肿瘤细胞治疗研究
英文原题：Role of Fcγ receptors in HER2-targeted breast cancer therapy.
Role of Fcγ receptors in HER2-targeted breast cancer therapy.
几种治疗性单克隆抗体（mAbs），包括靶向表皮生长因子受体、人表皮生长因子受体2（HER2）和CD20的抗体，在其作用机制中均介导片段结晶γ受体（FcγR）依赖性活动。
几种治疗性单克隆抗体（mAbs），包括靶向表皮生长因子受体、人表皮生长因子受体2（HER2）和CD20的抗体，在其作用机制中介导片段结晶γ受体（FcγR）依赖性活动。这些活动包括诱导抗体依赖性细胞介导的细胞毒性（ADCC）和抗体依赖性细胞吞噬（ADCP），这些是消除癌细胞的先天免疫机制。FcγR通过其对Fc片段的亲和力、细胞分布和诱导的免疫反应类型来区分。NK 细胞上的激活型FcγRIIIa（CD16A）在介导ADCC中发挥关键作用，而巨噬细胞上的激活型FcγRIIa（CD32A）和FcγRIIIa对介导ADCP很重要。FcγRIIIa和FcγRIIa的多态性产生与抗体Fc部分以不同亲和力结合的变体。这导致FcγR介导活动的差异，与多个临床设置中，从早期到转移性疾病，接受抗HER2 mAb曲妥珠单抗治疗的HER2+乳腺癌患者的不同治疗结果相关。尽管如此，曲妥珠单抗已彻底改变了HER2+乳腺癌治疗，并且已开发出几种HER2导向的mAbs，使用Fc糖工程或Fc蛋白工程来增强FcγR介导的功能。已批准的抗HER2 Fc工程化嵌合mAb的一个例子是margetuximab，它靶向与曲妥珠单抗相同的表位，但在IgG 1 Fc域中具有五个氨基酸替换，这些替换被故意引入以增加与激活型FcγRIIIa的结合并减少与抑制型FcγRIIb（CD32B）的结合。Margetuximab在体外增强Fc依赖性ADCC的能力比帕妥珠单抗（另一种针对不同HER2表位的已批准mAb）和曲妥珠单抗的联合用药更强。在接受过先前HER2抗体为基础治疗的患者样本中，Margetuximab给药还在离体条件下增强了HER2特异性B细胞和T细胞介导的反应。基于这些观察结果，HER2+乳腺癌治疗中一个值得追求的未来目标是推动联合治疗方案，通过增强的免疫机制更好地清除HER2+癌细胞。
Several therapeutic monoclonal antibodies (mAbs), including those targeting epidermal growth factor receptor, human epidermal growth factor receptor 2 (HER2), and CD20, mediate fragment crystallizable gamma receptor (FcγR)-dependent activities as part of their mechanism of action. These activities include induction of antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP), which are innate immune mechanisms of cancer cell elimination. FcγRs are distinguished by their affinity for the Fc fragment, cell distribution, and type of immune response they induce. Activating FcγRIIIa (CD16A) on natural killer cells plays a crucial role in mediating ADCC, and activating FcγRIIa (CD32A) and FcγRIIIa on macrophages are important for mediating ADCP. Polymorphisms in FcγRIIIa and FcγRIIa generate variants that bind to the Fc portion of antibodies with different affinities. This results in differential FcγR-mediated activities associated with differential therapeutic outcomes across multiple clinical settings, from early stage to metastatic disease, in patients with HER2+ breast cancer treated with the anti-HER2 mAb trastuzumab. Trastuzumab has, nonetheless, revolutionized HER2+ breast cancer treatment, and several HER2-directed mAbs have been developed using Fc glyco-engineering or Fc protein-engineering to enhance FcγR-mediated functions. An example of an approved anti-HER2 Fc-engineered chimeric mAb is margetuximab, which targets the same epitope as trastuzumab, but features five amino acid substitutions in the IgG 1 Fc domain that were deliberately introduced to increase binding to activating FcγRIIIa and decrease binding to inhibitory FcγRIIb (CD32B). Margetuximab enhances Fc-dependent ADCC in vitro more potently than the combination of pertuzumab (another approved mAb directed against an alternate HER2 epitope) and trastuzumab. Margetuximab administration also enhances HER2-specific B cell and T cell-mediated responses ex vivo in samples from patients treated with prior lines of HER2 antibody-based therapies. Stemming from these observations, a worthwhile future goal in the treatment of HER2+ breast cancer is to promote combinatorial approaches that better eradicate HER2+ cancer cells via enhanced immunological mechanisms.
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