St John's Institute of Dermatology, King's College London, London, UK; Department of Medical Oncology, Guy's and St Thomas' NHS Foundation Trust, London, UK.
St John's Institute of Dermatology, King's College London, London, UK.
Lancet. 2015 Feb 26;385 Suppl 1:S53. doi: 10.1016/S0140-6736(15)60368-3.
Nearly all anti-tumour antibodies are of a single class-namely, IgG. Efficacy might be improved by development of tumour-specific IgE antibodies, which have higher affinities for effector cell receptors and perform potent immune functions. MOv18IgE, which targets folate receptor α (FRα), is a novel system to model this hypothesis. Human chimeric MOv18 IgE has shown superior efficacy in two murine xenograft models compared with MOv18 IgG1. Our aim was to examine the potential of this antibody class to activate monocytes.
We developed an immunocompetent rat model system of rat tumour lung metastases expressing human FRα, and engineered surrogate rat MOv18 IgE and IgG antibodies to assess their efficacy and ability to recruit monocytes in the rat model system.
In-vivo assessment of the efficacy of rat MOv18 IgE demonstrated superior tumour growth restriction compared with rat MOv18 IgG (tumour occupancy 6·8% [SE 1·6] vs 16·0 [1·7]; p<0·0001). We measured significant CD68-positive (CD68+) macrophage infiltration of tumours after MOv18 IgE treatment (mean ratio of CD68+ cells in tumour vs periphery 3·6 [0·5] for MOv18 IgE-treated tumours vs 2·3 [0·3] for MOv18 IgG-treated tumours; p=0·03).
Our in-vivo studies using rat MOv18 IgE show the importance of monocyte recruitment in the efficacy of this antibody, and provide further evidence that tumour-specific IgE antibodies might offer improved efficacy against cancer by recruiting key immune effector cells.
Academy of Medical Sciences Starter Grant, Cancer Research UK New Agents Committee Grant.
几乎所有的抗肿瘤抗体都属于单一类别，即 IgG。通过开发针对肿瘤特异性 IgE 抗体，可能会提高疗效，因为 IgE 抗体对效应细胞受体的亲和力更高，并具有更强的免疫功能。MOv18IgE 靶向叶酸受体α（FRα），是一种用于模拟这一假设的新型系统。与人源嵌合 MOv18IgG1 相比，人源 MOv18IgE 在两种小鼠异种移植模型中显示出更好的疗效。我们的目的是研究这种抗体类别激活单核细胞的潜力。
我们开发了一种表达人 FRα 的免疫功能正常的大鼠肿瘤肺转移模型系统，并构建了工程模拟大鼠 MOv18IgE 和 IgG 抗体，以评估它们在大鼠模型系统中的疗效和募集单核细胞的能力。
体内评估大鼠 MOv18IgE 的疗效显示，与大鼠 MOv18IgG 相比，其肿瘤生长受到更显著的抑制（肿瘤占有率 6.8%[1.6] vs 16.0%[1.7]；p<0.0001）。我们在 MOv18IgE 治疗后测量到肿瘤中 CD68 阳性（CD68+）巨噬细胞的显著浸润（MOv18IgE 治疗肿瘤中 CD68+细胞与肿瘤周围的比值为 3.6[0.5]，而 MOv18IgG 治疗肿瘤中为 2.3[0.3]；p=0.03）。
我们使用大鼠 MOv18IgE 的体内研究表明，单核细胞募集在该抗体的疗效中具有重要意义，并进一步证明肿瘤特异性 IgE 抗体通过募集关键免疫效应细胞，可能为癌症治疗提供更好的疗效。
医学科学院启动基金，英国癌症研究协会新制剂委员会资助。
