Antibody‒drug conjugates with DHODH inhibitor as novel payload class for cancer and SARS-CoV-2 infection therapies

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 <b>TH-C8H</b> exhibited significant efficacy against gastric cancer <i>in vivo</i> as monotherapy and enhanced efficacy when combined with the ferroptosis inducer <b>RSL3</b>. The antiviral ADC <b>HG-C3</b> showed broad-spectrum anti-SARS-CoV-2 activity <i>in vitro</i> and <i>in vivo</i>. Our study expands the types of ADC payloads and provides novel insights into the development of innovative broad-spectrum ADCs.