Immune Modulating Antibody–Drug Conjugate (IM-ADC) for Cancer Immunotherapy
Lei He, Liangliang Wang, Zhisong Wang, Tiantian Li, Hui Chen, Yaning Zhang, Zeping Hu, Dimiter S. Dimitrov, Juanjuan Du, Xuebin Liao
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 D18 via a redox-cleavable linker. The resulting ADC HE-S2 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 HE-S2 treatment could lead to more pronounced tumor suppression than the treatment of D18 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.