Using the allergic immune system to target cancer: activity of IgE antibodies specific for human CD20 and MUC1
Using the allergic immune system to target cancer: activity of IgE antibodies specific for human CD20 and MUC1
复制标题
DOI：
10.1007/s00262-012-1299-0
复制
发表时间：
2012-12-01
影响因子：
5.8
通讯作者：
Mollick, Joseph A.
中科院分区：
文献类型：
--
作者：
Teo, Pearline Zhaoying;Utz, Paul J.;Mollick, Joseph A.
单抗被广泛应用于许多B细胞淋巴瘤和某些实体瘤的治疗。目前批准的所有治疗性单抗都是免疫球蛋白G(Ig G)亚型。我们推测，肿瘤特异性的IgE同型单抗可能是有效的癌症治疗方法。为了验证这一假设，我们制造了针对人类B细胞抗原CD20和上皮抗原MUC1的鼠-人嵌合IgE抗体。我们在这里证明了抗hCD20 IgE抗体在体外与纯化的脐带血过敏效应细胞一起使用时具有细胞毒活性。在效应-肿瘤比例为2：1时，肥大细胞和肿瘤特异性免疫球蛋白E诱导的肿瘤细胞死亡比对照免疫球蛋白E增加2.5倍。用嗜酸性粒细胞作为效应细胞时，也观察到了类似的结果。在体内乳腺癌小鼠模型中，给予抗hMUC1IgE可使HFC epsilon RI转基因小鼠的MUC1(+)肿瘤生长减少25%-30%。相比之下，局部产生的IgE和细胞因子对巨噬细胞、嗜酸性粒细胞和肥大细胞的趋化作用导致了肿瘤的完全根除。这些结果表明，由IgE和细胞表面抗原激活的变态反应效应细胞在体内外均具有诱导肿瘤细胞死亡的能力。嵌合抗体和HFC epsilon RI转基因小鼠的使用将极大地促进变态反应肿瘤学这一新兴领域的研究。
Monoclonal antibodies are widely used in the treatment of many B cell lymphomas and certain solid tumors. All currently approved therapeutic monoclonal antibodies are of the immunoglobulin G (IgG) isotype. We hypothesized that tumor-specific monoclonal antibodies of the IgE isotype may serve as effective cancer therapeutics. To test this hypothesis, we produced mouse-human chimeric IgE antibodies specific for the human B cell antigen CD20 and the epithelial antigen MUC1. We demonstrate here that anti-hCD20 IgE antibodies have in vitro cytotoxic activity when used with purified allergic effector cells derived from umbilical cord blood. At an effector-tumor ratio of 2:1, mast cells and tumor-specific IgE induced a 2.5-fold increase in tumor cell death, as compared to control IgE. Similar results were observed when eosinophils were used as effector cells. In an in vivo murine model of breast carcinoma, administration of anti-hMUC1 IgE reduced the growth of MUC1(+) tumors by 25-30 % in hFc epsilon RI transgenic mice. In contrast, local production of IgE and cytokines chemotactic for macrophages, eosinophils and mast cells led to complete tumor eradication. These results suggest that allergic effector cells activated by IgE and cell surface antigens have the capacity to induce tumor cell death in vitro and in vivo. The use of chimeric antibodies and hFc epsilon RI transgenic mice will greatly enhance investigations in the nascent field of allergo-oncology.