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An Elaborate New Linker System Significantly Enhances the Efficacy of an HER2-Antibody-Drug Conjugate against Refractory HER2-Positive Cancers

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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.
Author(s)
신설화박윤희박석순주은진박진고은정배동준김상엽정철웅송호영장세진정성윤송시열최은경
Issued Date
2021
Type
Article
Keyword
antibody drug conjugateHER2patient derived xenograft (PDX)
DOI
10.1002/advs.202102414
URI
https://oak.ulsan.ac.kr/handle/2021.oak/9583
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_doaj_primary_oai_doaj_org_article_07f3b7d48db44ed78a5f10cc750cb092&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,An%20Elaborate%20New%20Linker%20System%20Significantly%20Enhances%20the%20Efficacy%20of%20an%20HER2-Antibody-Drug%20Conjugate%20against%20Refractory%20HER2-Positive%20Cancers&offset=0
Publisher
Advanced Science
Location
미국
Language
한국어
ISSN
2198-3844
Citation Volume
8
Citation Number
23
Citation Start Page
2102414
Citation End Page
0
Appears in Collections:
Natural Science > Biological Sciences
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