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抗 HER3 单克隆抗体在结直肠腺癌小鼠模型中发挥抗肿瘤活性。

Anti‑HER3 monoclonal antibody exerts antitumor activity in a mouse model of colorectal adenocarcinoma.

机构信息

Department of Antibody Drug Development, Tohoku University Graduate School of Medicine, Sendai, Miyagi 980‑8575, Japan.

Institute of Microbial Chemistry (BIKAKEN), Numazu, Microbial Chemistry Research Foundation, Numazu‑shi, Shizuoka 410‑0301, Japan.

出版信息

Oncol Rep. 2021 Aug;46(2). doi: 10.3892/or.2021.8124. Epub 2021 Jun 29.

Abstract

HER3 belongs to the epidermal growth factor receptor (EGFR) family and is known to form an active heterodimer with other three family members EGFR, HER2, and HER4. HER3 is overexpressed in lung, breast, colon, prostate, and gastric cancers. In the present study, we developed and validated an anti‑HER3 monoclonal antibody (mAb), HMab‑17 (IgG, kappa), by immunizing mice with HER3‑overexpressed CHO‑K1 cells (CHO/HER3). HMab‑17 was found to react specifically with endogenous HER3 in colorectal carcinoma cell lines, using flow cytometry. The for HMab‑17 in CHO/HER3 and Caco‑2 (a colon cancer cell line) were determined to be 3.0x10 M and 1.5x10 M via flow cytometry, respectively, suggesting high binding affinity of HMab‑17 to HER3. Then, we assessed the HMab‑17 antibody‑dependent cellular cytotoxicity (ADCC) and complement‑dependent cytotoxicity (CDC) against Caco‑2, and evaluated its antitumor capacity in a Caco‑2 xenograft model. experiments revealed HMab‑17 had strongly induced both ADCC and CDC against Caco‑2 cells. experiments on Caco‑2 xenografts revealed that HMab‑17 treatment significantly reduced tumor growth compared with the control mouse IgG. These data indicated that HMab‑17 could be a promising treatment option for HER3‑expressing colon cancers.

摘要

HER3 属于表皮生长因子受体 (EGFR) 家族,已知与其他三个家族成员 EGFR、HER2 和 HER4 形成活性异二聚体。HER3 在肺癌、乳腺癌、结肠癌、前列腺癌和胃癌中过表达。在本研究中,我们通过用 HER3 过表达 CHO-K1 细胞(CHO/HER3)免疫小鼠,开发并验证了一种抗 HER3 单克隆抗体(mAb)HMab-17(IgG,kappa)。使用流式细胞术发现,HMab-17 特异性地与结直肠癌细胞系中的内源性 HER3 反应。通过流式细胞术分别确定 HMab-17 在 CHO/HER3 和 Caco-2(一种结肠癌细胞系)中的亲和力为 3.0x10 -9 M 和 1.5x10 -9 M,表明 HMab-17 对 HER3 具有高结合亲和力。然后,我们评估了 HMab-17 抗体依赖性细胞毒性(ADCC)和补体依赖性细胞毒性(CDC)对 Caco-2 的作用,并在 Caco-2 异种移植模型中评估了其抗肿瘤能力。效应细胞实验显示,HMab-17 对 Caco-2 细胞强烈诱导了 ADCC 和 CDC。Caco-2 异种移植实验表明,与对照小鼠 IgG 相比,HMab-17 治疗显著降低了肿瘤生长。这些数据表明,HMab-17 可能是治疗 HER3 表达型结肠癌的一种有前途的治疗选择。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b26c/8261196/cbfd4b242bad/or-46-02-8124-g00.jpg

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