High Peyton, Guernsey Cara, Subramanian Shraddha, Jacob Joan, Carmon Kendra S
Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center and UTHealth Houston, Houston, TX 77030, USA.
Pharmaceutics. 2024 Jul 2;16(7):890. doi: 10.3390/pharmaceutics16070890.
Current therapies targeting the human epidermal growth factor receptor (HER) family, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are limited by drug resistance and systemic toxicities. Antibody-drug conjugates (ADCs) are one of the most rapidly expanding classes of anti-cancer therapeutics with 13 presently approved by the FDA. Importantly, ADCs represent a promising therapeutic option with the potential to overcome traditional HER-targeted therapy resistance by delivering highly potent cytotoxins specifically to HER-overexpressing cancer cells and exerting both mAb- and payload-mediated antitumor efficacy. The clinical utility of HER-targeted ADCs is exemplified by the immense success of HER2-targeted ADCs including trastuzumab emtansine and trastuzumab deruxtecan. Still, strategies to improve upon existing HER2-targeted ADCs as well as the development of ADCs against other HER family members, particularly EGFR and HER3, are of great interest. To date, no HER4-targeting ADCs have been reported. In this review, we extensively detail clinical-stage EGFR-, HER2-, and HER3-targeting monospecific ADCs as well as novel clinical and pre-clinical bispecific ADCs (bsADCs) directed against this receptor family. We close by discussing nascent trends in the development of HER-targeting ADCs, including novel ADC payloads and HER ligand-targeted ADCs.
目前针对人类表皮生长因子受体（HER）家族的疗法，包括单克隆抗体（mAb）和酪氨酸激酶抑制剂（TKI），受到耐药性和全身毒性的限制。抗体药物偶联物（ADC）是发展最为迅速的抗癌治疗药物类别之一，目前有13种已获美国食品药品监督管理局（FDA）批准。重要的是，ADC是一种很有前景的治疗选择，有可能通过将高效细胞毒素特异性递送至HER过表达的癌细胞，并发挥mAb和有效载荷介导的抗肿瘤功效，来克服传统HER靶向治疗的耐药性。HER靶向ADC的临床效用在HER2靶向ADC（包括曲妥珠单抗恩美曲妥珠单抗和曲妥珠单抗德鲁昔单抗）的巨大成功中得到了体现。尽管如此，改进现有HER2靶向ADC的策略以及开发针对其他HER家族成员（特别是EGFR和HER3）的ADC，仍然备受关注。迄今为止，尚未有HER4靶向ADC的报道。在本综述中，我们详细阐述了处于临床阶段的EGFR、HER2和HER3靶向单特异性ADC，以及针对该受体家族的新型临床和临床前双特异性ADC（bsADC）。我们在结尾讨论了HER靶向ADC开发中的新趋势，包括新型ADC有效载荷和HER配体靶向ADC。
