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關(guān)鍵詞: PD-L1 inhibitor; immune checkpoint blockade; immunotherapy

Targeting the programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) interaction has become an established strategy for cancer immunotherapy. Although hundreds of small-molecule, peptide, and peptidomimetic inhibitors have been proposed in recent years, only a limited number of drug candidates show good PD-1/PD-L1 blocking activity in cell-based assays. In this article, we compare representative molecules from different classes in terms of their PD-1/PD-L1 dissociation capacity measured by HTRF and in vitro bioactivity determined by the immune checkpoint blockade (ICB) co-culture assay. We point to recent discoveries that underscore important differences in the mechanisms of action of these molecules and also indicate one principal feature that needs to be considered, which is the eventual human PD-L1 specificity.

靶向程序性細(xì)胞死亡蛋白 1/程序性細(xì)胞死亡 1 配體 1 (PD-1/PD-L1) 相互作用已成為癌癥免疫治療的既定策略。盡管近年來提出了數(shù)百種小分子、肽和擬肽抑制劑，但只有少數(shù)候選藥物在基于細(xì)胞的檢測中顯示出良好的 PD-1/PD-L1 阻斷活性。在本文中，我們根據(jù) HTRF 測量的 PD-1/PD-L1 解離能力和免疫檢查點阻斷 (ICB) 共培養(yǎng)測定確定的體外生物活性比較了來自不同類別的代表性分子。我們指出最近的發(fā)現(xiàn)強調(diào)了這些分子作用機制的重要差異，也表明了一個需要考慮的主要特征，即最終的人類 PD-L1 特異性。

高效搖瓶5L

We performed a comparison of the in vitro targeting of the PD-1/PD-L1 immune checkpoint with molecules selected from various classes, including small molecules, macrocyclic peptides, and monoclonal antibodies. For this, two standardized and popular techniques used in the available literature were applied: the protein-based Homogeneous Time-Resolved Fluorescence (HTRF) method and the cell-based Immune Checkpoint Blockade (ICB) assay. Using these methods, three parameters describing the in vitro potency of the tested compounds were determined: (i) IC50 values of the blockade of PD-1/PD-L1 complex formation (from HTRF); (ii) EC50 values of the reactivation of the effector T cells blocked with PD-L1 (from ICB); and (iii) maximal activation levels of the effector T cells, calculated as the % of the activation in the presence of therapeutic anti-PD-L1 antibody atezolizumab or durvalumab. Based on these parameters, a bubble plot was prepared to visualize the differences between groups of molecules (Figure 1). The numeric data are also presented in Table 1.

我們對 PD-1/PD-L1 免疫檢查點的體外靶向與選自各種類別的分子進行了比較，包括小分子、大環(huán)肽和單克隆抗體。為此，應(yīng)用了現(xiàn)有文獻(xiàn)中使用的兩種標(biāo)準(zhǔn)化和流行技術(shù)：基于蛋白質(zhì)的均相時間分辨熒光 (HTRF) 方法和基于細(xì)胞的免疫檢查點阻斷 (ICB) 檢測。使用這些方法，確定了描述受試化合物體外效力的三個參數(shù)：(i) PD-1/PD-L1 復(fù)合物形成阻斷的IC 50值（來自 HTRF）；(ii) 歐共體50被PD-L1（來自ICB）阻斷的效應(yīng)T細(xì)胞的再激活值；(iii) 效應(yīng) T 細(xì)胞的最大活化水平，計算為在治療性抗 PD-L1 抗體 atezolizumab 或 durvalumab 存在下的活化百分比。

血清培養(yǎng)基瓶500ml

來源：MDPI https://www.mdpi.com/1422-0067/22/21/11797/htm