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

  • J Med Chem. 2021 Nov 11;64(21):15716-15726. doi: 10.1021/acs.jmedchem.1c00961.
Lei He  1  2 ,  Liangliang Wang  1  3 ,  Zhisong Wang  1  2 ,  Tiantian Li  1 ,  Hui Chen  1  2 ,  Yaning Zhang  1 ,  Zeping Hu  1 ,  Dimiter S Dimitrov  4 ,  Juanjuan Du  1 ,  Xuebin Liao  1  2
Affiliations
  • 1. School of Pharmaceutical Sciences, Key Laboratory of Bioorganic Phosphorus Chemistry & Chemical Biology (Ministry of Education), Tsinghua University, Beijing 100084, China.
  • 2. Advanced Innovation Center for Human Brain Protection, Beijing Tiantan Hospital, Capital Medical University, Beijing 100088, China.
  • 3. Department of Radiation and Cellular Oncology, The Ludwig Center for Metastasis Research, University of Chicago, Chicago, Illinois 60637, United States.
  • 4. Center for Antibody Therapeutics, University of Pittsburgh, Pittsburgh, Pennsylvania 15216, United States.
PMID: 34730979 DOI: 10.1021/acs.jmedchem.1c00961
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.

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