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Abstract：
Cancer-specific monoclonal antibodies (CasMabs) that recognize cancer-specific antigens with in vivo antitumor efficacy are innovative therapeutic strategies for minimizing adverse effects. We previously established a cancer-specific anti-human epidermal growth factor receptor 2 (HER2) monoclonal antibody (mAb), H2Mab-250/H2CasMab-2. In flow cytometry and immunohistochemistry, H2Mab-250 reacted with HER2-positive breast cancer cells but did not show reactivity to normal epithelial cells. In contrast, a clinically approved anti-HER2 mAb, trastuzumab, strongly recognizes both breast cancer and normal epithelial cells in flow cytometry. The human IgG1 version of H2Mab-250 (H2Mab-250-hG1) possesses compatible in vivo antitumor effects against breast cancer xenografts to trastuzumab despite the lower affinity and effector activation than trastuzumab in vitro. This study compared the antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cellular cytotoxicity (CDC) between H2Mab-250-hG1 and trastuzumab. Both H2Mab-250-hG1 and trastuzumab showed ADCC activity against HER2-overexpressed Chinese hamster ovary -K1 and breast cancer cell lines (BT-474 and SK-BR-3) in the presence of human natural killer cells. Some tendency was observed where trastuzumab showed a more significant ADCC effect compared to H2Mab-250-hG1. Importantly, H2Mab-250-hG1 exhibited superior CDC activity in these cells compared to trastuzumab. Similar results were obtained in the mouse IgG2a types of both H2Mab-250 and trastuzumab. These results suggest the different contributions of ADCC and CDC activities to the antitumor effects of H2Mab-250-hG1 and trastuzumab, and indicate a future direction for the clinical development of H2Mab-250-hG1 against HER2-positive tumors.
摘要：
识别具有体内抗肿瘤功效的癌症特异性抗原的癌症特异性单克隆抗体(CasMab)是用于最小化副作用的创新治疗策略。我们先前建立了一种癌症特异性抗人表皮生长因子受体2（HER2）单克隆抗体（mAb），H2Mab-250/H2CasMab-2。在流式细胞术和免疫组织化学中，H2Mab-250与HER2阳性乳腺癌细胞反应，但未显示对正常上皮细胞的反应性。相比之下,临床批准的抗HER2单克隆抗体，曲妥珠单抗,在流式细胞术中强烈识别乳腺癌和正常上皮细胞。人IgG1版本的H2Mab-250(H2Mab-250-hG1)具有与曲妥珠单抗相容的针对乳腺癌异种移植物的体内抗肿瘤作用,尽管在体外比曲妥珠单抗具有更低的亲和力和效应子活化。这项研究比较了H2Mab-250-hG1和曲妥珠单抗之间的抗体依赖性细胞毒性（ADCC）和补体依赖性细胞毒性（CDC）。在存在人类自然杀伤细胞的情况下，H2Mab-250-hG1和曲妥珠单抗均显示出对HER2过表达的中国仓鼠卵巢-K1和乳腺癌细胞系（BT-474和SK-BR-3）的ADCC活性。观察到一些趋势,其中曲妥珠单抗与H2Mab-250-hG1相比显示更显著的ADCC效应。重要的是,与曲妥珠单抗相比,H2Mab-250-hG1在这些细胞中表现出优异的CDC活性。在H2Mab-250和曲妥珠单抗的小鼠IgG2a类型中获得了类似的结果。这些结果表明ADCC和CDC活性对H2Mab-250-hG1和曲妥珠单抗的抗肿瘤作用的不同贡献，并为H2Mab-250-hG1抗HER2阳性肿瘤的临床开发指明了未来的方向。
