Immune Modulating Antibody–Drug Conjugate (IM-ADC) for Cancer Immunotherapy

Abstract

Antibody-drug conjugate (ADC) and immune checkpoint blockade (ICB) offer promising approaches for cancer treatment. Here, we describe an ADC constructed by conjugating anti-PD-L1 THIOMAB with a bifunctional immunomodulator <b>D18</b> via a redox-cleavable linker. The resulting ADC <b>HE-S2</b> not only triggers a potent antitumor immune response by blocking the PD-1/PD-L1 interaction and activating the Toll-like receptor 7/8 (TLR7/8) signaling pathway but also upregulates its targeted PD-L1 expression via epigenetic regulation and/or IFN-γ induction, thus conferring more sensitivity to the PD-1/PD-L1 blockade. We identify that ADC <b>HE-S2</b> treatment could lead to more pronounced tumor suppression than the treatment of <b>D18</b> in combination with the anti-PD-L1 antibody. Accordingly, this study provides a novel ADC strategy to enhance the antitumor immune response to ICB therapy.