haiming Huang
来源：
Frontiers in Immunology
摘要：
人上皮生长因子受体 2 (HER2) 在许多肿瘤中发挥致癌作用，包括乳腺癌、胃癌和各种其他实体瘤。虽然抗 HER2 疗法已被批准用于治疗 HER2 阳性肿瘤，但仍需要开发新型 HER2 靶向药物来解决治疗耐药性。利用合成纳米抗体库和亲和力成熟，我们的研究鉴定了四种表现出高亲和力和特异性的抗 HER2 纳米抗体。这些纳米抗体识别 HER2-ECD 的三个不同表位。此外，我们构建了 VHH-Fc，发现它们促进了优异的内化并表现出适度的生长抑制。与曲妥珠单抗和帕妥珠单抗的组合相比，VHH-Fc组合或其与曲妥珠单抗的组合在配体非依赖性和配体驱动的肿瘤中均表现出更大或相当的抗肿瘤活性。最值得注意的是，在曲妥珠单抗耐药条件下，与帕妥珠单抗相比，靶向 HER2-ECD 结构域 I 的 A9B5-Fc 显示出显着增强的曲妥珠单抗协同抗肿瘤功效。我们的研究结果提供了具有高亲和力和非重叠表位识别的抗 HER2 纳米抗体。新型基于纳米抗体的 HER2 靶向抗体 A9B5-Fc 与 HER2-ECD I 结合，介导有前途的受体内化。它有潜力与曲妥珠单抗成为有效的协同合作伙伴，有助于克服获得性耐药性。版权所有 © 2023 Liu、Luan、Liu、Jiang、Deng、Xu、Yuan、Xing、Chen、Xing 和 Huang。
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.Copyright © 2023 Liu, Luan, Liu, Jiang, Deng, Xu, Yuan, Xing, Chen, Xing and Huang.