A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint.
A novel bispecific antibody for EGFR-directed blockade of the PD-1/PD-L1 immune checkpoint.
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DOI：
10.1080/2162402x.2018.1466016
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发表时间：
2018
期刊：
影响因子：
7.2
通讯作者：
Helfrich W
中科院分区：
文献类型：
--
作者：
Koopmans I;Hendriks D;Samplonius DF;van Ginkel RJ;Heskamp S;Wierstra PJ;Bremer E;Helfrich W
PD-L1 阻断抗体通过重新激活功能受损的抗原经历的抗癌 T 细胞，对选定的癌症患者产生显着的临床益处。然而，当前 PD-L1 阻断抗体的功效可能会因与正常细胞上广泛表达的 PD-L1 的“靶向/脱肿瘤”结合而降低。这种肿瘤选择性的缺乏可能会诱导所有经历过抗原的 T 细胞的普遍激活，这可能解释了治疗期间和治疗后频繁发生的自身免疫相关不良事件。为了解决这些问题，我们构建了一种双特异性抗体 (bsAb)，命名为 PD-L1xEGFR，以直接对表达 EGFR 的癌细胞进行 PD-L1 阻断，并更有选择性地重新激活抗癌 T 细胞。事实上，与具有不相关靶抗原特异性的类似 PD-L1 阻断 bsAb PD-L1xMock 相比，PD-L1xEGFR 在 EGFR+ 癌细胞上阻断 PD-L1 的 IC50 低约 140 倍。重要的是，当与表达 EGFR 的癌细胞共培养时，抗 CD3x 抗 EpCAM 重定向 T 细胞的激活状态、IFN-γ 产生和溶瘤活性得到增强。同样，当与表达 EGFR 的 CMVpp65 转染的癌细胞共培养时，PD-L1xEGFR 促进 CMVpp65 定向的 CD8+ 效应 T 细胞增殖和 IFN-γ 产生的能力得到增强。相比之下，临床上使用的PD-L1阻断抗体MEDI4736（durvalumab）促进T细胞活化，不加区别癌细胞上的EGFR表达。此外，在异种移植表达 EGFR 的癌细胞的小鼠中，与 111In-PD-L1xMock 相比，111In-PD-L1xEGFR 显示出显着更高的肿瘤摄取。总之，PD-L1xEGFR以EGFR定向的方式阻断PD-1/PD-L1免疫检查点，从而促进抗癌T细胞的选择性再激活。这种新颖的靶向方法可能有助于提高 PD-1/PD-L1 检查点阻断在 EGFR 过表达恶性肿瘤中的疗效和安全性。
PD-L1-blocking antibodies produce significant clinical benefit in selected cancer patients by reactivating functionally-impaired antigen-experienced anticancer T cells. However, the efficacy of current PD-L1-blocking antibodies is potentially reduced by ‘on-target/off-tumor’ binding to PD-L1 widely expressed on normal cells. This lack of tumor selectivity may induce a generalized activation of all antigen-experienced T cells which may explain the frequent occurrence of autoimmune-related adverse events during and after treatment. To address these issues, we constructed a bispecific antibody (bsAb), designated PD-L1xEGFR, to direct PD-L1-blockade to EGFR-expressing cancer cells and to more selectively reactivate anticancer T cells. Indeed, the IC50 of PD-L1xEGFR for blocking PD-L1 on EGFR+ cancer cells was ∼140 fold lower compared to that of the analogous PD-L1-blocking bsAb PD-L1xMock with irrelevant target antigen specificity. Importantly, activation status, IFN-γ production, and oncolytic activity of anti-CD3xanti-EpCAM-redirected T cells was enhanced when cocultured with EGFR-expressing carcinoma cells. Similarly, the capacity of PD-L1xEGFR to promote proliferation and IFN-γ production by CMVpp65-directed CD8+ effector T cells was enhanced when cocultured with EGFR-expressing CMVpp65-transfected cancer cells. In contrast, the clinically-used PD-L1-blocking antibody MEDI4736 (durvalumab) promoted T cell activation indiscriminate of EGFR expression on cancer cells. Additionally, in mice xenografted with EGFR-expressing cancer cells 111In-PD-L1xEGFR showed a significantly higher tumor uptake compared to 111In-PD-L1xMock. In conclusion, PD-L1xEGFR blocks the PD-1/PD-L1 immune checkpoint in an EGFR-directed manner, thereby promoting the selective reactivation of anticancer T cells. This novel targeted approach may be useful to enhance efficacy and safety of PD-1/PD-L1 checkpoint blockade in EGFR-overexpressing malignancies.