NIHR Biomedical Research Centre at Guy's and St Thomas's Hospitals and King's College London, Cutaneous Medicine & Immunotherapy Unit, St John's Institute of Dermatology, Division of Genetics & Molecular Medicine, King's College London School of Medicine, Guy's Hospital, King's College London, London, UK.
Clin Exp Allergy. 2011 Oct;41(10):1400-13. doi: 10.1111/j.1365-2222.2011.03770.x. Epub 2011 May 16.
IgE antibodies, sequestered into tissues and retained locally by the high-affinity IgE receptor, FcɛRI, on powerful effector cells such as mast cells, macrophages and eosinophils, may offer improvements in the therapy of solid tumours. The chimeric antibody, MOv18 IgE, against the human ovarian carcinoma antigen, folate receptor α (FRα), is more effective than its IgG1 counterpart in xenograft models of ovarian cancer. Although MOv18 IgE binds to a single epitope on FRα and cannot cross-link IgE receptors on basophils, there remains a risk that components in the circulation of ovarian cancer patients might cross-link FRα-MOv18-IgE-receptor-FcɛRI complexes on basophils to cause type I hypersensitivity.
To assess the propensity for MOv18 used in a therapeutic setting to cause FcɛRI-mediated type I hypersensitivity.
As validated readouts of the potential for MOv18 to cause FcɛRI-mediated type I hypersensitivity we measured release of a granule-stored mediator from a rat basophilic leukaemia cell line RBL SX-38 stably transfected with human tetrameric (αβγ2) FcɛRI, and induction of CD63 on blood basophils from patients with ovarian carcinoma and healthy controls ex vivo.
Serum FRα levels were increased in ovarian cancer patients compared with healthy controls. MOv18 IgE alone, or in the presence of its antigen recombinant human FRα, or of healthy volunteer (n=14) or ovarian carcinoma patient (n=32) sera, did not induce RBL SX-38 cell degranulation. Exposure to FRα-expressing ovarian tumour cells at target-to-effector ratios expected within tumours induced degranulation. MOv18 IgE did not induce expression of CD63 in blood basophils from either healthy volunteers (n=6), or cancer patients, despite detectable levels of circulating FRα (n=5).
These encouraging data are compatible with the hypothesis that, when ovarian carcinoma patients are treated with MOv18, FcɛRI-mediated activation of effector cells occurs within the tumour mass but not in the circulation mandating, with due caution, further pre-clinical studies.
IgE 抗体被封闭在组织中，并通过高亲和力 IgE 受体 FcɛRI 保留在强大的效应细胞（如肥大细胞、巨噬细胞和嗜酸性粒细胞）中，这可能为实体瘤的治疗提供改善。针对人卵巢癌抗原叶酸受体α（FRα）的嵌合抗体 MOv18 IgE 比其 IgG1 对应物在卵巢癌的异种移植模型中更有效。尽管 MOv18 IgE 结合在 FRα 上的单个表位上，并且不能交联嗜碱性粒细胞上的 IgE 受体，但仍然存在循环中的卵巢癌患者的成分可能交联 FRα-MOv18-IgE-受体-FcɛRI 复合物在嗜碱性粒细胞上引起 I 型超敏反应的风险。
评估 MOv18 在治疗环境中引起 FcɛRI 介导的 I 型超敏反应的倾向。
作为 MOv18 引起 FcɛRI 介导的 I 型超敏反应的潜在性的验证读出，我们测量了从稳定转染人四聚体（αβγ2）FcɛRI 的大鼠嗜碱性白血病细胞系 RBL SX-38 中释放颗粒储存介质，以及从卵巢癌患者和健康对照者的血液嗜碱性粒细胞中诱导 CD63 的情况。
与健康对照者相比，卵巢癌患者的血清 FRα 水平升高。MOv18 IgE 单独，或在其抗原重组人 FRα 存在下，或在健康志愿者（n=14）或卵巢癌患者（n=32）血清存在下，均未诱导 RBL SX-38 细胞脱粒。在预期肿瘤内的靶标与效应物比值下暴露于表达 FRα 的卵巢肿瘤细胞诱导脱粒。MOv18 IgE 并未诱导来自健康志愿者（n=6）或癌症患者（n=5）的血液嗜碱性粒细胞中 CD63 的表达，尽管可检测到循环 FRα 的水平。
这些令人鼓舞的数据与假设一致，即当卵巢癌患者接受 MOv18 治疗时，FcɛRI 介导的效应细胞的激活发生在肿瘤块内，但不在循环中，需要谨慎进行进一步的临床前研究。
