纳米颗粒 Toll 样受体 9 激动剂增强抗 Glypican-1 抗体的抗肿瘤活性。

Nano-particulate Toll-like Receptor 9 Agonist Potentiates the Antitumor Activity of Anti-Glypican-1 Antibody.

机构信息

Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Japan.

Laboratory of Immune Signal, National Institute of Biomedical Innovation, Health and Nutrition, Ibaraki, Japan.

出版信息

Anticancer Res. 2023 Jun;43(6):2425-2432. doi: 10.21873/anticanres.16410.

DOI:10.21873/anticanres.16410

PMID:37247902

Abstract

BACKGROUND/AIM: Monoclonal antibodies (mAbs) that target tumor antigens have recently been developed. Their antitumor activity is mainly achieved through antibody-dependent cellular cytotoxicity (ADCC) via effector cells such as tumor-infiltrated macrophages and natural killer (NK) cells. CpG oligodeoxynucleotides (ODNs) have potent antitumor activity and are considered to increase the tumor infiltration of macrophages and NK cells; however, a completely solubilized novel CpG-schizophyllan (SPG) complex, K3-SPG, displays more potent antitumor activity. We recently reported the significant antitumor activity of anti-glypican-1 (GPC1) mAb against GPC1-positive esophageal squamous cell carcinoma (ESCC) via ADCC. The aim of this study was to evaluate the potential synergistic antitumor activity of anti-GPC1 mAb and K3-SPG and elucidate the underlying mechanisms using a xenograft model of GPC1-positive human ESCC cells.

MATERIALS AND METHODS

The established human esophageal cancer cell line TE14 was subcutaneously injected into SCID mice. Xenograft mice were treated with anti-GPC1 mAb, K3-SPG, or their combination. Antitumor activity was evaluated by measuring the tumor volume. For FACS analysis, agents were administrated, and tumors were resected 1 day after the final treatment.

RESULTS

Anti-GPC1 mAb or K3-SPG monotherapy showed dose-dependent antitumor activity, and combination therapy with anti-GPC1 mAb and K3-SPG showed antitumor activity (p=0.0859). Flow cytometry revealed significantly increased numbers of macrophages (p=0.0133) and of the ratio of activated NK cells/total NK cells (p=0.0058) following K3-SPG or combination therapy.

CONCLUSION

Combination therapy with K3-SPG and anti-GPC1 mAb or another antitumor mAb may represent a new cancer treatment option acting via ADCC.

摘要

背景/目的：近年来，已开发出靶向肿瘤抗原的单克隆抗体 (mAb)。它们的抗肿瘤活性主要通过效应细胞（如肿瘤浸润性巨噬细胞和自然杀伤 (NK) 细胞）的抗体依赖性细胞毒性 (ADCC) 来实现。CpG 寡脱氧核苷酸 (ODN) 具有很强的抗肿瘤活性，被认为可以增加巨噬细胞和 NK 细胞对肿瘤的浸润；然而，一种完全溶解的新型 CpG-裂褶菌 (SPG) 复合物 K3-SPG 显示出更强的抗肿瘤活性。我们最近报道了通过 ADCC 抗 Glypican-1 (GPC1) mAb 对 GPC1 阳性食管鳞状细胞癌 (ESCC) 的显著抗肿瘤活性。本研究旨在评估抗 GPC1 mAb 和 K3-SPG 的潜在协同抗肿瘤活性，并使用 GPC1 阳性人 ESCC 细胞的异种移植模型阐明潜在机制。

材料和方法

将已建立的人食管癌细胞系 TE14 皮下注射到 SCID 小鼠中。用抗 GPC1 mAb、K3-SPG 或它们的组合处理异种移植小鼠。通过测量肿瘤体积评估抗肿瘤活性。对于 FACS 分析，在最后一次治疗后 1 天给予药物并切除肿瘤。

结果

抗 GPC1 mAb 或 K3-SPG 单药治疗均表现出剂量依赖性抗肿瘤活性，而抗 GPC1 mAb 和 K3-SPG 的联合治疗显示出抗肿瘤活性（p=0.0859）。流式细胞术显示 K3-SPG 或联合治疗后巨噬细胞数量显著增加（p=0.0133），活化 NK 细胞/总 NK 细胞的比例增加（p=0.0058）。