Anti-HER3 monoclonal antibody exerts antitumor activity in a mouse model of colorectal adenocarcinoma
Anti-HER3 monoclonal antibody exerts antitumor activity in a mouse model of colorectal adenocarcinoma
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DOI：
10.3892/or.2021.8124
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发表时间：
2021-08-01
期刊：
影响因子：
4.2
通讯作者：
Kato, Yukinari
中科院分区：
文献类型：
--
作者：
Asano, Teizo;Ohishi, Tomokazu;Kato, Yukinari
HER 3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、HER 2和HER 4形成活性异源二聚体。HER 3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HER 3过表达的CHO-K1细胞（CHO/HER 3）免疫小鼠，开发并验证了抗HER 3单克隆抗体（mAb）H（3）Mab-17（IgG（2a），kappa）。流式细胞术检测发现H（3）Mab-17与大肠癌细胞系中的内源性HER 3特异性反应。经流式细胞术测定，H（3）Mab-17在CHO/HER 3和Caco-2（结肠癌细胞系）中的KD分别为3.0 × 10（-9）M和1.5 × 10（-9）M，表明H（3）Mab-17与HER 3的结合亲和力较高。然后，我们评估了H（3）Mab-17对Caco-2的抗体依赖性细胞毒性（ADCC）和补体依赖性细胞毒性（CDC），并在Caco-2异种移植模型中评估了其抗肿瘤能力。体外实验显示H（3）Mab-17对Caco-2细胞具有强烈的ADCC和CDC诱导作用。Caco-2异种移植物的体内实验显示，与对照小鼠IgG相比，H（3）Mab-17治疗显著降低了肿瘤生长。这些数据表明，H（3）Mab-17可能是HER 3表达结肠癌的一种有希望的治疗选择。
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), H(3)Mab-17 (IgG(2a), kappa), by immunizing mice with HER3-overexpressed CHO-K1 cells (CHO/HER3). H(3)Mab-17 was found to react specifically with endogenous HER3 in colorectal carcinoma cell lines, using flow cytometry. The K-D for H(3)Mab-17 in CHO/HER3 and Caco-2 (a colon cancer cell line) were determined to be 3.0x10(-9) M and 1.5x10(-9) M via flow cytometry, respectively, suggesting high binding affinity of H(3)Mab-17 to HER3. Then, we assessed the H(3)Mab-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. In vitro experiments revealed H(3)Mab-17 had strongly induced both ADCC and CDC against Caco-2 cells. In vivo experiments on Caco-2 xenografts revealed that H(3)Mab-17 treatment significantly reduced tumor growth compared with the control mouse IgG. These data indicated that H(3)Mab-17 could be a promising treatment option for HER3-expressing colon cancers.