一种新颖的Fc工程HER2双特异性抗体，具有增强的抗肿瘤活性。
A Novel Fc-Engineered Anti-HER2 Bispecific Antibody With Enhanced Antitumor Activity.
发表日期：2023 Mar 20
作者：
Mehdi Mohammadi, Mahmood Jeddi-Tehrani, Forough Golsaz-Shirazi, Mohammad Arjmand, Fatemeh Torkashvand, Tannaz Bahadori, Mohammad Ali Judaki, Fariba Shiravi, Hengameh Ahmadi Zare, Farzaneh Notash Haghighat, Maryam Mobini, Fazel Shokri, Mohammad Mehdi Amiri
来源：
Cellular & Molecular Immunology
摘要：
人皮肤生长因子受体2（HER2）在多种癌症中已被证明过表达。靶向HER2的单克隆抗体（mAbs）治疗已被批准为一种治疗模式。尽管mAbs在肿瘤治疗中具有疗效，但许多患者并未从此治疗平台中受益。改性晶体可部分结构（Fc）是一种改善治疗mAbs效果的常见方法。迄今为止，FDA已批准了5种改性Fc的mAbs。我们最近开发了一种由曲妥珠单抗变量域和我们的新型人源化抗HER2mAb hersintuzumab构建的抗HER2双特异性mAb BiHT。 BiHT表现出了有希望的抗肿瘤活性，与父mAbs的组合一样有力。在这里，我们旨在改变BiHT的Fc以提高其治疗效果。改性Fc的BiHT（MBiHT）与BiHT相似地与重组HER2及其亚区结合。它还识别不同细胞系上的天然HER2，抑制它们的增殖，下调HER2表达，并抑制下游信号通路，类似于BiHT。与BiHT相比，MBiHT在不同的肿瘤细胞系中显示出更强的抗体依赖性细胞毒活性。它也比BiHT更有效地抑制裸鼠卵巢异种移植瘤的生长。我们的发现表明，MBiHT可能是治疗HER2过度表达的癌症类型的有力候选药物。版权所有©2023 Wolters Kluwer Health公司。保留所有权利。
Human epidermal growth factor receptor 2 (HER2) overexpression has been demonstrated in a variety of cancers. Targeted therapy with anti-HER2 monoclonal antibodies (mAbs) has been approved as a therapeutic modality. Despite the efficacy of mAbs in tumor treatment, many patients do not benefit from this therapeutic platform. Fragment crystallizable (Fc) engineering is a common approach to improve the efficacy of therapeutic mAbs. Five Fc-engineered mAbs have so far been approved by FDA. We have recently developed an anti-HER2 bispecific mAb, BiHT, constructed from variable domains of trastuzumab, and our novel humanized anti-HER2 mAb, hersintuzumab. BiHT displayed promising antitumor activity as potently as the combination of the parental mAbs. Here, we aimed to modify the Fc of BiHT to improve its therapeutic efficacy. The Fc-engineered BiHT (MBiHT) bound to recombinant HER2 and its subdomains with an affinity similar to BiHT. It also recognized native HER2 on different cell lines, inhibited their proliferation, downregulated HER2 expression, and suppressed downstream signaling pathways similar to BiHT. Compared with BiHT, MBiHT displayed enhanced antibody-dependent cellular cytotoxicity activity against various tumor cell lines. It also inhibited the growth of ovarian xenograft tumors in nude mice more potently than BiHT. Our findings suggest that MBiHT could be a potent therapeutic candidate for the treatment of HER2-overexpressing cancer types.Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.