Recombinant IgE antibodies for passive immunotherapy of solid tumours: from concept towards clinical application
Recombinant IgE antibodies for passive immunotherapy of solid tumours: from concept towards clinical application
复制标题
DOI：
10.1007/s00262-011-1162-8
复制
发表时间：
2012-09-01
影响因子：
5.8
通讯作者：
Gould, Hannah J.
中科院分区：
文献类型：
--
作者：
Karagiannis, Sophia N.;Josephs, Debra H.;Gould, Hannah J.
治疗性抗体彻底改变了一些癌症的治疗并改善了许多患者的预后。其中一半以上被批准用于治疗血液恶性肿瘤，但仍然迫切需要针对实体瘤的有效抗体。临床上可用的抗体属于 IgG 类，这是人类血液中最常见的抗体类，而其他类尚未得到广泛考虑。我们假设 IgE 是一类通常与过敏相关的组织驻留抗体，其独特的特性可以通过与其效应细胞上特定受体的强亲和力触发强大的免疫反应，可用于卵巢癌和乳腺癌等实体瘤的被动免疫治疗。我们的实验室通过评估两种具有相同特异性 (MOv18) 但不同同种型的嵌合抗体（一种针对肿瘤抗原叶酸受体 α (FR α) 的 IgG1 和 IgE）来检验这一概念。后者证明了 IgE 在疾病相关模型中针对肿瘤产生卓越免疫反应的能力。我们鉴定了表达 Fc ε 受体的细胞、单核细胞/巨噬细胞和嗜酸性粒细胞，它们被 MOv18 IgE 激活，通过 ADCC 和 ADCP 等机制杀死肿瘤细胞。我们还将这一概念应用于市售的治疗药物——人源化 IgG1 抗体曲妥珠单抗，并设计了一种 IgE 对应物，它保留了曲妥珠单抗限制表达 HER2/neu 的肿瘤细胞增殖的功能，但也激活了效应细胞，通过不同的机制杀死肿瘤细胞。正在进行的疗效、安全性评估和未来 IgE 疗法的首次人体临床研究构成了这一概念的关键指标，为实体瘤的抗体免疫疗法提供了新的范围。
Therapeutic antibodies have revolutionised treatment of some cancers and improved prognosis for many patients. Over half of those available are approved for haematological malignancies, but efficacious antibodies for solid tumours are still urgently needed. Clinically available antibodies belong to the IgG class, the most prevalent antibody class in human blood, while other classes have not been extensively considered. We hypothesised that the unique properties of IgE, a class of tissue-resident antibodies commonly associated with allergies, which can trigger powerful immune responses through strong affinity for their particular receptors on effector cells, could be employed for passive immunotherapy of solid tumours such as ovarian and breast carcinomas. Our laboratory has examined this concept by evaluating two chimaeric antibodies of the same specificity (MOv18) but different isotype, an IgG1 and an IgE against the tumour antigen folate receptor alpha (FR alpha). The latter demonstrates the potency of IgE to mount superior immune responses against tumours in disease-relevant models. We identified Fc epsilon receptor-expressing cells, monocytes/macrophages and eosinophils, activated by MOv18 IgE to kill tumour cells by mechanisms such as ADCC and ADCP. We also applied this notion to a marketed therapeutic, the humanised IgG1 antibody trastuzumab and engineered an IgE counterpart, which retained the functions of trastuzumab in restricting proliferation of HER2/neu-expressing tumour cells but also activated effector cells to kill tumour cells by different mechanisms. On-going efficacy, safety evaluations and future first-in-man clinical studies of IgE therapeutics constitute key metrics for this concept, providing new scope for antibody immunotherapies for solid tumours.