An Elaborate New Linker System Significantly Enhances the Efficacy of an HER2‐Antibody‐Drug Conjugate against Refractory HER2‐Positive Cancers. Issue 23 (18th October 2021)

• Record Type: Journal Article
• Authors: Shin, Seol Hwa; Park, Yun‐Hee; Park, Seok Soon; Ju, Eun Jin; Park, Jin; Ko, Eun Jung; Bae, Dong Jun; Kim, Sang‐Yeob; Chung, Chul‐Woong; Song, Ho Young; Jang, Se Jin; Jeong, Seong‐Yun; Song, Si Yeol; Choi, Eun Kyung
• Is Part Of: Advanced science. Volume 8:Issue 23(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-10-18
• Subjects: antibody drug conjugate -- HER2 -- patient derived xenograft (PDX); Science -- Periodicals; 505
• DOI: 10.1002/advs.202102414
• Languages: English
• ISSNs: 2198-3844

Abstract

Abstract: Human epidermal growth factor receptor 2 (HER2) is overexpressed in breast and gastric cancers and this causes poor clinical outcomes. Although both T‐DM1 and Enhertu are approved as an HER2‐targeting antibody‐drug conjugate (ADC), the effects of these drugs are still not satisfactory to eradicate diverse tumors expressing HER2. To address this shortfall in HER2‐targeted therapeutics, an elaborate cleavable linker is created and a novel HER2‐targeting ADC composed with trastuzumab and monomethyl auristatin F, which is being investigated in a phase 1 clinical trial and is referred to as LegoChem Bisciences‐ADC (LCB‐ADC). LCB‐ADC displays a higher cytotoxic potency than T‐DM1 and it also has a higher G2/M arrest ratio. In animal studies, LCB‐ADC produces noticeable tumor growth inhibition compared with trastuzumab or T‐DM1 in an HER2 high‐expressing N87 xenograft tumor. Especially, LCB‐ADC shows good efficacy in terms of suppressing tumor growth in a patient‐derived xenograft (PDX) model of HER2‐positive gastric cancer as well as in T‐DM1‐resistant models such as HER2 low‐expressing HER2 low expressing JIMT‐1 xenograft tumor and PDX. Collectively, the results demonstrate that LCB‐ADC with the elaborate linker has a higher efficacy and greater biostability than its ADC counterparts and may successfully treat cancers that are nonresponsive to previous therapeutics. Abstract : Antibody‐drug conjugate (ADC), delivering a severe toxin to selective tumor cells utilizing a high‐affinity of antibody has emerged as the most promising biotherapeutics for cancer. Here it is demonstrated that the application of the elaborate linker‐drug technology to human epidermal growth factor receptor 2‐ADC enables to eradicate the diverse cancer types rarely responding to previous therapeutics.