Immune Modulating Antibody–Drug Conjugate (IM-ADC) for Cancer Immunotherapy,Journal of Medicinal Chemistry

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Immune Modulating Antibody–Drug Conjugate (IM-ADC) for Cancer Immunotherapy
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-11-03 , 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}

Affiliation

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.

中文翻译：

用于癌症免疫治疗的免疫调节抗体-药物偶联物 (IM-ADC)

抗体-药物偶联物 (ADC) 和免疫检查点阻断 (ICB) 为癌症治疗提供了有希望的方法。在这里，我们描述了一种 ADC，它通过抗 PD-L1 THIOMAB 与双功能免疫调节剂D18通过氧化还原可切割的接头偶联而成。由此产生的 ADC HE-S2不仅通过阻断 PD-1/PD-L1 相互作用和激活 Toll 样受体 7/8 (TLR7/8) 信号通路来触发有效的抗肿瘤免疫反应，而且还上调其靶向 PD-L1通过表观遗传调控和/或 IFN-γ 诱导表达，从而赋予对 PD-1/PD-L1 阻断更高的敏感性。我们发现 ADC HE-S2治疗可能导致比D18治疗更明显的肿瘤抑制与抗 PD-L1 抗体联合使用。因此，本研究提供了一种新的 ADC 策略来增强对 ICB 治疗的抗肿瘤免疫反应。

更新日期：2021-11-11

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