Antibody‒drug conjugates with DHODH inhibitor as novel payload class for cancer and SARS-CoV-2 infection therapies
Zhirui Liu, Lunzhi Yuan, Pengyun Li, Fei Xie, Ming Zhou, Lianqi Liu, Ting Wei, Yi Guan, Ningshao Xia, Zhibing Zheng, Tong Cheng, Dian Xiao, Xinbo Zhou, Song Li
TL;DR
This paper introduces a new class of antibody-drug conjugates using DHODH inhibitors, showing effectiveness against cancer and SARS-CoV-2.
Contribution
The study introduces DHODH inhibitors as a novel payload class for ADCs with antitumor and antiviral applications.
Findings
The antitumor ADC TH-C8H was effective against gastric cancer and enhanced by RSL3.
The antiviral ADC HG-C3 showed broad-spectrum anti-SARS-CoV-2 activity.
Stability-controllable linkers were developed to suit different therapeutic needs.
Abstract
Despite remarkable achievements in antibody‒drug conjugates (ADCs), payloads remain limited. The identification of ADC payloads with novel mechanisms will increase therapeutic options and expand indications. Herein, we describe the use of dihydroorotate dehydrogenase inhibitors (DHODHi) as a novel payload class that provides highly potent ADCs for antitumor and antiviral therapies. Technical innovations include the development of stability-controllable linkers to meet the distinct requirements of acute viral infections and chronic tumor conditions. The antitumor ADC TH-C8H exhibited significant efficacy against gastric cancer in vivo as monotherapy and enhanced efficacy when combined with the ferroptosis inducer RSL3. The antiviral ADC HG-C3 showed broad-spectrum anti-SARS-CoV-2 activity in vitro and in vivo. Our study expands the types of ADC payloads and provides novel insights into…
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Taxonomy
TopicsHER2/EGFR in Cancer Research · Biochemical and Molecular Research · Colorectal Cancer Treatments and Studies