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An Elaborate New Linker System Significantly Enhances the Efficacy of an HER2-Antibody-Drug Conjugate against
Seol Hwa Shin1,2,3, Yun-Hee Park4, Seok Soon Park2,3
1Asan Medical Institute of Convergence Science and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
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.
Insights
A new HER2-targeting antibody-drug conjugate (ADC), LegoChem Bisciences-ADC (LCB-ADC), shows superior efficacy and stability over existing treatments. This novel ADC holds promise for treating HER2-positive cancers, including those resistant to current therapies.
Area of Science:
- Oncology
- Pharmacology
- Biotechnology
Background:
- HER2 overexpression in breast and gastric cancers correlates with poor outcomes.
- Current HER2-targeting antibody-drug conjugates (ADCs) like T-DM1 and Enhertu have limitations in eradicating diverse HER2-expressing tumors.
- There is a need for more effective HER2-targeted therapeutics.
Purpose of the Study:
- To develop and evaluate a novel HER2-targeting ADC with an elaborate cleavable linker.
- To compare the efficacy and stability of the novel ADC, LegoChem Bisciences-ADC (LCB-ADC), against existing treatments.
- To assess LCB-ADC's potential in treating HER2-positive cancers, including T-DM1-resistant models.
Main Methods:
- Development of a novel ADC (LCB-ADC) using trastuzumab and monomethyl auristatin F with an elaborate cleavable linker.
- In vitro assessment of cytotoxic potency and G2/M arrest ratio.
- In vivo evaluation in HER2-expressing N87 xenograft and patient-derived xenograft (PDX) models of HER2-positive gastric cancer.
- Assessment in T-DM1-resistant models, including HER2 low-expressing JIMT-1 xenograft and PDX models.
Main Results:
- LCB-ADC demonstrated higher cytotoxic potency and a greater G2/M arrest ratio compared to T-DM1.
- LCB-ADC exhibited significant tumor growth inhibition in HER2-high N87 xenografts compared to trastuzumab or T-DM1.
- LCB-ADC showed efficacy in suppressing tumor growth in HER2-positive gastric cancer PDX models and T-DM1-resistant models.
Conclusions:
- LCB-ADC, featuring an elaborate cleavable linker, exhibits enhanced efficacy and biostability over current ADC counterparts.
- This novel ADC demonstrates potential for treating HER2-positive cancers unresponsive to existing therapies.
- LCB-ADC represents a promising advancement in HER2-targeted cancer therapeutics.
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