| 摘要: |
| ［摘要］ 在过去几十年，人们对人表皮生长因子受体2（HER2）致癌机制认识的提高促进了HER2靶向疗法的开发，例如抗HER2单克隆抗体、酪氨酸激酶抑制剂、双特异性抗体以及抗体偶联药物，这些药物目前通常用于HER2阳性乳腺癌。单克隆抗体曲妥珠单抗是目前HER2靶向治疗的基石，其作用机制是通过抗体的抗原结合片段识别肿瘤细胞表面的HER2位点，然后通过可结晶段（Fc）与免疫细胞表面的Fc受体(FcR)结合，介导抗体依赖性的细胞毒作用（ADCC）和抗体依赖的细胞吞噬作用（ADCP），其中Fcγ受体（FcγR）是主要发挥作用的FcR家族成员。但人体内FcγR存在基因的多态性，不同基因表型的个体与曲妥珠单抗之间有不同的亲和力，亲和力低的患者使用曲妥珠单抗抗肿瘤效果差，所以基于曲妥珠单抗的结构，通过对其Fc段进行改造，如糖基化修饰和氨基酸变异，可增强Fc与FcR之间的亲和力和结合密度，进而增强ADCC和ADCP作用，其中Fc段氨基酸变异的抗HER2单抗马吉妥昔单抗已应用于临床。同时单克隆抗体的抗原结合片段也可通过进一步改造识别不同的HER2表位或者同时识别非HER2表位，增加了免疫细胞表面FcγR结合位点的密度并促进ADCC，此类药物包括帕妥珠单抗、双特异性抗体等。该文对乳腺癌抗HER2单克隆抗体研究进展作一综述。 |
| 关键词: 乳腺癌 人表皮生长因子受体2 单克隆抗体 靶向治疗 |
| DOI：10.3969/j.issn.1674-3806.2022.06.04 |
| 分类号:R 737.9 |
| 基金项目: |
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| Research progress of novel HER2-targeted monoclonal antibodies for breast cancer |
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ZHOU Han-xing, XU Fei
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Department of Internal Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510000, China
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| Abstract: |
| ［Abstract］ Over the past few decades, an improved understanding of the carcinogenicmechanism of human epidermal growth factor receptor 2(HER2) has led to the development of HER2-targeted therapies such as HER2-targeted monoclonal antibodies, tyrosine kinase inhibitors, bispecific antibodies, and antibody-drug conjugate, which are currently commonly used for HER2-positive breast cancer. Among them, the monoclonal antibody trastuzumab is the cornerstone of the current HER2-targeted therapy and its mechanism is to mediate antibody-dependent cytotoxicity(ADCC) and antibody-dependent cellular phagocytosis(ADCP) through the binding of fragment crystallizable(Fc) to Fc receptors(FcR) on the surface of immune cells after the fragment of antigen binding of the antibody recognizes the HER2 site on the surface of tumor cells. Among the FcR, Fcγ receptors(FcγR) are the main group of the FcR family. However, because of gene polymorphism of FcγR in the human body, individuals with different phenotypes have different affinities with trastuzumab. Patients with low affinity who receive the monoclonal antibody trastuzumab have poor anti-tumor effects. And by engineering its Fc fragment through glycosylation modification and amino acid mutation based on the structure of trastuzumab, the affinity and binding density between Fc and FcR can be enhanced, thereby improving the effects of ADCC and ADCP. One of the anti-HER2 monoclonal antibody magetuximab with amino acid mutation in the Fc fragment has been used in clinical practice. Furthermore, the antigen-binding fragments of monoclonal antibodies can also be further modified to recognize different HER2 epitopes or simultaneously recognize non-HER2 epitopes, which increases the density of FcγR binding sites on the surface of immune cells and then promotes ADCC.These drugs include pertuzumab and various upcoming bispecific antibodies. In this paper, the research progress of novel HER2-targeted monoclonal antibodies for breast cancer is reviewed. |
| Key words: Breast cancer Human epidermal growth factor receptor 2(HER2) Monoclonal antibody Targeted therapy |
