TY - JOUR
T1 - Immune Modulating Antibody-Drug Conjugate (IM-ADC) for Cancer Immunotherapy
AU - He, Lei
AU - Wang, Liangliang
AU - Wang, Zhisong
AU - Li, Tiantian
AU - Chen, Hui
AU - Zhang, Yaning
AU - Hu, Zeping
AU - Dimitrov, Dimiter S.
AU - Du, Juanjuan
AU - Liao, Xuebin
N1 - Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021/11/11
Y1 - 2021/11/11
N2 - 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-γinduction, 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.
AB - 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-γinduction, 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.
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U2 - 10.1021/acs.jmedchem.1c00961
DO - 10.1021/acs.jmedchem.1c00961
M3 - Article
C2 - 34730979
AN - SCOPUS:85119086426
SN - 0022-2623
VL - 64
SP - 15716
EP - 15726
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 21
ER -