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靶向 T 细胞的双特异性抗体 ERY974 与化疗联合应用可增强对非炎症肿瘤的疗效。

Combination of T cell-redirecting bispecific antibody ERY974 and chemotherapy reciprocally enhances efficacy against non-inflamed tumours.

机构信息

Research Division, Chugai Pharmaceutical Co., Ltd., 200 Kajiwara, Kamakura, Kanagawa, 247-8530, Japan.

Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka, 412-8513, Japan.

出版信息

Nat Commun. 2022 Sep 7;13(1):5265. doi: 10.1038/s41467-022-32952-3.

DOI:10.1038/s41467-022-32952-3
PMID:36071036
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9452528/
Abstract

Identifying a strategy with strong efficacy against non-inflamed tumours is vital in cancer immune therapy. ERY974 is a humanized IgG4 bispecific T cell-redirecting antibody that recognizes glypican-3 and CD3. Here we examine the combination effect of ERY974 and chemotherapy (paclitaxel, cisplatin, and capecitabine) in the treatment of non-inflamed tumours in a xenograft model. ERY974 monotherapy shows a minor antitumour effect on non-inflamed NCI-H446 xenografted tumours, as infiltration of ERY974-redirected T cells is limited to the tumour-stromal boundary. However, combination therapy improves efficacy by promoting T cell infiltration into the tumour centre, and increasing ERY974 distribution in the tumour. ERY974 increases capecitabine-induced cytotoxicity by promoting capecitabine conversion to its active form by inducing thymidine phosphorylase expression in non-inflamed MKN45 tumour through ERY974-induced IFNγ and TNFα in T cells. We show that ERY974 with chemotherapy synergistically and reciprocally increases antitumour efficacy, eradicating non-inflamed tumours.

摘要

在癌症免疫治疗中，识别对非炎症肿瘤具有强大疗效的策略至关重要。ERY974 是一种人源化 IgG4 双特异性 T 细胞重定向抗体，可识别磷脂酰聚糖-3 和 CD3。在这里，我们在异种移植模型中研究了 ERY974 与化疗（紫杉醇、顺铂和卡培他滨）联合治疗非炎症肿瘤的效果。ERY974 单药治疗对非炎症 NCI-H446 异种移植肿瘤的抗肿瘤作用较小，因为 ERY974 重定向 T 细胞的浸润仅限于肿瘤基质边界。然而，联合治疗通过促进 T 细胞浸润到肿瘤中心并增加肿瘤内 ERY974 的分布来提高疗效。ERY974 通过诱导 T 细胞中 IFNγ 和 TNFα 诱导胸苷磷酸化酶的表达，促进卡培他滨转化为其活性形式，从而增加卡培他滨诱导的细胞毒性。我们表明，ERY974 与化疗具有协同和相互增强的抗肿瘤作用，可根除非炎症肿瘤。

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